“Introduction”
A group of studies that focus on
the physicochemical and derived properties of a new drug candidate thus helping
in sorting out problems in poor drug performance and drug development.
Or Preformulation may be defined as
the phase of research and development in which physicochemical and derived
properties of drugs are studied in-order to develop safe, effective, stable
dosage form with reproducible results.
Preformulation studies provide
bases for formulation of a discovered drugs. Or we can say it is the first step
of formulation development which gave us information about the behavior of the
drugs. Preformualtion studies contain two different type of studies which are:
Physicochemical Studies : included are solubility, crystallinity,
polymorphism, chemical stability, physical stability, ionization etc.
Derived Properties: it includes those properties which are derived
from the basic (primary) properties, like bulk density and tape density etc.
Objective of Preformulation Studies
- · To Find out or to Know about the physicochemical and derived properties of drugs.
- · To determine kinetics and stability of drugs.
- · To find out drugs compatibility with other excipients.
- · To find about the safe drugs storage, mechanical processes thus ensuring the quality.
Physicochemical Properties of Drugs
Aqueous Solubility
Aqueous solubility is taken as a
standard because all the GIT environment (Fluids) is aqueous (watery) and polar
in nature. Drugs must have aqueous solubility if it is supposed to be given via
oral route. If drug is not solubilized it can limit the absorption because only
soluble drug molecules are the candidates for absorption from the GIT membrane
to the blood.
Solubility is defines as concentration of a substance (solid dosage
form may also contain suspension etc), at which it is in equilibrium in a
solvent at a specific temperature and PH. Solubility is the measure that how
much a solute (drug) is dissolved in a liquid.
Importance of solubility
- Solubility is required for solid dosage form to be absorbed from GI membrane (particularly in passive diffusion).
- It is Directly Related to the extent of drug absorption. Mean Grater the solubility of drug greater will be the amount of drug absorbed (but unionized form).
- Drug Having high solubility are more absorbed. Drugs having less then 1% solubility are poorly absorbed.
Extent of Solubility is Shown By
Vant Hoff Equitation
Activity coefficient shows the
intermolecular forces between the Drug-Drug molecules (solute molecules). Solvent
Solute interaction must be greater then the solute-solute interaction to have
solubility of solute.
Various Methods are followed to
find the solubility of drugs. Which includes adding excess amount of solute
(drug) to defined media and agitating until equilibrium is established at a specific
temperature. High throughput screening and Spectroscopic methods and various others
are also applicable to find solubility.
Ionization:
Ka is the representative of
dissociation of ions, and is called dissociation constant. Pka is the negative
log of Ka. Pka is the PH at which half of the molecules are in ionized state. Or
Pka simply may be called plus minus 2 PH, which is basic and Pka value of 5 will be 100 percent ionized at PH 3 at
acidic medium 50 percent ionized at PKa=PH of 5 and unionized at PH 7. It means
that this basic drug will be ionized at acidic medium which if of course the
general case for all base. And vice versa for acids.
Dissolution Rate:
Dissolution is the rate limiting
step for those drugs having poor solubility and intended for rapid biological
activity. In some case drug are required to be dissolved rapidly for rapid
action, just like antihypertensive, pain killers and antianginal drugs for the
conditions which are acute. For chronic conditions slow dissolution rate is
required. But some time a combination of rapid and slow dissolution rate is
required. Dissolution rate can be
described form Noyes-Whitney equitation which is in figure 18.3 below.
Determination of
Dissolution Rate
Dissolution Rate can be determined
by two different method.
Constant Surface Method: Dissolution rate of a substance under
constant surface area (gives intrinsic dissolution rate).
Particulate Dissolution : the surface area does not remain constant
when the dissolution is ongoing. This method give the real picture of
dissolution.
Partition Coefficient
Partition coefficient
shows the lipophilic and hydrophilic tendencies of substances(drugs). It is
defined as “the concentration of ratio of unionized drug distributed between
phases at equilibrium:
P= Co/Cw
where Co is the concentration of
drug in octanol and Cw is the concentration in water. Log of P is used in
Pharmaceutical industry. It is shown from the above basic equitation of
Partition coefficient that greater the value of P grater will be solubility in
octanol hence showing more lipophilicity and vice versa. Octanol is used along
with water because octanol contain the same characters as the biological
membrane having both polar and non polar end.
Permeability
Permeability is
the ability of drugs to pass biological membrane. Three factors define
permeability, includes Lipophilicity, Molecular size and polarity.
Lipophilic drugs
having high partition coefficient , pass easily through biological membrane.
But drug with excessive high partition coefficient may sequester in the tissues
or cells thus limiting the permeability. Molecular size also have impact on
permeability. Small molecule can easily cross the membrane as compare to large
molecule. Polarity bring the bigger scene where the polar drugs can’t breach the biological membrane thus decreasing
the bioavailability of the drugs. Generally Lipinski’s rule of five is
applicable for permeability of drug but not common to all drugs limitations are
there:
- v There must be less then 5 hydrogen bond donors NH+ and OH etc.
- v There must be not more then 10 hydrogen bond acceptors, Number of nitrogen and oxygen.
- v Molecular weight should be less then 500 Dalton.
- v Log P value must not be more then 5.
This rule is
called rule of five because it contain every thin multiple of 5. Infect 4
Assumptions are made there.
Crystallinity
Crystalline
substances are less soluble compared to amorphous substances. But incase of
drugs amorphous forms is not preferable because it is less stable form with
high energy thus can change from amorphous to crystalline form, leading to
variance is other properties. Reproducible
results can,t be attained from amorphous form that why crystalline form is preferred.
Polymorphism
Crystals of various
drugs have various structures. Polymorphism is drugs having more then one
crystal habit (outer appearance). Change in Crystal Habit (structure) is due to
the internal arrangement of atoms or molecules. Various forms of crystals of
drugs have change in physical properties like dissolution, boiling temperature and
chemical stability etc. The highest melting specie is usually the most stable
one. The polymorph with highest energy is called metastable which is usually the
most soluble but least stable and convert from one from to another form thus
limiting the reproducibility of results.
Pseudopolymorphism
Some drugs
molecules carry solvates molecules along with it from the solvent form which it
is recovered. Just like Erythromysin monohydrate and Erythromysin trihydrate.
When the solvent molecules are water then it is called hydrated form or
hydrates.
Usually the
un-hydrated forms are more soluble forms for a drug. But it is not hard and
fast rule. Just like Erythromysin trihydrate form is mole soluble then the
monohydrated and unhydrated form.
Particle Size and Shape
Rate of
dissolution is directly proportional to the particle size just because particle
size affect surface area of particles exposed. Drug having low water solubility
can be improved by reducing their size and thus increase in their Cmax and Bioavailability.
For Example increase in the bioavailability of micronized Griseofulvin as
compared to rough form. Particle Shape has effects on the Flow properties of
drugs when in Mechanical processing.
Other Properties
like Hygroscopicity, Melting point stability and Derived properties like tape
density and bulk densities etc are also studied in Preformulation.
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