2. The meaning of “pre-formulation” literally refers to the steps to be undertaken
before formulation proper.
Prior to the development of dosage forms, it is essential that certain
fundamental physical and chemical properties of potential drug molecules and
other derived properties of drug powder are determined.
This first learning phase is referred as “Preformulation”.
Determination of these properties for the drug substance and the drug product
decides subsequent events and approaches in formulation development and by
this the formulator may confirm that there are no significant barriers to the
compounds development.
Thus preformulation can be described as “the process of optimizing the
delivery of drug, through the determination of physico-chemical properties of
the new compound, and thus affording for the development of an efficacious,
stable, and safe dosage form”.
So, the overall objective of preformulation studies is to generate information
useful to the formulator in developing stable and bioavailable dosage forms
that can be mass produced.
3. Establish the identity and physico-chemical parameters of a new drug
substance.
Establish its kinetic rate profile.
Establish its physical characteristics.
Establish its compatibility with common excipients.
Preformulation testing
The prior steps in this includes determination of organo-leptic
properties,quantity and extent of purity of drug and physico-chemical
properties.
1. Identity of drug:
-- includes description of drug substances.
--determination of colour, odour, and taste of new drug is done and
recording of these properties should be done in specified terminology.
Colour Taste Odour
Off-white Acidic Pungent
Cream yellow Bitter Sulfurous
Tan Bland Fruity
Shiny Sweet Aromatic
Tasteless Odourless
4. Unpleasant colour, odour, taste can be modified by appropriate methods and the
modified forms must be screened for their influence on stability and
bioavailability of the active drug.
2. Quantitative by analytical methodology and estimation of
purity:
Investigators must be sure that the early samples used for preformulatin
studies should be pure and presence of impurities must be determined, as they
may affect measured properties.
The tools in the assessment of purity includes------>
for qualitative information DSC,DTA and M.P.( hot stage microscopy)
for quantitative information QDSC, PRSA
The other techniques such as TLC,HPLC,Paper,Gas can also be employed.
3. Physico-chemical parameters:
These are associated with great precision and accuracy and incase of a
new drug substance, two fundamental properties are considered as mandatory
and these should be determined first. This is the concept of minimum
preformulation. These are…
1. Solubility
2. Ionization constant (Pka and Pk
b)
the other includes melting point, solid-state properties, partition co-efficient ,
Surface characteristics, Dissolution, Flow properties of powder drug, vapour
pressure, wettability, hygroscopicity and drug-excipient compatibility.
5. 1. Solubility:-
The solubility of every new drug i.e., acidic or basic, must be determined
over PH
range 1 to 8.
It has been investigated that unless a compound has an aqueous solubility in
excess of 1% (10mg/ml) over the PH range1-7 at 370C, then potential
bioabsorption problems may occur
A solubility of less than 1 mg/ml indicates the need for a salt. In the range of
1-10 mg/ml, serious consideration should be given to salt formation.
Importance of solubility:-
Knowledge of solubility of a drug substance not only helps in making judgement
concerning its bioavailability but also is useful
in the development of appropriate media for dissolution testing
for development of an injectable dosage form for certain pharmacological and
comparitive bio-availability studies.
for the formulator in choosing the right solvent for the purpose of granulation
and coating.
Methodology for determination of solubility:-
Solubilities are determined by exposing an excess of solid to the liquid &
assaying after equilibrium has been established. This is usually in the range of
60-72 hr and to establish that equilibrium&sampling at earlier points is
necessary.
6. As purity cannot be assessed for first few batches, solubility is determined by the
use of Phase-solubility diagram. In this usually, the data from experiments is
collected and the drug/solvent ratio is determined. Graph is plotted by taking this
ratio on Y-axis, and solubility on X-axis.
No deviation from horizontal line No impurities
Deviation Presence of impurities. These impurities may increase/ decrease in
solubility.
Salt formation:-
Selection of salt determines the extent of improvement in solubility. It is
often better to use a weak acid or base to form the salt because such salt is less
soluble and will be less hygroscopic which is beneficial. Conversely, a salt prepared
from strong acid or base is freely soluble but also very hygroscopic which may
leads to stability problems.
A weak base with an intrinsic solubility > 1mg/ml will be freely soluble
in g.i.t. and indeed it is better to formulate with a salt which control the PH
of
diffusion layer.
7. 2. Pka(Ionization constant):-
75% of drugs are weak bases; 20% weak acids and 5%non-
ionic,amphoteric.
Factors usually important in the absorption of weakly acidic and basic are
1. PH
at the site of absorption
2. Ionization constant (Pk
)
3. Solubility of un-ionized species
The ionization constant refers to equation---
HB +H2O H3O+
+ B-
This relationship can be given by Henderson-Hesselbach equation which shows the
concentrations of un-ionised and ionised species…….
For bases PH
= Pk
a + log [unionised] / [ionised]
For acids PH
= Pk
a + log [ionised] / [unionised]
Methodology for determination:
1. Acid-base potentiometric titrations:
This is for compounds with reasonable solubility. These titrations can be
performed on 100 ml portions using titrants of 0.1M. The procedure entails the
measurement of PH
as a function of amount of titrant added. Accurate value can be
obtained by measuring PH
at half-neutralization point where PH
= Pk
a (inflection
point). So, determination of PH
indicates Pk
a value.
8. 2. Use of co-solvent:-
For drugs that are amines, the free base is poorly soluble, and in this
case the Pka is often estimated by performing the titration in a solvent containing
some organic solvent (e.g.: ethanol). By the addition of different concentrations of
organic solvents (e.g.:5%,10%,15%,20%) some extrapolation can be carried out to
0% solvent concentration to estimate the aqueous Pka.
3. Spectrophotometric method:-
For the substances that are carboxylic acids (HA) the species A-
usually absorbs in the U.V. region and its conc. can be determined
spectrophotometrically. HA, on the other hand, will absorb at a different
wavelength, so that ratio A-/HA can be determined in a series of buffers of
different PH. Hence Pk
a can be found as the intercept by plotting PH as a function
of log [(A-
)/(HA)] by Henderson-Hesselbach equation.
PH
= Pk
a + log (A-
) / (HA)
3. Melting point:-
Determination of M.P.of solids further confirms the properties of
formulated compound and conditions to be maintained in formulation process. So,
determination of M.P. is essential for preformulation process. Because when heat
is supplied to the formulated compound on above M.P. range, leads to phase
changes sometimes . This may leads to conversion of active compound to
inactive / toxic form. E.g.: Metastable (low M.P.) stable (high M.P.)
9. Methodology:
A: Capillary melting:- The observation of melting in a capillary tube in contact with a
heated metal block. This gives information about melting range but not m.p.
B: Hot stage microscopy:- It includes the visual observation of melting under a
microscope equipped with a heated and lagged sample stage. The heating rate is
controllable and up to 3 transitions can be registered. It is more precise since the
phase transition (firstmelt, 50% melt, and completion) can be registered on a
recorder.
C: DSC &DTA:- Sample size is only 2-5 mg required.
DTA measures the temperature difference between sample and a
reference as a function of temperature/ time when heating at constant rate.
DSC is similar to DTA except that the instrument measures amount of
energy required to keep the sample at the same temperature as reference i.e., it
measures the enthalpy of transition.
4. Dissolution:-
Usually, the absorption of solid drugs adminstered orally can be depicted
as-
Solid drug in kd Drug in solution ka Drug in systemic
aqueous solution in g.i. fluids circulation
kd & ka Rate constants for dissolution and absorption
If kd << ka Absorption is dissolution rate limited
It is therefore essential to investigate the dissolution behaviour of drug sub’s
especially with moderate and poor solubility.
10. The knowledge of comparitive dissolution rates of different chemical ( salt, ester,
prodrug) & physical ( polymorph, solvates etc), forms of a drug is necessary in
selecting the optimum form for further development.
INTRINSIC DISSOLUTION:-
The dissolution rate of solid in its own solution is given by Noyes-Nernst
equation…….
dc/ dt dissolution rate
A surface area of dissolving solid
dc/ dt = AD (Cs-C) / hv D diffusion coefficient
C solute conc. In bulk medium
h diffusion layer thickness
v volume of the dissolution medium
Cs solute conc. In diffusion layer
During the early phase of dissolution, Cs >> C & is equal to saturation solubility ‘S’
Here A,v can be held as constants. Under these conditions and at const. temp and
Agitation, the equation is given as……
dc/ dt = KS where K= AD/ hv & dc/dt= intrinsic D.R
Knowledge of this value helps the preformulation scientist in predicting if absorption
would be dissolution- rate limited.
11. METHODOLOGY:- ROTATING-DISK METHOD: This method allows for the
determination of dissolution from a constant surface.
PARTICLE DISSOLUTION:
Another method for the dissolution of solids. Here no effort is made
to maintain the surface area constant
Methodology: Weighed amount of powder sample from a particular sieve fraction
is introduced in the dissolution medium. Agitation is provided by constant- speed
propeller. Particulate dissolution is used to study the influence on dissolution of
particle size, surface area and mixing with excipients.
Eg: analysis of phenacetin granules
5. Surface characteristics :-
A. PARTICLE SHAPE AND SIZE: Poorly soluble drugs in a finely sub divided
state sows more bioavailability than that of coarse material. It can be attained by
grinding should reduce coarse material to approximately 10-40 microns range.
METHODOLOGY:
1.Microscopy :Rapid technique for estimating range of size(1-!00 microns) &
shape
Requires counting of large number of particles when quantitative
information is desired.
Not suited for rapid, quantitative size determinations
2. Optical microscopy: Material is observed by suspending it in a non-dissolving
fluid. (water/ mineral oil). In this, change to an amorphous state after grinding can
12. 3. Coulter-counter apparatus: The instrument will measure particle size distribution of
any powder properly dispersed in a suspending medium. The principle of this
include- blockage of an electrical conductivity path. This phenomenon of light
blockade has been adopted by USP to monitor the level of foreign particles in
parenteral products.
Other techniques such sieving, centrifugation and sedimentation techniques also can
be employed.
2. SURFACE AREA: The determination of particle area is also increasing attention
and particle area shows an inverse relationship with particle size.
The theory involved in this BET theory of adsorption.
The theory states that most substances will adsorb a monomolecular layer of a
gas under certain conditions of partial pressure (of gas) & temp.
By knowing …..a) the monomolecular capacity of adsorbent
b) Area of the adsorbate molecule…….
Surface area can be calculated
Most commonly used adsorbate is nitrogen.
Methods employed :- The techniques used for this are a) volumetric technique
b) Gravimetric technique
C) Dynamic method
13. 6. Partition coefficient :-
Lipid solubility of a drug is an important factor in the assessment of
its absorption potential, because GI membranes are largely lipoidal in nature. This
lipid solubility can be obtained by determining how a drug substance distributes
itself between water and an immiscible organic solvent. This is referred as
“Partition coefficient”.
APPLICATIONS : A) Solubility both in aqueous and in mixed solvents.
B) Drug absorption in vivo
C) Partition chromatography : In making choice of column
(Hplc / Tlc) & choice of mobile phase (eluent).
METHODOLOGY: Shake-flash method:
The brief procedure includes, dissolving the drug in
any one of the phases and shaken with the other partitioning solvent for 30 mins,
allowed to stand for 5 min & then the majority of lower aqueous phase is runoff and
centrifuged for 60 min at 2000 rpm. The aqueous phase is assayed before and after
partitioning to give k o
w.
7.Vapour pressure : (Enthalpy of Vapourisation):
A substance must possess low vapour pressure and if it is high it
may leads to stability problems and content uniformity problems and sometimes
interaction with other compounds may take place.
14. METHODOLOGY: A good estimate of vapour pressure can be obtained by using a
pierced thermal analysis cell, placing it on a vacuum electro balance and
monitoring the weight loss rates. These loss rates are proportional to vapour
pressures.
8. Solid-State Properties:-
Solids usually exists in crystalline, amorphous or a combination of both.
There are 6 crystal systems…. Cubic, tetragonal, orthorhombic, monoclinic,
triclinic and hexagonal. (differ in internal structure)
Crystal habit is of 5 types…. Tabular, platy, prismatic, acicular, bladed, equant.
(differ in external structure)
crystal can exist in different states and these includes:
A) Polymorphism
B) Pseudo- polymorphism
C) Isomorphous crystal forms
A) POLYMORPHISM:
Many drug substances can exist in more than one crystalline form
with different space lattice arrangements. This property is known as
”polymorphism” and crystals are termed as” Polymorphs”.
Many solids may be prepared in a particular polymorphic form via. Appropriate
manipulation of conditions of crystallization such as……
15. changing the nature of solvent, temp, rate of cooling etc.
Polymorphism is common particularly with certain
structural groups. 63% of barbiturates, 67% of steroids, and 40% of
sulphonamides.
Methodology:
1. X-ray diffraction of powder.
2. Differential thermal analysis and Differential scanning calorimetry
B) PSEUDO-POLYMORPHISM:
Occasionally, a solid crystallizes, entrapping solvent molecules in a
specified lattice position and in a fixed stoichiometry, resulting in a solvate, or
pseudopolymorph.The solvents includes– water, methanol, ethanol, acetone,
chloroform, benzene, toulene,etc. The distinction between these forms and true
forms can be obtained by determining the melting point.
C) ISOMORPHOUS CRYSTALS:
Isomorphism is the ability of forming crystals of similar shape by
different chemical substances. Such substances are said to be isomorphous( same
shape). Isomorphism is due to same chemical constitution.
E.g.: Magnesium sulphate, MgSO4.7H2O and Zinc sulphate , ZnSO4.7H2O
9. Powder flow properties: It includes ---- a) BULK DENSITY
b) ANGLE OF REPOSE
16. A) BULK DENSITY:
The flowability of a powder is evaluated by comparing the poured
density and tapped density of a powder and the rate at which it packed down.
It is expressed by
Carr’s Compressibility index and Hausner ratio
Carr’s index % = [(Tapped density – Poured density)/ Tapped density]*100
Hausner index = Tapped density / Poured density
Type of flow Carr’s index(%) Hausner index
Excellent flow 5-15 <1.25 Good flow (=20% carr’s
index)
Good flow 12-16 >1.25 Poor flow (= 33% carr’s
index)
Fair to passable 18-21 1.25-1.5 glidant is to be added
Poor flow 23-35
Very poor flow 33-38
Extremely poor flow >40
17. B) ANGLE OF REPOSE:
A Static heap of powder, when only gravity acts upon it, will
tend to form a conical mount. One limitation exists, the angle to the horizontal
cannot exceed a certain value and this is known as the “ angle of repose ”.If any
particle temporarily lies outside this limiting angle, it will slide down the adjacent
surface under the influence of gravity until the gravitational pull is balanced by the
function caused by interparticulate forces.
The following values of angle of repose represent the type of flow.
Angle of repose Type of flow
<25 Excellent
25-30 Good
30-40 Passable
>40 Very poor
18. 10. DRUG – EXCIPIENT COMPATIBILITY:-
The successful formulation of a stable and effective solid dosage form depends on
the careful selection of the excipients which are added to facilitate administration,
promote the consistent release and bioavailability of drug and protect it from
degradation.
Drug No interaction
50%of mixture of Excipient
drug & Excipient DSC recommended
Excipient Interaction
H.P.L.C.
or T.L.C.
Alternative excipient YES Drug No
suggested Breakdown
19. Aulton’s pharmaceutics (The design and manufacture of medicines)
– by Michael E. Aulton Third edition
Topic Pharmaceutical preformulation Pg: 336-359
Solid – state properties Pg: 110-120
Preformulation Testing – by Deodatt A. Wadke, Abu
T.M.Serajuddin,
and Harold Jacobson
