AIM: Preformulation studies

Principle: Essentials of Pharmaceutical Preformulation is a study guide which describes the

basic principles of pharmaceutical physicochemical characterisation. Successful
preformulation requires knowledge of fundamental molecular concepts (solubility, ionisation,
partitioning, hygroscopicity and stability) and macroscopic properties (physical form, such as
the crystalline and amorphous states, hydrates, solvates and co-crystals and powder
properties), familiarity with the techniques used to measure them and appreciation of their
effect on product performance, recognising that often there is a position of compromise to be
reached between product stability and bioavailability.

Objective: The objectives of the preformulation study are:-

(1) to establish the physico-chemical parameters of a new drug

(2) to determine its kinetics and stability

(3) to establish its compatibility with common excipients.

Preformulation studies may have asignificant impact on manufacturing, storage, and

performance of drug products. It not only helps to guide dosage form selection, but also
provides insights into how drug products should be processed and stored to ensure their
quality.
METHODS OF ANALYSIS: A)Solubility Studies

One of the most widely studied techniques during preformulation analysis is solubility profile
of drug candidate. It is the backbone study of preformulation stage that determines the
performance of developed formulation. Solubility and permeability forms the scientific basis
of biopharmaceutics classification system (BCS), which can provide framework for designing
type of drug delivery system.

a) Partition coefficient

Partition coefficient (Log P) value is defined as ratio of unionized drug distributed between
aqueous and organic phase. Oil-water partition coefficient gives the idea about drug’s ability
to cross the lipidic membrane. Lipophilic/hydrophilic balance is one of the most important
contributing factors for optimum drug absorption and delivery. Due to lipidic nature of
biological membrane, the amount of drug absorbed depends heavily on its lipophilicity. It is
The unionized form of molecule that has better lipophilicity and hence it has received so
much importance.

LogP=(Coil/Cwater)

If the value of Log P is 0, it indicated that drug has equal distribution in water and partition
solvent. Value of Log P less than 1 is indicative of higher water solubility and value greater
than 1 is indicative of higher lipidic solubility. For optimum solubility and absorption, a
proper hydrophilic-lipophilic balance is necessary.

Determination of Log P value in biological system is next to impossible task, so several

methods are available to determine partition coefficient of molecule in vitro, which are as
follows:

Shake flask method

Chromatographic method (HPLC)

Computation based on software

Countercurrent/filter probe method

Highly used method is shake flask method that utilizes octanol-water system to determine
drug’s partitioning behaviors. There are several reasons behind selection of octanol as
partitioning solvent, which can be explained as follows:

Octanol is believed to mimic the lipoidal character of biological membrane as it contains

polar head and nonpolar tail.Octanol is organic compound that is immiscible with water;
however, some of the water is expected to be present in polar head portion.Solubility
parameter for most of the drugs resembles with that of octanol.

B) The Bulk Character:

Crystalline vs amorphous form

Amorphous drugs have randomly arranged molecules or atoms in the molecular lattice.
Typical amorphous forms are obtained by techniques like precipitation, rapid cooling after
melting, and lyophilization. One of the most important advantages associated with
amorphous form is the higher solubility and hence the higher dissolution rate. More often
than not drugs with low water solubility lead to poor bioavailability and variable clinical
response. So, polymorphic form may overcome this problem with main challenge of stability.
Crystalline form is characterized by regular spacing between molecular lattices in three-
dimensional structure. One of the striking advantages associated with this form is the
impeccable stability at a cost of lower water solubility than amorphous form.Various
techniques are available to study crystallinity like X-ray, differential scanning microscopy,
differential thermal analysis, hot stage microscopy, and the most important one that is
scanning electron microscopy.

b) Polymrphism

Polymorphism is the ability of a compound (or element) to crystallize as more than one
distinct crystalline species with different internal lattices. Chemical stability and solubility
changes due to polymorphism can have an impact on a drug’s bioavailability and its
development program. Chloramphenicol palmitate exists in three crystalline polymorphic
forms (A,B, and C) and an amorphous form.

Polymorphs can be classified as one of two types: enantiotropic (one polymorph can be
reversibly changed into another by varying temperature or pressure, e.g. sulfur) or
monotropic (one polymorphic form is unstable at all temperatures and pressures, e.g. glyceryl
stearates).

c) Hygroscopy

Hygroscopicity can be defined as the capacity of a compound to absorb atmospheric

moisture. Amount of moisture absorbed depends on atmospheric conditions and surface area.
Deliquescent substance absorbs moisture to a greater extent and liquefies itself

Slightly hygroscopic: Increase in weight is ≥ 0.2 % w/w and < 2 % w/w.

Hygroscopic: Increase in weight is ≥ 0.2 % w/w and <15 % w/w.

Very hygroscopic: Increase in weight is ≥ 15% w/w.

Deliquescent: Sufficient water is absorbed to form a solution.

C) Micromeretic properties:

a) Particle Character

Particle size-Particle size greatly affects a number of quality parameters like dissolution rate,
solubility, bioavailability, content uniformity, and lack of grittiness.A number of methods are
available to determine particle size, which are as follows:

Microscopy

Sedimentation rate

Coulter counter method

Surface area determination by nitrogen adsorption method

Apart from particle size, particle shape plays an important role during preformulation phase
as the shape of particle may influence surface area, flow properties, and compaction force.

Aspirin Paracetamol

b) Density and Porosity

Density can be defined as ratio of mass of a substance to its volume, which greatly depends
on particle size distribution and shape. The main problem arises during determination of bulk
volume is the voids, which can be interparticulate, open, and closed intraparticulate. So by
considering the presence of different types of void volume, various densities are proposed.
True density: It is defined as total volume of solids excluding all space greater than molecule
diameter. True density can be measured with helium pycnometer.

Bulk density: It is defined as total volume occupied by entire powder mass. It can be
determined by placing previously sieved powder bulk into a graduated cylinder and
measuring the volume in milliliters. Division of original weight and attended volume gives
idea about bulk density.

Tapped density: It is determined by placing graduated cylinder containing known weight of

sample on tapped density apparatus and is operated for the fixed number of taps until a
constant volume is attained. Ratio of total amount of substance taken to the final constant
volume gives idea about tapped density.

c) Powder Flow Proprties:

Flow property of material can be affected by a number of factors including frictional forces,
surface tension forces, electric forces, and van der Waals forces.

Efficient flow of drug substance powder is needed for effective tablet formulation.

Normally, flow property of solid drug substance can be measured by Hausner ratio, Carr’s
index, and angle of repose, and in case of liquids or semisolid, rheology and thixotropy.

Correlation between Carr’s index, Hausner’s ration, and flowability.

Another way of measuring flow property is angle of repose, which provides the idea
resistance to the movement of particle. It can be represented by the following formula:

tanθ=2h/D.
It is the maximum angle that can be obtained between height of pile and a horizontal plane. It
gives a brief idea about internal cohesive and frictional levels. There are basically two types
of methods that are available, which are as follows:

Static angle of repose

Fixed funnel method

Fixed cone method

Dynamic angle of repose

Rotating cylinder method

C) Stability Analysis:

Stability of molecule-The main objective of determining stability of molecule is to identify

the conditions in which molecule is susceptible to deteriorate and to determine degradation
pathway. The mechanism of degradation and condition provides the idea about proper
designing of formulation, suitable molecular modification, appropriate storage condition, and
selection of proper packaging material.

The major mechanisms by which a molecule undergoes degradation are hydrolysis,

oxidation, photolysis, and racemization. Out of these mechanisms, hydrolysis is perhaps the
most studied after oxidation.

Drug excipient compatibility-Excipients are added along with the active pharmaceutical
ingredient in formulations. Most excipients possess biological activity but having role in
administration, mediating the release of the active component, and providing stability against
degradation. However, inappropriate excipients can also give rise to inadvertent and/or
unintended effects, which can affect the chemical nature, the stability, and the bioavailability
of the API, and consequently, their therapeutic efficacy and safety. So study about interaction
between active ingredient and inactive ingredient can provide idea about type of
incompatibility and the justification behind the inactive ingredient selection. Change in
organoleptic properties of formulation. Changes in in vivo performance of formulation, that
is, dissolution. Decreased potency of active ingredient. Generation of toxic degradation
product. Change in physical appearance of formulation, that is, color, phase conversion. The
drug-excipient incompatibility may result in change in physical, chemical, microbiological,
or therapeutic properties of formulation.
Learning Outcome-

S.NO Sample Bulk Tapped Carr’ Hausner’ Angle of repose Relative

Density Density s s Ratio (Fixed height method) Flowability
Index

1) Paracetamol 0.41 0.76 85.3 1.835 35.5° Poor

%

2) Lactose 0.45 0.71 57% 1.57 39.69° Poor

3) HPMC 0.34 0.5 47% 1.47 36.86° Poor

4) Aspirin 0.47 0.69 67% 1.69 0.42° Poor