PREFORMULATION

Dr. Kabali Moses MPS

Bpharm MPharm Pharmaceutics
Introduction
• Preformulation is a stage of drug development during
which studies are done to characterize and establish
the physicochemical properties of the new drug entity.
• Preformulation studies ensure development of a safe,
efficacious and stable formulation.

• Prior to the development of any dosage form of new

drug, it is essential that certain fundamental physical &
chemical properties of drug powder are determined
and this determines approaches to formulation of the
drugs.
Rationale for Preformulation
• To establish the necessary physicochemical properties of
new drug substance.

• To establish compatibility of NDE with common excipients.

• To determine its kinetics and stability.

• To provide insights on formulation approaches,

processing, storage
Physicochemical properties
assessed:
• Stability
• Solubility
• Particle size analysis
• Crystallinity
• Melting point.
• Rheology( powder flow properties)
• Partition coefficient.
• Assay development: a method for qualitative and
quantitative analysis
Properties cont…
• Permeability
• Dissolution rate.
• pKa,
• Organoleptic properties.
• Polymorphism.
• Hygroscopicity.
 1. Solubility
• The solubility of a candidate drug molecule is the amount of
the drug (solute) that dissolves in a given solution (solvent) to
produce a saturated solution at constant temperature and
pressure.
• Solubility changes with temperature and pressure.

• Most drugs in discovery have a poor solubility which gives a

big problem resulting from poor dissolution, poor absorption
hence limited bioavailablity.

• A drug is considered highly soluble when the highest dose

strength is soluble in 250 mL or less of aqueous media over
the pH range of 1 to 7.5.
 Description Parts of solvent required
for one part of solute

Very soluble <1

Freely soluble 1 - 10
Soluble 10 - 30
Sparingly soluble 30 - 100
Slightly soluble 100 - 1000
Very slightly soluble 1000 - 10,000
Insoluble > 10,000
Solubility studies
Solubility should ideally be measured at two
temperatures: 4°C and 37°C.
• 4°C to ensure Physical stability.
• 37°C to support Biopharmaceutical evaluation.

Analytic methods useful for solubility measurement

include HPLC, UV spectroscopy, Fluorescence
spectroscopy and Gas chromatography.

 Reverse phase HPLC offer accurate and efficient

mean of collecting solubility data of drug.
• The most frequent causes of low oral bioavailability are
attributed to poor solubility and low permeability
(check biopharmaceutics classification)

• The solubility of acidic or basic drug will show

difference in solubility with changes in pH.
Biopharmaceutical classification
Techniques of enhancing solubility.
• Addition of co-solvent.-Involves adding another
solvent to improve the solubility of a material which
was poorly soluble to the first solvent. The two solvents
must be miscible. Eg.Phenobarbitone is insoluble in
water. A clear solution is obtained by dissolving in
mixture of Alcohol, Glycerin, Propylene glycol.

• Hydotrophy. A hydrotrope is a compound that

solubilizes hydrophobic compounds in aqueous
solutions by means other than micellar solubilization.
sodium benzoate, sodium citrate, urea, niacinamide.
Cont…
• Reduction of particle size.
• Temperature change. Increasing temperature?
• pH change method:- For weak acidic drug:- increase
pH, For weak base drug:- decrease pH
• Complexation. eg by using cyclodextrins.
• Solubilization. Solubility of an otherwise sparingly
soluble substance is increased by the presence of
surfactant micelles .
 2. Crystallinity
• Crystal habit & internal structure (molecular
arrangement) of drug can affect bulk physicochemical
properties. Crystal habit is description of outer appearance of
crystal.

• Depending of internal structure, drugs are classified as

crystalline and amorphous drugs. Amorphous forms
have random arrangement. Crystalline forms have
repetitious arrangement of molecules.

• Amorphous forms have a high solubility and high

dissolution hence but a low stability compared to
Cont…
Crystalline drugs have a higher stability but low
solubility.

Techniques employed in studying crystallinity include:

Microscopy, Hot stage microscopy,Thermal
analysis, X-ray diffraction
3. Hygroscopicity
• The degree of Hygroscopicity is classified into four

• ✓ Slightly hygroscopic: increase in weight is ≥ 0.2%

classes:

• ✓ Hygroscopic : increase in weight is ≥ 0.2 % w/w

w/w and < 2% w/w

• ✓ Very hygroscopic : increase in weight is ≥ 15%

and < 15 % w/w

• ✓ Deliquescent : sufficient water is adsorbed to form

w/w

a solution.

• Analytical methods that can be used include:

4. Particle size
Particle size influences: Dissolution rate, Suspendability
Uniform distribution, Penetrability, Lack of grittiness.

Particle size can be evaluated by:

• Sieving (5μ-150μ)
• Microscopy(0.2μ-100μ)
• Sedimentation rate method(1μ-200μ)
• Light energy diffraction(0.5μ-500μ)
• Laser holography(1.4μ-100μ)
5. Powder flow properties
• Fine particle posses poor flow by filling void spaces
between larger particles causing packing &
densification of particles.
• Powder flow can be improved By using glidant e.g. Talc
• Powder flow properties can be measured using carr
index, angle of repose

CARR’S INDEX(%) =(TAPPED DENSITY – POURED DENSITY) X 100

TAPPED DENSITY
Determination Of Powder Flow Properties
Carr’s Index Index
Ratio properties
<10 Excellent
11-15 Good
16-20 Fair
21-25 Passable
26-31 Poor
32-37 Very poor
Determination Of Powder Flow Properties

By determining Angle Of Angle Of Type Of

Repose. Repose Flow
A greater angle of repose ( In
indicate poor flow. degree)
It should be less than 30°. & <25 Excellent
can be determined by
following equation. 25-30 Good
tan θ = h/r.
where, θ = angle of repose. 30-40 Passable
h=height of pile.
>40 Very poor
6. Polymorphism
• It is the ability of the compound to crystallize as more
than one distinct crystalline species with different
internal lattice.

Polymorphs are of 2 types:

• Enatiotropic
• Monotropic

Polymorophs may differ in hardness, solubility, melting

point, density, compressibility.
Polymorphism can be determined by thermoanalysis, x-
ray diffraction.
7. Stability
• Drug stability is the ability of the pharmaceutical
dosage form to maintain the physical, chemical,
therapeutic and microbial properties during its storage.
• Stability studies can be long term stability studies (real
time studies) or accelerated studies.

• In real time studies: drugs are kept under normal

storage conditions of temperature, moisture, and
pressure and tests carried to determine the time taken
for the product to lose its potency
Cont…
• Accelerated studies involve subjecting the drug to high stress
conditions of temperature and pressure and tests taken to
determine time taken for the drug to lose its potency.
• Data obtained from conditions of high stress can be used to
estimate the shelf time of product at normal storage
conditions using Arrhenius equation.

• Shelf life of a drug can also be obtained using rate reaction

kinetic
• Refers to the time taken for a drug to reduce to 90% of its
original concentration
Order Integrated rate equation Half-life equation

1  kt
log c   log co
2.3
2 1 1
  kt
c co

3
① A solution of a drug contained 500 units/mL
when prepared. It was analyzed after 40 days
and was found to contain 300 units/mL.
Assuming the decomposition is first order, at
what time will the drug have decomposed to one-
half of its original concentration?

② The initial concentration of a drug decomposing

according to first-order kinetics is 94 units/mL.
The specific decomposition rate, k, obtained from
an Arrhenius plot is 2.09 × 10-5 hr- 1 at room
temperature, 25°C. Previous experimentation has
shown that when the concentration of the drug
falls below 45 units/mL it is not sufficiently
potent for use and should be removed from the
market. What expiration date should be assigned
to this product?
③ The initial concentration of active principle
in an aqueous preparation was 5.0 x10-3 g
cm-3. After 20 months the concentration was
shown by analysis to be 4.2 x10-3 g cm-3. The
drug is known to be ineffective after it has
decomposed to 70% of its original
concentration. Assuming that decomposition
follows first- order kinetics, calculate the
expiry date of the drug preparation.
 Storage conditions
Lengths of studies chosen sh’d be sufficient to cover storage,
shipment, & subsequent use.

a) Drug substances - General

case Study Storage condition Minimum time
period
Long term 25°C ± 2°C / 60% ± 5% r.h. or
30°C ± 2°C / 65% ± 5% r.h. 12
months
Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months
Accelerated 40°C ± 2°C / 75% ± 5% r.h. 6
months
b) Drug substances - intended for storage in a
Refrigerator
Study Storage condition Minimum time
period
Long term 5°C ± 3°C 12
months
Accelerated 25°C ± 2°C / 60% ± 5% r.h. 6
months
c) Drug substances - intended for storage in Freezer
Study Storage condition Minimum time
period
Long term -20°C ± 5°C 12
months
• Storage conditions
• Cold place: store at temp btn 2℃ & 8℃
• Cool place: store at temp btn 8℃ & 25℃
• Room temp: prevailing temp in the working area
• Warm: store at temp btn 30℃ & 40℃
• Excessive heat: store at temp >40℃
• Controlled RT: store at temp btn 20℃ & 25℃
• Freezer: store at temp btn -10℃ & -20℃
8. Organoleptics
Color Odour Taste

off-white pungent acidic

cream-yellow sulfurous bitter

shiny fruity sweet

aromatic tasteless

odourless tasteless
Taste and odour

• If taste is considered as unpalatable, consideration is to

be given to the use of a less soluble chemical form of
the drug.

• The odour and taste may be suppressed by using

appropriate flavors and excipients or by coating the
final product.
9. Purity
• Designed to estimate the levels of all known &
significant impurities & contaminates in the drug
substance under evaluation.
• Occasionally, an impurity can affect stability. e.g. Metal
contamination

The techniques used for characterizing the purity

of drug include:
• Thin layer chromatography.
• HPLC, paper chromatography & gas chromatography
are also useful.
10. pKa ionization constant
• Most drug candidates are either weak acids or bases,
therefore, one of the most pertinent determinations
carried out prior to development is the pKa or
ionization constant.

• It is useful to know the extent to which the molecule is

ionized at a certain pH, since properties such as
solubility, stability, drug absorption and activity are
affected by this parameter.
Cont…
• Henderson–Hasselbach equation relates pKa to the pH
of the solution and the relative concentrations of the
dissociated and undissociated parts of a weak acid:
11. The Partition and Distribution
Coefficients
• The lipophilicity of an organic compound is usually
described in terms of a partition coefficient (log P),
which can be defined as the ratio of the concentration
of the unionized compound,at equilibrium, between
organic and aqueous phases:
• log P = 0 means that the compound is equally soluble
in water and in the partitioning solvent.
• If the compound has a log P = 5, then the compound is
100,000 times more soluble in the partitioning solvent.
• log P = –2 means that the compound is 100 times more
soluble in water, i.e., it is quite hydrophilic.
 End
Any questions??