Pre formulation Studies

Group 1
 Contents
• Introduction
• Importance and Objectives of Pre formulation
Studies
• Vital areas of Pre formulation Research
• Drug Stability Studies
• Analytical Techniques used
• Advancement in Study
Pre-formulation Studies and
Product Development
Iqra Younas
06331513036
 Introduction
• The proper design and formulation of a dosage form
requires consideration of physical, chemical and
biologic characteristics of all drug substances and
pharmaceutical ingredients to be used in fabricating
the product.
• The drug and pharmaceutical materials must be
compatible to produce to produce a drug product
that is stable, efficacious, attractive, easy to
administer and safe.
• This information may dictate many of subsequent event
& approaches in formulation development. This first
learning phase is called as preformulation.
• Preformulation is a branch of Pharmaceutical Science
that utilizes biopharmaceutical principles in the
determination of physicochemical properties of the drug
substance.
Definition
“Investigation of physico-chemical properties of the new
drug compound that could affect drug performance and
development of an efficacious dosage form”.
 Importance
• Preformulation studies are an important foundation tool
early in the development of both API and drug products.
• They influence:
Selection of the drug candidate itself
Selection of formulation components
API & drug product manufacturing processes
Determination of the most appropriate container / closure
system
Development of analytical methods
Assignment of API retest periods
The synthetic route of the API
Toxicological strategic management process
• The preformulation is the first step in the rational
development of a dosage form of a drug substance
alone and when combined with excipients.
• Preformulation commences when a newly
synthesized drug shows a sufficient pharmacologic
promise in animal model to warrant evaluation in
man.
• Its main focus is to generate useful information to
the formulator to design an optimum drug delivery
system.
• Before embarking on a formal programme of
preformulation, scientist must consider the
following:
1. Available physicochemical data (including chemical
structure, different salt available)
2. Anticipated dose.
3. Supply situation and development schedule
4. Availability of stability-indicating assay
 Pre-formulation Characterization
Bulk Properties Stability
• Organoleptic • Solid state (oxygen, light, compatibility)
• Crystallinity and Polymorphism • Solution (pH, buffers, solvent,
temperature)
• Water adsorption
• Compatibility with excipients (other
• Particle size, shape, and surface area
additives)
• Bulk density
• Adhesion Biopharmaceutical Properties
• Powder flow • Absorption (route, rate, extent,
• Compressibility mechanism, absorption windows, food
effects)
Physico-chemical Properties • Metabolism (first pass metabolism,
• Solubility analysis enzyme induction, metabolism in GIT)
• Ionization • Duration of action (dosing, controlled
release)
• Partition coefficient
• Dose
• Dissolution
Objectives of Pre formulation
Studies
Saadullah Yaqoob
06331513029
 Need for Dosage Forms
• The main objective is to generate information useful
to the formulation in developing most stable and
bioavailable dosage form.
• For a potent and low drug it could be difficult for the
patients to take appropriate and exact dose of a drug
from bulk material.
• This urges the need for designing the dosage form
and pre-formulation studies.
 Reasons for Designing a Dosage Form

A) Protection
• To protect the drug from external environmental
conditions such as atmospheric oxygen, temperature
and humidity (coated tablets, capsules)
• To prevent degradation of acid labile drug from
gastric acid in the stomach (enteric coated).
 Improve Therapeutic Activity
• To provide optimal drug action on the appropriate
site (ointments, creams, transdermal patches).
• Placement of drugs directly into body’s orifices
(rectal, vaginal, suppositories).
• To provide optimal drug action in the blood
stream or body tissues (injections, inhalants,
inhalant aerosols).
• To provide bioavailability of drug with narrow
absorption window (gastroretentivity delivery).
 Patient Compliance

• Accuracy of dose by providing unit dose (tablets,

capsules).
• Reduction in frequency of dosing (sustained and
prolonged release delivery).
• Masking the bitter taste or odour of the drug(Film
coated tablets, capsules, suspensions, emulsion).
• Placement of drugs within body tissues and cavities
(Otic, rectal, vaginal, buccal, sublingual).
• Ease of handling and administration (chewable
tablets).
 Pre formulation Studies

• Before beginning the proper pre-formulation studies,

it is important to glance into the following factors:
• Innovative molecule.
• Therapeutic category of drug compound.
• Physicochemical properties of drug, excepients and
possible interactions with drug.
• Therapeutic dose/potency of compound.
• Stability parameters.
 Goals of Pre formulation

• Selection of correct form of the drug substance

(solid, liquid, gas) based on the type of dosage form
development.
• Evaluation of physical and chemical properties of
drug substance.
• To understand biopharmaceutical properties of drug.
• To reduce drug development time and cost.
• To produce safe, effective and reproducible drug
delivery system.
Vital areas of Pre formulation
Research
Mahnoor Khalid
06331513026
 Organoleptic Properties
• Organoleptic Properties are those properties which
are evaluated after an impression on the organs of
sense.
• It refers to the evaluation of drugs by properties like
• colour
• odour
• taste
• size
• shape
• texture etc.
Bulk characterization
 Crystallinity
• Crystal habit & internal structure of drug can affect
bulk & physicochemical property of molecule.
• Crystal habit is description of outer appearance of
crystal.
• Internal structure is molecular arrangement within the
solid.
• Change within the internal structure usually alters
crystal habit.
Example: Conversion of sodium salt to its free acid form
produce both change in internal structure & crystal habit.
 Structural Classification of Compounds
• Depending on internal structure compounds are classified
as
1. Crystalline
2. Amorphous
• Crystalline compounds are characterized by repetitious
spacing of constituent atom or molecule in three
dimensional array.
• In amorphous form atom or molecule are randomly placed
and solubility & dissolution rate are greater for amorphous
form, as amorphous form has higher thermodynamic
energy.
• Example: Amorphous form of Novobiocin is well absorbed
whereas crystalline form results in poor absorption.
 Melting Points of Amorphous and Crystalline
Solids
Crystalline Solids Amorphous Solids
• Have sharp,well defined • Donot have sharp, well
melting points. defined melting points.
• All the component atoms or • All the component atoms or
ions are at same distance ions are at different distance
from the same number and from the different number
type of neighbouring and type of neighbouring
atoms,ions or molecules. atoms,ions or molecules.
• Intermolecular forces are • Intermolecular forces are
uniform. non uniform.
• Same amount of thermal • Different amounts of thermal
energy is needed to break energy are needed to
every interaction. overcome these different
interactions.
 Polymorphism
• It is the ability of the compound to exist in more than
one crystalline forms.
• Different crystalline forms are called polymorphs.
• Polymorphs are of 2 types
1. Enatiotropic
2. Monotropic
• The polymorph which can be changed from one form
into another by varying temp or pressure is called as
Enantiotropic polymorph.
• Example: Sulphur.
• One polymorph which is unstable at all temp. &
pressure is called as Monotropic polymorph.
• Example: Glyceryl stearate.
 Physical Properties of Polymorphs
• Polymorphs differ from each other with respect to
their physical property such as
o Solubility
o Melting point
o Density
o Hardness
• Example: Chloromphenicol exist in A,B & C forms, of
these B form is more stable & most preferable.
• Polymorphism can be measured by optical
microscopy, scanning electron microscopy, hot stage
microscopy, thermal analysis and X-ray diffraction
 Particle Size

• Particle size is characterized using these terms very

coarse, coarse, moderately coarse, fine, veryfine.
• Particle size can influence variety of important
factors
o Dissolution rate
o Solubility
o Uniform distribution
o Penetrability
o Lack of grittiness
• There are many different methods available for
particle size analysis such as Sieving,
Sedimentation and microscopy.
 Particle Size and Sieve number

• Granules pass through 4-12 sieve size.

• Granules passing through 12-20 sieve size are usually
used for tablet making.
Physicochemical Consideration
Of Drug
Sidra Bashir
06331513031
 Powder flow properties
• Powder flow properties can be affected by change in
particle size, shape & density.
• The flow properties depends upon force of friction
and cohesion between one particle to another.
• Fine particle posses poor flow by filling void spaces
between larger particles causing packing &
densification of particles.
• By using glident we can alter the flow properties. e.g.
Talc
 Determination of Powder Flow Properties
• By determining Angle of Repose.
• A greater angle of repose
indicate poor flow.
• It should be less than 30°. & can
be determined by following
equation.
tan θ = h/r
• where, θ = angle of repose.
h=height of pile. r= radius.
 Determination of Powder Flow Properties

• Measurement of free flowing

powder by compressibility.
• It is also known as Carr's index.

C= 100(ᵨT-ᵨB/ᵨT)

• It is simple, fast & popular

method of predicting powder
flow characteristics.
 Solubility Study
• The amount of substance that passes into solution in
order to establish equilibrium at constant
temperature and pressure to produce a saturated
solution.
• If solubility is < 1 mg/ml indicates need for salt
formation to improve solubility.
• If solubility is < 1 mg/ml in pH= 1 to 7, pre
formulation study should be initiated.
• Solubility should ideally be measured at two
temperatures: 4°C and 37°C.
 Solubility Study

• Important goal of the pre

formulation effort is to devise a
method for making solutions of the
drug.
• Orally administered drug must
dissolve in the aqueous fluid of the
GIT prior to absorption. Solubility
can be improved by addition of co-
solvents.
• Solubility can by determined by :
Equilibrium method
Turbidometric method
 pKa Determination
• pKa is the dissociation constant of a drug.
• The non ionized substances is lipid soluble thus
dissolve in lipid material of the membrane and
transported by passive diffusion.
• Where as, the ionized substances is a lipid insoluble
therefore permeation is slow.
• Ionization constant (pKa) Can be calculated by
Henderson Hasselbach equation
• For acidic drugs….pH= pKa+ log [ionized drug]
/[unionized drug]
• For basic drugs….pH= pKa+ log[unionized drug]
/[ionized drug]
  Partition Coefficient
• Partition coefficient influence permeation of a drug
across biological membrane.
• Following administration, the drug must travel
through a variety of membranes to gain access to the
target area.
K=Co/Cw
• Drug with extremely high partition co-efficient (i.e.
very oil-soluble ) readily penetrate the membranes.
• While drugs with excessive aqueous solubility i.e. low
oil/water partition co-efficient cannot penetrate the
membrane
 Dissolution
• It is controlled by several physicochemical properties- chemical
form, crystal habit, particle size, solubility and surface area.
• Noyes-Whitney equation
dC / dt= AD (Cs-C)/hV
• dC/dt = Dissolution rate
• A= surface area of dissolving solid
• D = diffusion coefficient
• h = diffusion layer thickness
• C = solute concentration in the bulk medium
• V = volume of dissolution medium
• Cs = solute concentration in diffusion layer
Drug Stability Studies

Ayesha Mazhar
06331513028
 Stability Studies
• Stability testing provides evidence on how the quality
of a drug substance or product varies over a given
time period and under the influence of
environmental factors including temperature,
humidity and light.
• The studies are designed to include testing of
attributes susceptible to change during storage and
are likely to influence quality, safety and efficacy.
Objectives of Drug Stability Testing

Objectives of drug
stability testing
Types of Stability
 Drug Degradation and Stability
Chemical instability of medicinal agents may take many
forms because the drugs in use today are of such
diverse chemical constitution. Chemically, drug
substances are alcohols, phenols, aldehydes, ketones,
esters, ethers, acids, salts, alkaloids, glycosides, and
others, each with reactive chemical groups having
different susceptibilities to chemical instabilities.
 Hydrolysis
• It is a solvolysis process in which (drug) molecules
interact with water molecules to yield breakdown
products.
• Decomposition by hydrolysis may be prevented in
other liquid drugs by suspending them in a non-
aqueous vehicle.
• Reconstitution of powdered drugs by adding a
specified volume of purified water just before
dispensing.
• Refrigeration is advisable for most preparations.
• Buffering agents may be added.
 Oxidation
• It destroys many drug types including aldehydes,
alcohols, phenols, sugars, alkaloids, and unsaturated
fats and oils. Chemically, oxidation is loss of electrons.
• Autoxidation occur spontaneously under the initial
influence of atmospheric oxygen.
• The oxidative process is diverted and the stability of
the drug is preserved by agents called antioxidants,
which react with one or more compounds in the drug
to prevent progress of the chain reaction.
• Oxygen-sensitive drugs may be prepared in the dry
state and packaged in sealed containers with the air
replaced by an inert gas such as nitrogen.
 Trace Metals Presence
• Trace metals originating in the drug, solvent,
container, or stopper are a constant source of
difficulty in preparing stable drugs.
• The rate of formation of color in epinephrine
solutions, for instance, is greatly increased by the
presence of ferric, ferrous, cupric, and chromic ions.
• Trace metals can be removed by,
-thorough purification of the source
-chemical complex formation
 Photolysis

• Light can also act as a catalyst to oxidation reactions,

transferring its energy (photons) to drug molecules,
making the latter more reactive through increased
energy capability.
• As a precaution against acceleration of oxidation,
sensitive preparations are packaged in light-resistant
or opaque containers
 pH

• Another factor that can affect the stability of drug in

solution is the pH of the preparation.
• Each drug must be maintained in solution at the pH
most favorable to its stability. This varies from
preparation to preparation
• In addition chemical decarboxylation, and
deamination and polymerization can cause drug
instability.
 Stability Testing
Long term stability testing Short term or accelerated
stability testing
conducted at 25°C ±2°C and at a relative conducted for 6 months at 40°C with 75%
humidity of 60% ± 5% for 12 months relative humidity or at 30°C and 60%
(minimum) relative humidity
Samples maintained under these Short-term accelerated studies are used
conditions may be retained for 5 years or to determine the most stable of the
longer, during this time they are observed proposed formulations for a drug product
for physical signs of deterioration and
chemically assayed.
Analytical Techniques

Ayesha Abbasi
06331513062
 Thermal Methods of Analysis

Thermal analysis plays a critical role in compatibility studies

and has frequently been employed for quick assessment of
physicochemical incompatibility. There are three different
types of thermal analyses, which include:
• Differential Scanning Calorimetry (DSC):
DSC curves of pure components are compared to the curves
obtained from 1:1 physical mixtures. A significant shift in
the melting of the components or appearance of a new
exo/endothermic peak and/or variation in the
corresponding enthalpies of reaction in the physical mixture
indicate incompatibility.
• Isothermal Micro-calorimetry
It allows determination of minute amounts of evolved
or absorbed heat. The thermal activity of API, excipient
and their mixtures are measured individually in the
calorimeter and the thermal activity (heat flow) at a
constant temperature is monitored.
• Hot Stage Microscopy (HSM)
HSM is a visual thermal analysis technique, which
allows efficient monitoring of solid state interactions
that could be erroneously interpreted as incompatibility
by DSC. This technique only requires very small
quantity of sample when performing compatibility
studies.
 Spectroscopic Techniques
•Vibrational Spectroscopy
– FT-IR Spectroscopy
– Diffuse Reflectance Spectroscopy (DRS)
•Powder X-ray Diffraction (PXRD)
PXRD is of great help for compatibility studies during processes
like compression, wet granulation, etc. and bring on changes in
crystallinity/amorphicity and polymorphic forms of API in the
presence of excipients.
•Solid State Nuclear Magnetic Resonance Spectroscopy (ss
NMR)
ss NMR has shown immense potential in the qualitative and
quantitative analysis of pharmaceutical solids.
• It has a unique advantage for detecting compatibility
in crystalline as well as amorphous components in a
mixture.
• Other spectroscopic techniques include:
Ultraviolet/Visible spectroscopy, Infrared spectroscopy,
Fluorescence/Phosphorescence spectroscopy, Raman
spectroscopy, X-ray spectroscopy, Flame emission and
Atomic absorption spectroscopy.
 Microscopic technique
• Scanning electron microscopy (SEM)
Chromatography
• Gas Chromatography (GC)
• Thin Layer Chromatography (TLC)
• Paper Chromatography
• Column Chromatography
• High-Performance Liquid Chromatography (HPLC)
HPLC exhibit a percentage loss of the API. We provide liquid
chromatography-mass spectrometry/mass spectrometry
(LC–MS/MS) to further characterize the incompatibility
products.
Recent Advancements in Product Development
• Surfactant systems are essential for any poorly soluble
drug candidate to be formulated in a liquid dosage
form. Various categories of surfactants available are
anionic, cationic, or non-ionic in nature.
• Although however, anionic and non-ionic surfactants
are considered relatively safe, these surfactants can
also cause cytotoxicity if used in excess of their
recommended concentration.
• In one of the recent studies the authors have
developed surfactant-free formulation by using octanyl
succinate modified starch for oral drug delivery.
• The computer simulation GastroPlusTM requires
input of numerous data such as MW, log P, pKa,
particle density, and Peff. It also required a series of
assumptions such as stomach and intestinal transit
times, intestinal surface area etc. As a result this
simulation may not be able to predict accurate in
vivo absorption and permeability due to large
number of variables. Another commercial software
program known as PK-SIM® is also available for
physiological based absorption modeling.