Preformulation

(Preformulation)
PRESENTED BY:-
Prajal M.Christian
M. Pharm. sem-1
Enroll.No:172120820004
DEPARTMENT OF PHARMACEUTICS
B.K.MODY GOVT. PHARMACY COLLEGE, RAJKOT.
GUIDED BY:-
Dr. Sunny R. Shah
Assistant professor
SEMINAR

 Idea about preformulaion
 Drug –excipient compatibity study
 Stability kinetics
 Stability testing

• It is defined as phase of research and
development in which preformulation scientist
characterize physical & chemical properties of
new drug molecule in order to develop safe,
effective, and stable dosage form.
• Investigation of physical & chemical properties
of a drug and mixer of drug & excipient
3

• Prior to development of dosage form with new
drug candidate, it is essential that some
fundamental physicochemical properties of
new drug molecule are determined. There
information may dectate many of subsequent
event and possible approaches in formulation
development.

 To formulate an innovative,elegant, safe, efficacious dosage
form with forms capable of delivering the substances for its
intended use.
 To formulate new dosage form of already existing drug.
 Determination of all the properties of drug and the best suitable
dosage form for the drug molecule.
 The major goal of preformulatoin is to gather data, Which will
permit the rational development of safe and efficacious dosage
form..

DIRECT BENEFITS
 Gives direction for development of formulation in choice
of dosage form,excipients,composition,physical structure.
 Helps in adjustment of Pharmacokinetics and
biopharmaceutical properties.
 Support for process development of drug substance
(yield,filtration..).
 Produce necessary and useful data for development of
analytical methods.
6

Receive new drug
substance
Obtain all available
information
If not available, do the
literature search.
Determine physical property
of the new API.
Macroscopic and
Microscopic examination
Determine polymorphs,
solvates and hydrates.
Stability testing at
normal and
exaggerated
condition.
Determine their
solubility, partition co-
efficient, pKa,
dissolution rate.
If poor bioavailability test results due to solubility,
pKa, P, etc. make new salt or ester
If satisfactory
Check lot to lot
uniformity
Select most stable, active
form for bioavailability
testing.
Check API stability with
excipients
Prepare worksheet and final
preformulation report and issue to
product development dept.

9
I. PHYSICAL CHARACTERISTICS
A. BULK CHARACTERISTIC
1) Particle Size & Surface Area.
2) Polymorphism.
3) Crystallinity.
4) Hygroscopicity.
5) Flow properties & Bulk density.
6) Compressibility.
7) Drug-Excipient Compactibility.
8) Electrostatic charge.
9) Osmolarity.
10) Rheology.
11) Wettability.

10
B. SOLUBILITY ANALYSIS
1) Aqueous Solubility.
a. Intrinsic solubility.
b. Ionization constant.
2) Solubilization.
3) Partition Coefficient.
4) Thermal effect.
5) Common ion effect.
6) Dissolution.
C.STABILITY ANALYSIS
1) Solid State Stability.
2) Solution State Stability.

11
II.CHEMICAL CHARACTERISTIC
1) Oxidation.
2) Hydrolysis.
3) Photolysis.
4) Racemization.
5) Polymerization.
6) Isomerization.
7) Decarboxylation.
8) Enzyme Decomposition.

“When we mix two or more API and / or
excipient with each other & if they are
antagonistic & affect adversely the safety,
therapeutic efficacy, appearance or
elegance then they are said to be
incompatible.’’
DEFINITION

Types of
Incompatibility
Physical Chemical Therapeutic

 Why to screen excipients?
1.need to minimize no.of model formulations
2.provide rational basis for selecting excipients
3.Formulation stability studies are time
consuming.
 Goal of the study( Identify the excipients that)
1.are compatible with API
2.do not have impact on the stability of API
 Importance
1.Stabity of formulation can be maximised.
2.Helps to avoid surprise problems.
3.Essential for IND submission.
4.Bridges drug discovery and drug development

COMPATIBILITY TESTS
Aspects of compatibility tests are:
1. Identification of compatible excipients for a formulation.
2. Identification of stable storage conditions.
Types:
1. Solid state reactions:
- much slower and difficult to interpret.
2. Liquid state reactions:
- easier to detect
- According to Stability Guidelines by FDA following conditions
should be evaluated for solutions or suspensions
1. Acidic or alkaline pH.
2. Presence of added substances
3. High oxygen and nitrogen atmospheres.
4. Effect of stress testing conditions.

STEPS IN COMPATIBILITY STUDY
There are four steps to consider.
1. Sample preparation
2. Statistical design
3. Storage
4. Method of analysis

SAMPLE PREPARATION
FOR SOLID STATE REACTIONS:
 SampleA: - mixture of drug and excipient
 SampleB: - SampleA+ 5% moisture
 SampleC: - Drug itself without excipients
 All the samples of drug-excipient blends are kept for 1-3
weeks at specified storage conditions.
 Then sample is physically observed .
 It is then assayed by TLC or HPLC or DSC.
 Whenever feasible, the degradation product are identified by
MASS SPECTROSCOPY, NMR or other relevant analytical
techniques.
 To determine Solid state stability profile of a new
compound….
 To test the Surface Oxidation…..

FOR LIQUID STATE REACTIONS:
o Place the drug in the solution of additives.
o Both flint and amber vials are used.
o This will provide information about
-Susceptibility to oxidation.
-Susceptibility to light exposure.
-Susceptibility to heavy metals.
o In case of oral liquids, compatibility with ethanol,
glycerin ,sucrose, preservatives and buffers are
usually carried out.

Known Incompatibilities
Functional group Incompatibility Type of reaction
Primary amine Mono & Di-saccharides
Amine-Aldehyde &
Amine-Acetal
Ester,
Lactone
Basic component
Ester base hydrolysis, Ring
opening,
Aldehyde Amine, Carbohydrate
Aldehyde-Amine, Schiff base
Or Glycosylamine formation
Carboxyl Base Salt formation
Alcohol Oxygen
Oxidation to Aldehyde
& Ketones
Sulfhydryl Oxygen Dimerization
Phenol Metal Complexation
Gelatin- Capsule Shell Cationic Surfactant Denaturation

ANALYTICAL TECHNIQUES USED TO DETECT
DRUS-EXCIPIENT COMPATIBILITY
1. Thermal methods of analysis
 DSC- Differential Scanning Calorimetry
 DTA- Differential Thermal Analysis
2. Accelerated Stability Study
3. FT-IR Spectroscopy
4. DRS-Diffuse Reflectance Spectroscopy
5. Chromatography
 SIC-Self Interactive Chromatography
 TLC-Thin Layer Chromatography
 HPLC-High Pressure Liquid Chromatography
6. Miscellaneous
 Radiolabelled Techniques
 Vapour Pressure Osmometry
 Flourescence Spectroscopy

1) DIFFRENTIAL THERMALANALYSIS
 Thermal Analysis is useful in the investigation of solid-
state interactions.
 It is also useful in the detection of eutectics.
 Thermograms are generated for pure components and their
physical mixtures with other components.
 In the absence of any interaction, the thermograms of
mixtures show patterns corresponding to those of the
individual components.
 In the event that interaction occurs, this is indicated in the
thermogram of a mixture by the appearance of one or more
new peaks or the disappearance of one or more peaks
corresponding to those of the components.

2) DSC- DIFFERENTIAL SCANNING
CALORIMETRY
o DSC is widely used to investigate and predict any physico-
chemical interaction between drug and excipients involving
thermal changes..
o METHOD
-The preformulation screening of drug-excipient interaction
requires (1 : 1)Drug:excipient ratio, to maximize the likehood
of observing an interaction.
-Mixture should be examined under N2 to eliminate oxidative
and pyrrolytic effects at heating rate ( 2, 5 or 100 c / min) on
DSC apparatus.

LIMITATIONS OF DSC
o If thermal changes are very small, DSC can’t be used.
o DSC can not detect the incompatibilities which occur
after long term storage.
Eg. MCC / ASPIRIN…
o Not applicable if test material exhibits properties that
make data interpretation difficult.
ADVANTAGES:
-Fast
-Reliable and very less sample required.

3) ACCELARETED STABILITY STUDY
 Different formulations of
the same drug are prepared.
 Samples are kept at 40ºC /
75 % RH.
 Chemical stability is
assessed by analyzing the
drug content at regular
interval.
 Amt. of drug degraded is
calculated.
 % Drug decomposed VS
time(month) is plotted.

4) DIFFUSE REFLECTANCE SPECTROSCOPY
 Principle:
“Penetration of a portion of incident radiation flux into the
interior of the solid sample, return of some portion of
radiation to the surface of sample following partial
absorption and multiple scattering at boundary of individual
sample particles.”
 Detects the decomposed products, along with physical and
chemical adsorption of excipients on to A.P.I. and vice versa.
 Example:
Ethanol mediated interaction between dextroamphatamine
sulphate and spray dried lactose in solid–solid mixture.

 Diffuse reflectance spectroscopy is gaining increasing popularity
among preformulation scientists as a tool to detect and monitor
drug-excipient interactions.
 In this technique solid drugs, excipients, and their physical
mixtures are exposed to incident radiation.
 A portion of the incident radiation is partly absorbed and partly
reflected in a diffuse manner.
 The diffuse reflectance depends on the packing density of the
solid, its particle size, and its crystal form, among other factors.
 When these factors are adequately controlled, diffuse reflectance
spectroscopy can be used to investigate physical and chemical
changes occurring on solid surfaces.

5) SELF INTERACTIVE CHROMATOGRAPHY
 SIC is useful for proteinous drug and excipients.
METHOD:-
 SIC is a modified type of affinity chromatography.
 Here,drug is made immobilized as the SP & soln. to be
tested( excipient soln.) acts as MP.
 Measure Rt (Retention time) & compare with non –retained
marker.

PRINCIPLE:-
For different mobile phases (i.e. different excipients) the
injected drug have different interactions (may be repulsive or
attractive) with the SP of drug leads to shift in retention time
(Rt)
When interaction
is repulsive,a
sharper peak is
obtained at a
shorter retention
time
When no net
interaction between
the immobilized
drug,Rt=dead
volume of column.
When attractive
interactions,it will
have longer
retention time&
wider peak
FIGURE-1 FIGURE-2 FIGURE-3

6) TLC AND HPTLC
o TLC is generally used as confirmative test of compatibility
after performing DSC.
o S.P. consist of powder (Silica, Alumina, Polyamide, Cellulose
& Ion exchange resin) adhered onto glass, plastic or metal
plate.
o Solution of Drug, Excipient & Drug: Excipient mixture are
prepared & spotted on the same baseline at the end of plate.
o The plate is then placed upright in a closed chamber containing
the solvent which constitutes the M.P.

7) RADIO LABELLED TECHNIQUES:
 It is important when the API is having radio–activity.
 Method is carried out by using either 3H or 13C.
 Highly sensitive method but the cost of carrying out
the method & the availability of well established
other techniques & methods, this method is
generally not preferred.

ORDER OF REACTION:
ZERO ORDER REACTION
 When the reaction rate is independent of concentration
of the reacting substance, it depends on the zero power of
the reactant and therefore is zero order reaction.

 Rate of concentration decrease =
-dCx = K……………………………(1)
dt
 Integrating the equation yields
X= Kt + constant…………………(2)
 The unit of K is conc time-1, with typical units of
mole L-1 s-1.
 Half-life is given by equation
t1/2 = Co/2k.

GRAPH FOR ZERO ORDER
time
concentration
Slope = k
The value of K indicate the amount of drug that is
degraded per unit time, and intercept of line at time zero is
equal to constant in equation (2).

FIRST ORDER REACTION
 If concentration of reactant X is ‘a’ at beginning of reaction
when t = 0, & if amount that has reacted after time t is
denoted by x then amount of X remaining at time t will be
(a-x).
 log (a-x) = log a – Kt/2.303
 half-life of drug is calculated by equation
t1/2 = 0.693
k

GRAPH FOR FIRST ORDER
time
log(a-x)
Slope = -k/2.303
If first order law is obeyed then a graph of log (a-x) vs time t
will give straight line with slope of –K/2.303 and an intercept
of log a at t = 0.

SECOND ORDER REACTION
 Rate of change in conc. of product and reactant is dependent
on second power of conc. of single reactant or to first powers
of the conc. of two reactants.
 Unit of second order reaction is conc.-1 time-1 and SI unit is
Lmol-1 sec-1.
 Half-life in this case is t1/2 = 1/ak.
 The equation for this second order reaction is shown below
Kt = 2.303 log b(a-x) , a ≠ b
(a-b) a(b-x)
or Kt = 1 - 1 , a = b
a-x a

GRAPH FOR SECOND ORDER
time
log b(a-x)/a(b-x)
Slope = (a-b)k/2.303

METHODS TO DETERMINE
ORDER OF REACTION
SUBSTITUTION METHOD
INITIAL RATE METHOD
HALF-LIFE DETERMINATION METHOD
SOFTWARE TOOLS FOR SECOND ORDER REACTIONS
DATA PLOTTING METHOD

METHOD TO DETERMINE OVERAGES
 STEP I: - Perform the experiment and find out
concentration of drug remaining at different time
intervals at different temperature including room
temperature. Plot the graph of concentration vs time
for different temp.
 As shown in the figure measure the slope and from
that get rate Constant K.

STEP :2 - Calculation for overages
 Plot the graph of time (Days) Vs conc. remaining.
 Extrapolate line from Y- axis, at 90% to the X- axis. The
intersect point will give shelf life.
 To maintain or increase the shelf life as per need (from a to b as
shown in fig.) draw a parallel line from Y to that of X, the
intersect point at Y- axis will give the value of overages per 100
unit.
As shown in the figure,
 The value of overages is 20%. So need to add 20 unit drug
more to preexisting formulation

Most important guidelines are
 Food and Drug Administration (FDA)
 International Conference on Harmonization (ICH)
 European Union Guidelines (EU)
 Japanese Guidelines (MHW)
 Therapeutic Good Administration (TGA) – For Australia
 Gulf Central Committee (GCC) – For Gulf Countries
 Association of South East Asian Nations (ASEAN)
 Eastern Mediterranean Region etc.

ICH GUIDLINE
What is ICH?
The International Conference on Harmonization (ICH) of
Technical Requirements for Registration of
Pharmaceuticals for Human Use is a unique project that
brings together the regulatory authorities of Europe,
Japan and the United States and experts from the
pharmaceutical industry in the three regions to discuss
scientific and technical aspects of product registration.

Objectives of ICH:
 More economical use of human, animal, and material
resources.
 Elimination of unnecessary delay in the global
development & availability of new medicines.
 Maintaining safeguards on Quality, safety & efficacy, and
regulatory obligations to protect public health.

 TOPICS OF ICH: Four Broad Categories - QSEM
 Quality (Q): Topics related to Manufacturing QA.
 Safety (S): Topics related to non-clinical pharmacology &
toxicology studies.
 Efficacy (E): Topics related to Clinical studies in humans.
 Multidisciplinary (M): Topics affecting more than one
discipline.
 Our concern is only with quality topics.
 QUALITY TOPICS: Consists of six subtopics:-
 Q1: Stability testing
 Q2: Analytical methods validation
 Q3: Impurity testing
 Q4: Pharmacopoeias
 Q5: Quality of Biotechnological products
 Q6: Specifications for new drug substances & products.
 Our concern is only Q1 (i.e. Stability testing).

SPECIFIC GUIDELINES UNDER Q1
Q1A (R2): Stability testing of new drug substances and
products.
Q1B: Photo-stability of new drug substances and
products.
Q1C: Stability testing of new dosage forms.
Q1D: Bracketing & Matrixing designs for stability testing
of new drug substances and products.
Q1E: Evaluation of Stability data.
Q1F Stability Data Package for Registration Applications in
Climatic Zones III and IV.
Q5C: Stability testing of biotechnological/biological products.

1) For Active Substance :
 Stress Testing
 Selection of Batches
 Container Closure System
 Specification
 Testing Frequency
 Storage Conditions
 Stability Commitment
 Evaluation
 Statements/ Labelling

2) For Pharmaceutical Product :
 Selection of Batches
 Container Closure System
 Specification
 Testing Frequency
 Storage Conditions
 Stability Commitment
 Evaluation
 Statements/ Labelling
 In-use stability
 Variations
 On-going Stability Studies

Stability Protocol and Report
1) Batches tested
2) General information
3) Container/closure system
4) Literature and supporting data
5) Stability-indicating analytical methods
6) Testing plan
7) Test parameters
8) Test results
9) Other requirements (post-approval commitments)
10) Conclusions

1.PROCESSING
FACTORS
 Particle size reduction
(or milling)
 Wet granulation
 Compression
 Properties of polymeric
 film
coatings
 Excipients
 Radiation
2. ENVIRONMENTAL FACTORS
2.1 Outside the dosage form
 Temperature
 Light
 Humidity
2.2 Inside the dosage form
Oxidation
Metal
PH
Ionic strength
General acid base catalysis/buffer
Packaging components
6.FACTOR OF STABILITY STUDY

 Pharmaceutics- The science of Dosage Form Design by M. E. Aulton.
(2nd edition): pg.113
 The Science & Practice of Pharmacy by Remington.(19th edition): pg.1447
 The Theory & Practice of Industrial Pharmacy by Leon Lachman, Herbet A.
Lieberman, Joseph L. Kaing.(3rd edition): pg.171
 Pharmaceutical Dosage Forms by Leon Lachman, H. A. Lieberman; Vol.1:
pg.1
 Pharmaceutical Dosage Forms & Delivery Systems by H.C. Ansel,
L.V.Allen
 P’ceutical preformulation &formulation, A practical guide by Mark
gibson

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