Goals of Preformulation

1. Establish the necessary physicochemical parameters of

a new drug substance.
2. Determine drug kinetic rate profile.
3. Develop a stability indicating assay.
4. Establish drug compatibility with common excepients.
 Goals of Preformulation

1. Establish the necessary physicochemical parameters of

a new drug substance.
2. Determine drug kinetic rate profile.
3. Develop a stability indicating assay.
4. Establish drug compatibility with common excepients.
Compatibility tests
Types of incompatibility
?
 Compatibility tests
Aim
?

Which excepient Which

Drug/Excepient
ratio
 Compatibility tests
Methods
?

Solid dosage form Liquid dosage form

FDA Guidelines
 Compatibility test for solid dosage forms
Stopper + Wax

Drug + Excepient

Room Temperature 55oC

Without water With water Without water With water

Compare to drug stored under same conditions

Compatibility test for solid dosage forms
Stopper + Wax

Drug + Excepient

Room Temperature 55oC

Visual Analytical assay Quantitative relation

examination of certain excepient
character and
interaction rate
 Compatibility test for liquid dosage forms

Aqueous solution Non-aqueous solution

Parenteral Oral
 Compatibility test for liquid dosage forms
Aqueuos solution compatibility

Parentral Oral
Drug + Excepient solution
-Heavy metals -Ethanol
-Heavy metals+chelating agent -Glycerin
-Oxygen and nitrogen atmosphere -Sucrose
-Autoclaving -Preservative
-Different blugs -Buffers
Compatibility test for liquid dosage forms
Aqueuos solution compatibility

Parentral Oral
Drug + Excepient solution

Visual Analytical
examination assay
 Compatibility tests
Drug : Excipient ratio

The preformulation screening of drug-excipient interaction

requires (1 : 1) Drug:excipient ratio, to maximize the likehood of
observing an interaction.
???
Some researchers recommend ratios of :
1:5 for diluents
3:1 for binder & disintegrants
5:1 for lubricant
10:1 for colourant
 Compatibility tests
Analytical Methods

Chromatography Vapour Accelerated

Pressure Storage Testing
Osmometry
Non-thermal Thermal
Analysis Analysis
Radio Labelled
Techniques Fluoroscence
Measurement
Spectroscopy
 Compatibility tests
Methods
Chromatography

TLC HPLC
 Compatibility tests
Methods
Chromatography

TLC HPLC
 Compatibility tests
Methods
Chromatography

TLC HPLC
Advantages :
Changes in
Evidence ofthe chromatograph such as appearance of NEW
degradation
Spots or Peak
SPOT or peaksorisolation.
change in Rf values or Rt means significant
Quantification
interaction. to obtain Kinetic data.
 Compatibility tests
Methods
Thermal Analysis

Differential scanning Thermogravimetric Isothermal

calorimetry analysis microcalorimetry

Calorimetry is the science of heat. It is about how a given material responds to

temperature changes on both the atomic and macroscopic level. It reveals
important information about the arrangement and interaction of the atoms.
Differential scanning calorimetry
(DSC)

Is a thermoanalytical technique in which the difference in

the amount of heat required to increase the temperature
of a sample and reference is measured as a function of
temperature.

For solid state

Differential scanning calorimetry
(DSC)
Applications
It detects physical transformation such as melting,
dehydration or crystallization
>- exothermic

Crystallisation Cross-Linking
(Cure)

Glass
Heat Flow

Transition

Melting

Temperature
Differential scanning calorimetry
(DSC)
Applications
It detects physical transformation such as melting,
dehydration or crystallization

Phase equilibrium Compatibility of drug

diagrams of enantiomers with excepients
Differential scanning calorimetry
(DSC)

DSC thermogram for API, Croscarmilose and physical mixture of both

Differential scanning calorimetry
(DSC)

DSC thermogram for API, Lactose and physical mixture of both

Heat conduction microcalorimetry
•Isothermal heat conduction microcalorimetry is an
analytical method allowing determination of minute
amounts of evolved or absorbed heat.
•The sensitivity is 10 000-fold higher than the sensitivity of
conventional differential scanning calorimetry (DSC).

•By microcalorimetry heat flow signals in the range of µW

are detectable.

•The rate of heat flow is proportional to the rate of the

process taking place.
Heat conduction microcalorimetry

Fig. 8. Concentration dependent drug-associated heat flow at 258C for a drug concentration
of 8.7% NEA and various concentrations of E2-hemihydrate
Heat conduction microcalorimetry
For a reaction
A+B=C+D

First order Zero order

Heat conduction microcalorimetry

20 80oC
75oC
10
Ø

Zero-order
0

-10

1 2
Time (days)
Heat conduction microcalorimetry

Applications
Heat conduction microcalorimetry detects
chemical changes. BUT it gives no direct
information about the chemical nature of the
reaction

For liquid and solid state

Heat conduction microcalorimetry

Applications

Drug stability Drug/excepient compatibility

Liquid state Solid state

-Oxidation -Kinetics
-Decomposition -crystallization
-Kinetics
 Thermogravimetric analysis
•Measures the amount and rate of change in the weight of
a material as a function of temperature or time in a
controlled atmosphere.

•Measurements are used primarily to determine the

composition of materials and to predict their thermal
stability at temperatures up to 1000°C.

•The technique can characterize materials that exhibit

weight loss or gain due to decomposition, oxidation or
dehydration.  
For solid state
 Compatibility tests
Methods
Non-thermal Analysis

FT-IR Spectroscopy X-ray diffraction

 FT-IR Spectroscopy

•Is the absorption measurement of different IR

frequencies by a sample positioned in the path of an IR
beam.
•Different functional groups absorb characteristic
frequencies of IR radiation.
•The main goal of IR spectroscopic analysis is to
determine the chemical functional groups in the sample.
FT-IR Spectroscopy
 FT-IR Spectroscopy
Common Applications

•Identification of compounds by matching spectrum of unknown

compound with reference spectrum (fingerprinting)
•Identification of functional groups in unknown substances.
•Identification of reaction components and kinetic studies of reactions
•Detection of molecular impurities or additives present in small
amounts .
•Analysis of formulations such as insecticides and copolymers
FT-IR Spectroscopy

Detects chemical
interations

For liquid and solid state

K. A.Mohammed, H. K. Ibrahim, M. M.
Ghorab, Drug Deliv, 2014.
 X-ray diffraction
•X-rays interact with crystalline substances to give a
diffraction pattern.
•The X-ray diffraction pattern of a pure substance is like a
fingerprint of the substance.
•In a mixture of substances, each produces its pattern
independently of the others.
•The powder diffraction method is thus ideally suited for
characterization and identification of polycrystalline
phases.
X-ray diffraction
 Transdermal nonaqueuos solution compatibility
-Compatibility with different excepients
-Release and permeation characteristics

In vitro In vivo

With membrane Without membrane

(ex-vivo)
Nonaqueuos solution compatibility
110
Amount released

100 Flux of oily solution release

90 Flux of solution+membrane release

90

6 12 18 24
Time (units)

Chein et al., Drug Dev Ind Pharm, 1983.

 Transdermal nonaqueuos solution compatibility
-Compatibility with different excepients
-Release and permeation characteristics

In vitro In vivo

With membrane Without membrane

(ex-vivo)

Sacrifice
Emulsion compatibility

Preformulation is very formulation oriented:

-Surfactant selection
-Calculation of surfactant amount
-Measuring CMC
-Calculating the required HLB
-pH stability profile of the surfactant in presence of other
emulsion components
Emulsion compatibility

Micro/nanoemulsion
Gel compatibility

Preformulation is very formulation oriented:

-Polymer selection
-Drug stability in the gel
Preformulation studies → expected outcomes
The product will:
•Meet specifications (assay, impurities &
dissolution rate)
•Be consistent within & between batches.
•Is palatable to the patient.
•Have optimum chemical & physical stability.
•Fewer formulations fail stability & BA studies
•Have cost effective manufacture.