preformulation concepts, drug excipient interactions different methods

1. Preformulation Concepts
Drug excipient interactions different
Methods
Presented By;
Vamshi Pradeep N
M pharm
department of pharmaceutics

2. Preformulation Concepts
Almost all drugs are marketed as tablets, capsules or both. Prior to the
development of these major dosage forms, it is essential that certain
fundamental, physical and chemical properties of the drug molecule and
other properties of the drug powder are determined.
This first learning phase is known Preformulation
Definition:-
It can be defined as an investigation of physical and chemical properties of a
drug substance - alone and or when combined with excipients.

3. Objective
 to generate information useful to the formulation in developing most stable
and bioavailable dosage form that can be produced.
Determine kinetic rate profile.
Establish physical characteristics.
Establish compatibility with common excipients.
Provide insights into how drug products should be processed and stored to
ensure their quality.
To develop an optimal drug delivery system

4. This data collection include information such as:
•Gross particle size
• Melting point
• Infrared analysis
•Thin-layer chromatographic purity
•And other characteristics
These data are useful in guiding, and becoming part of, the main body of
preformulation work.

5. Drug excipient interactions
Changes in the physical, chemical or therapeutic properties of a
dosage form resulting from the interaction of the API with excipients
or other components of the drug product.
An incompatibility in dosage form can result in any of the following
changes:
•change in colour/appearance
• loss in mechanical properties (eg, tablet hardness)
•changes to dissolution performance
•physical form conversion
•loss through sublimation
•decrease in potency
•increase in degradation products.

6. The drug-excipients interactions can be broadly
classified as
1. Physical interactions
2. Chemical interactions
3. Physiological/biopharmaceutical interactions

7. 1. Physical interactions
•These types of interactions are quite common but are very difficult to detect
in dosage forms.
•Drug substances and excipients interact without undergoing changes
involving breaking or formation of new bonds.
•The components of the drug product retain their chemical structure but
undergo changes which alter their physical properties.
•Physical interactions may result in changes in dosage uniformity, colour,
odour, flow properties, solubility, sedimentation rate, dissolution rate etc
Ex , physical interaction between an API and an excipient is that between
primary amine drugs and microcrystalline cellulose.

8. 2. Chemical interactions
• This involves the interaction of drug substance and excipient
through chemical degradation pathway.
• The formulation undergoes a chemical reaction in which the
constituent atoms are rearranged via bond breakage and bond
formation to produce an unstable chemical entity.
• Changes in the study samples are analyzed by a chromatographic-
based assessment or by any other analytical method.
Ex,
1. Surfactants like TWEEN 180 and other non ionic surfactants
undergoes OXIDATION and leads to degradation of proteins.
2. Co-solvent like propylene-glycol leads to HEMOLYSIS with
nicotinamide and dimethylisosorbide.

9. 3. Physiological/Biopharmaceutical Drug-excipient
Interactions
•These occurs after the drug product has been administered to the patient.
• Excipients are included in a formulation specifically because they
interact with the physiological fluids and function in certain ways e.g.,
disintegrants in immediate release tablets and capsule formulations

10. Methods for drug excipient interactions
The drug excipient compatibility studies are carried out with an
intent to identify, quantify and predict potential interactions
(physicalor chemical) along with the impact of these interactions on
the manufacturability, quality and performance of the final drug
product.
1.Thermal techniques.
2. Spectroscopic techniques.
3. Chromatographic techniques.

11. 1) Thermal techniques.
• The physicochemical properties of drug substances are measured as a
function of temperature.
• In this method, the test samples are subjected to a controlled
temperature over a given period of time.
a) Differential Scanning Calorimetry (DSC)
b) Isothermal Microcalorimetry
c) Differential Thermal Analysis (DTA)
Advantages
 Requires of short time of analysis
 Low sample consumption
 Provides useful indications of any potential incompatibility.
 It gives meaningful results without requirement of multiple sample
preparations.

12. a. Differential Scanning Calorimetry (DSC)
In this technique, the DSC curves of pure samples are compared to
that obtained from 50% mixture of the drug and excipient (usually
5mg of the drug in a ratio of 1:1 with the excipient).
It is assumed that the thermal properties (melting point, change in
enthalpy, etc.) of blends are the sum of the individual components if
the components are compatible with each other.
An absence, 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
indicates incompatibility.

13. Advantages of DCS:
■Requires of short time of analysis.
■ Low sample consumption.
■ Provides useful indications of any potential incompatibility.
Limitations of DSC:
■Conclusions based on DSC results alone may be misleading and
have to be interpreted carefully.
■ DSC cannot be used if thermal changes are very small.
■ DSC cannot detect the incompatibilities which might occur after
long-term storage

14. b. Isothermal microcalorimetry
➤This is an extremely sensitive and invaluable tool used to
determine drug-excipient incompatibilities. It measures minute
amounts of heat emitted or absorbed by a sample in a variety of
processes.
➤In a typical drug-excipient compatibility study, a solution,
suspension, or solid mixture of drug substance and excipient is
placed in the calorimeter and the thermal activity (heat gained
or evolved) at a constant temperature is monitored.

15. Advantages of Isothermal microcalorimetry
■Samples are not heated, and so the changes are observed as it might
typically occur at ambient conditions.
■ It is sensitive to small changes in heat gained or evolved, thus small
samples, or slow processes, may be investigated.
■ It gives meaningful results without requirement of multiple sample
preparations.
■ Does not require long storage times.

16. C. Differential Thermal Analysis (DTA)
It is an analytical technique in which the changes in temperature
between a test sample and an inert reference under controlled and
identical conditions is used to identify and quantitatively analyze the
chemical composition of a substance.
When the test sample and inert reference are heated to a sufficient
temperature, the thermal changes in the test sample which lead to the
absorption or emission of heat can be detected relative to the inert
reference (control).
The differences in temperature are then plotted against time, or against
temperature.

17. Advantages of Differential Thermal Analysis
•DTA technique yield data that are considerably more fundamental in
nature.
• Enthalpy change (under a DTA peak) is not affected by the heat capacity
of the sample.

18. 2. Spectroscopic techniques.
a) Vibrational Spectroscopy
b) Flourescence spectroscopy / Fluorometry
a) Vibrational Spectroscopy
 Using this method, information on the molecular structure and
environment of organic compounds are generated.
 These vibrations are commonly studied by infrared and Raman
spectroscopies.
b) Flourescence spectroscopy / Fluorometry
Analyzes fluorescence properties of samples in order to provide
information regarding their concentration and molecular environments

19. The spectra obtained are indicative of the nature of chemical bonds
present in the test sample, and when pieced together can be used to
identify the chemical structure or composition of a given sample.
Fluorescence spectroscopy has also been used in:
1. Carrying out limit test where the impurities are fluorescent or can
simply be rendered fluorescent.
2. Determination of fluorescent drugs in low dose formulations
containing non- fluorescent excipients.
3. Studying the binding of drugs to components in complex
formulations and measuring small amount of drugs and for studying
drug-protein binding in bioanalysis.

20. 3. Chromatographic techniques
Chromatography is an analytical technique frequently used in
pharmaceutical research for separating sample mixture into its individual
components.
a) THIN LAYERCHROMATOGRAPHY (TLC)
 TLC is widely used in drug- excipient compatibility study as a
confirmative test of compatibility after performing DSC.
 An excipient is considered to be potentially compatible with the drug
substance if the spots produced have identical Rf value

21. References :
1. Lachman/Lieberman's "The Theory and Practice Of
IndustrialPharmacy" Fourth Edition 2013.
2. Modern Pharmaceutics Fourth Edition, Revised and Expanded,
Edited By G.S.Banker & C.T.Rhodes, Marcel Dekker pg387-389.
3. Nishath Fathima, Tirunagari Mamatha, Husna Kanwal Qureshi,
Nandagopal Anitha and Jangala Venkateswara Rao (2011). Drug-
excipient interaction and its importance in dosage form
development. Journal of Applied Pharmaceutical Science 01 (06);
2011: 66-71

22. 4. Chaurasia G. (2016). A Review on Pharmaceutical Preformulation
Studies in Formulation and Development of New Drug Molecules.
International Journal of Pharmaceutical Science and research, 7(6):
2313-2320.
5. https://www.pharmapproach.com/drug-excipient-
compatibility-studies/

23. Thank You