the ppt gives information regarding few preformulation test which can be performed for drug.

1. PREFORMULATION STUDIES
7/26/2023 1
SUBMITTED TO:
Dr. Sajeev KB
Professor, Department of Pharmaceutics
ABMRCP, Bengaluru
SUBMITTED BY:
S Kishor kumar Singha
ACP22PHCE005
M.Pharm(1ST sem)
Department of Pharmaceutics
ABMRCP, Bengaluru

2. CONTENTS:
1. INTRODUCTION
2. OBJECTIVES OF PREFORMULATION
3. PRINCIPALAREAS FOR PREFORMULATION RESEARCH
7/26/2023 2

3. INTRODUCTION:
PREFORMULATION:
Study to characterise physical and chemical properties of drug molecule.
To develop a safe, effective and stable dosage form.
7/26/2023 3

4. OBJECTIVES OF PREFORMULATION
1. To find the necessary physicochemical properties like solubility, crystal form of new drug
substance.
2. To determine kinetic release of drug from dosage form.
3. To establish physical characteristics.
4. To establish compatibility with common excipients.
7/26/2023 4

5. PRINCIPALAREAS FOR
PREFORMULATION RESEARCH :
7/26/2023 5
PHYSICO-CHEMICAL
PROPERTIES
BULK
CHARACTERISATION
SOLUBILITY
ANALYSIS
STABILITY
ANALYSIS
• ORGANOLEPTIC
PROPERTIES.
• PARTICLE
SHAPE AND
SIZE.
• PURITY.
• SURFACE AREA.
• CRYSTALLINITY
AND
POLYMORPHISM.
• HYGROSCOPICITY.
• PARTICLE SIZE
CHARACTERIZATI
ON.
• BULK DENSITY.
• POWDER FLOW
PROPERTIES.
• IONISATION
CONSTANT, pKa.
• pH SOLUBILITY
PROFILE.
• COMMON ION
EFFECT.
• PARTITION
COEFFICIENT.
• DISSOLUTION.
• SOLID STATE
STABILITY.
• SOLUTION STATE
STABILTY.
• DRUG-EXCIPIENT
COMPATIBILITY.
• ACCELERATED
STABILITY
STUDIES.
• LONG TERM
STABILITY
STUDIES.

6. ORGANOLEPTIC PROPERTIES
7/26/2023 6
• Colour, odour, taste of the new drug must be recorded.
COLOUR ODOUR TASTE
• OFF-WHITE. • PUNGENT. • ACIDIC.
• CREAM YELLOW. • SULPUROUS. • BITTER.
• TAN. • FRUITY. • BLAND.
• SHINY. • AROMATIC. • SWEET.
• ODOURLESS

7. BULK CHARACTERISATION:
Crystallinity:
Crystal habit and internal structure of drug can affect bulk and physicochemical property of the
drug.
Crystal habit is description of the outer appearance of crystal.
Internal structure is molecular arrangement within the solid.
7/26/2023 7

8. DIFFERENT SHAPES OF CRYSTALS
7/26/2023 8

9. DIFFERENT SHAPES OF CRYSTALS:
Depending on internal structure compounds is classified as
1. Crystalline.
2. Amorphous.
Crystalline compounds are characterized by repetitious spacing of constituent
atom or molecule in 3-dimensional array.
In amorphous form atom or molecule are randomly placed.
Dissolution rates and solubility are greater for amorphous form.
7/26/2023 9

10. POLYMORPHISM
Ability of the compound to crystallize to more than one distinct crystalline
species with different internal lattice.
Polymorph are of 2 types:
1. Enantiotropic.
2. Monotropic.
7/26/2023 10

11. ANALYTICAL METHODS FOR THE
CHARACTERIZATION OF SOLID FORMS
METHOD MATERIAL REQUIRED PER SAMPLE
MICROSCOPY 1mg
HOT STAGE MICROSCOPY 1mg
DIFFERENTIAL SCANNING CALIROMETRY 2-5mg
INFRARED SPECTROSCOPY 2-20mg
X-RAY POWDER DIFFRACTION 500mg
SCANNING ELECTRON MICROSCOPY 2mg
DISSOLUTION/ SOLUBILITY ANALYSIS mg to g
7/26/2023 11

12. MICROSOPY:
Advantage :
 By this method we can study crystal morphology and difference between polymorphic form.
Disadvantage:
 This require a well trained optical crystallographer, as there are many possible crystal habit and
their appearance at different orientation.
7/26/2023 12

13. HOT STAGE MICROSCOPY:
The polarizing microscope fitted with hot stage is useful for investigating
polymorphism, melting point, transition temperatures.
Disadvantage:
 Organic molecules can degrade during the melting process.
7/26/2023 13

14. THERMALANALYSIS
Differential Scanning Calorimetry (DSC) & differential thermal analysis.
Measures heat loss and heat gain from physical or chemical changes within a
sample.
To find out the purity of the sample.
To find out the number of polymorph and to find the ratio of each polymorph.
To find out the thermal degradation of a drug or excipients.
7/26/2023 14

15. X-RAY DIFFRACTION:
Random orientation of crystal lattice in the powder causes the x-ray to scatter in
a reproducible pattern of peak intensities.
The diffraction pattern is characteristic of a specific crystalline lattice for a given
compound.
The peaks are observed which indicates crystalline powder.
No peaks are observed indicates the amorphous forms.
7/26/2023 15

16. HYGROSCOPICITY:
The degree of hygroscopicity is classified into four classes:
7/26/2023 16

17. HYGROSCOPICITY (Cont.)
Significance of hygroscopy test:
 To decide the storage condition.
 Special packaging, e.g. With desiccant.
 Moisture level of powder sample may affect the flowability.
Analytical methods used are :
 Gravimetry.
 Karl fischer titration.
 Gas chromatography.
7/26/2023 17

18. PARTICLE SIZE:
Particle size is characterized using these terms:
Very coarse, coarse, moderately coarse, fine, very fine, microfine, superfine.
Particle size can influence:
Dissolution rate.
Uniform distribution.
7/26/2023 18

19. METHODS TO DETERMINE
PARTICLE SIZE:
 SIEVING.
 MICROSCOPY.
 COULTER COUNTER.
 HIAC COUNTER.
 BRAUNER, EMMETT AND TELLER NITROGEN ADSORPTION METHOD.
7/26/2023 19

20. POWDER FLOW PROPERTIES:
Powder flow properties can be affected by change in particle size, shape & density.
The flow properties depend upon the following:
1. Force of friction.
2. Cohesion between one particle to another.
 Powder flow can be determined by:
1. Angle of repose.
2. Carr’s compressibility index.
3. Hausner’s ratio.
7/26/2023 20

21. ANGLE OF REPOSE
It is determined by the equation, tan Ꝋ = h/ r, where, Ꝋ = angle of repose, h = height of the pile,
r = radius.
7/26/2023 21
ANGLE OF REPOSE (Ꝋ) TYPE OF FLOW (AS PER USP)
25-30 EXCELLENT
31-35 GOOD
36-40 FAIR
41-45 PASSABLE
46-55 POOR
56-65 VERY POOR
≥65 VERY, VERY POOR

22. COMPRESSIBILITY INDEX AND
HAUSNER RATIO:
7/26/2023 22
CARR’S INDEX(%) =(TAPPED DENSITY – POURED DENSITY) *100
TAPPED DENSITY
HAUSNER RATIO = TAPPED DENSITY/ BULK DENSITY

23. COMPRESSIBILITY INDEX HAUSNER RATIO FLOW CHARACTER
≤10 1.00-1.11 EXCELLENT
11-15 1.12-1.18 GOOD
16-20 1.19-1.25 FAIR
21-25 1.26-1.34 PASSABLE
26-31 1.35-1.45 POOR
32-37 1.46-1.59 VERY POOR
>38 >1.60 VERY VERY POOR
7/26/2023 23
COMPRESSIBILITY INDEX AND
HAUSNER RATIO:
SCALE OF FLOWABILITY (AS PER USP)

24. SOLUBILITY STUDIES
Preformulation solubility studies include :
1. pKa Determination
2. pH Solubility profile
3. Solubilization mechanism
4. Rate of dissolution
 Analytical methods useful for solubility measurements include hplc, uv spectroscopy, gas
chromatography, fluorescence spectroscopy.
 Solubility depends on ph, temperature, ionic strength and buffer concentrations.
7/26/2023 24

25. pKa DETERMINATIONS:
It is the dissociation constant of a drug.
The unionised is lipid soluble thus permeates through lipid membrane.
The ionised substance is lipid insoluble therefore permeation is slow.
Degree of ionisation depends on pH.
7/26/2023 25

26. HENDERSON-HASSELBALCH
EQUATION
FOR ACIDIC COMPUNDS :
FOR BASIC COMPOUNDS:
7/26/2023 26
pH  pKa 
[unionized]
[ionized]
pH  pKa 
[ionized]
[unionized]

27. METHODS FOR DETERMINING pKa
OF A DRUG:
Detection of spectral change by uv spectroscopy at a range of pH.
Potentiometric titrations:
1. Maximum sensitivity for compounds with pKa In the range of 3 to 10.
 Effect of temperature on solubility:
1. The solubility process is endothermic. Increasing the solution temperature increases the drug solubility.
2. Solutes that are ionised when dissolved, the process is exothermic thus supressing the solubility.
7/26/2023 27

28. SOLUBILISATION:
1. For drug candidates with poor water solubility, preformulation studies should
include limited experiments to identify the possible mechanisms for solubilisation.
2. Means of increasing the solubility are:
(I) Addition of a cosolvent to the aqueous system e.g. Ethanol, propylene glycol and
glycerin.
(II) pH change method.
(III) Reduction of particle size.
7/26/2023 28

29. SOLUBILIZATION
IV. Hydrotrophy
V. Addition of surfactant.
VI. Complexation.
7/26/2023 29

30. PARTITION COEFFICIENT:
1. Partition coefficient is defined, as the ratio of un-ionized drug concentrations between the
organic and aqueous phases, at equilibrium.
2. It is a measurement of drug liphophilicity , the ability to cross the cell membrane.
7/26/2023 30

31. STABILITYANALYSIS:
 Quantitative assessment of chemical stability of new drug. This
involves:
1. Stability study in toxicology formulation.
2. Stability in solution state.
3. Stability in solid state.
7/26/2023 31

32. STABILITY STUDY IN
TOXICOLOGY FORMULATION:
A new drug is administered to animals through oral route either by
(i) Mixing the drug in the feed
(ii) In the form of solution
(iii) In the form of suspension in aqueous vehicle
Feed may contain water, vitamin, minerals (metal ions), enzymes and different functional groups that may severely reduce the
stability of the new drug. So stability study should be carried out in the feed and at laboratory temperature.
 For solution and suspension, the chemical stability at different temperature and pH should be checked.
For suspension-state the drug suspension is occasionally shaken to check dispersibility.
7/26/2023 32

33. SOLUTION STABILITY:
Identification of condition to form a stable solution.
Stability of a new drug may depend on:
(I) pH,
(II) IONIC STRENGTH,
(III) CO-SOLVENT,
(IV) LIGHT,
(V) TEMPERATURE,
(VI) OXYGEN.
7/26/2023 33

34. pH STABILITY STUDY :
A. Experiments to confirm decay at the extremes of ph and temperature. Three stability studies are
carried out at the following conditions:
 0.1 N HCL SOLUTION AT 90⁰C.
 SOLUTION IN WATER AT 90⁰C.
 0.1 N NAOH SOLUTION AT 90⁰C.
B. Now aq. Buffers are used to produce solutions with wide range of pH values but with constant
level of drug concentration, co solvent and ionic strength.
C. All the rate constant at a single temperature are plotted as a function of pH.
7/26/2023 34

35. IONIC STRENGTH :
The pH-stability studies should be carried out at a constant ionic strength that is compatible with body
fluids.
Ionic strength of a buffer can be calculated by
Where, mi = Molar concentration of the ion, Zi = Valency of that ion.
For computing, μ all the ionic species of the buffer solution and drugs are also taken into calculation.
7/26/2023 35

36. TEMPERATURE :
The rate constant (k) of degradation reaction of a drug varies with temperature according to arrhenius equation.
where, k = Rate constant, A = Frequency factor, Ea = Energy of activation, R = Ideal gas constant
T = Absolute temperature
Shelf life of the drug may be calculated.
If the drug is sufficiently stable, liquid formulation development may be started at once. If the drug is unstable,
further investigations may be necessary.
7/26/2023 36

37. SOLID STATE STABILITY :
 Identification of stable storage conditions for drug in the solid state and identification of compatible excipients
for a formulation.
 Solid state reactions are much slower, so the rate of appearance of decay product is measured (not the amount of
drug remaining unchanged).
 To determine the mechanism of degradation thin layer chromatography (tlc), fluorescence or uv / visible
spectroscopy may be required.
 To study polymorphic changes dsc or ir-spectroscopy is required.
 In case of surface discoloration due to oxidation or reaction with excipients, surface reflectance equipment may
be used.
7/26/2023 37

38. ROLE OF EXCIPIENTS IN DOSAGE
FORM DESIGN:
BINDERS
GLIDANTS
COLORING AGENTS
PRESERVATIVES
FLAVOURING AGENT
FILM FORMERS
DILUENTS
DISINTEGRANTS
LUBRICANTS
7/26/2023 38

39. IDEAL PROPERTIES OF EXCIPIENT:
7/26/2023 39
EXCIPIENTS
FEASIBLE
NO INTERACTION WITH
DRUG
STABLE FOR HANDLING
COST
EFFECTIVE

40. TYPES OF DRUG EXCIPIENT
INTERACTION:
1. PHYSICAL DRUG EXCIPIENT INTERACTIONS.
2. CHEMICAL DRUG EXCIPIENT INTERACTIONS.
3. BIOPHARMACEUTICAL/ PHYSIOLOGICAL DRUG EXCIPIENT
INTERACTIONS.
4. EXCIPIENT-EXCIPIENT INTERACTIONS.
7/26/2023 40

41. PHYSICAL DRUG-EXCIPIENT
INTERACTION:
Physical interactions alter the rate of dissolution, dosage uniformity, colour,
flow properties etc.
Do not involve chemical changes.
They are difficult to detect.
Physical interaction can be either beneficial or detrimental to the product
performance depending on its application.
7/26/2023 41

42. BENEFITS OF PHYSICAL DRUG-
EXCIPIENT INTERACTION :
1. Improves bioavailability of sparingly water soluble drugs. E.G: complexation.
2. Increase surface area of drugs available for dissoution. Adsorption of drugs on
excipient surface can increase the surface area of the drug .
3. Improves dissolution rate and bioavailability of hydrophobic drugs.
7/26/2023 42

43. CHEMICAL DRUG-EXCIPIENT
INTERACTION:
1. It involves the interaction of drug substance and excipient through chemical degradation
pathway.
2. Chemical interaction have delirious effect on formulation, hence they must be avoided.
3. Hydrolysis.
4. Oxidation.
5. Photolysis.
6. Polymerization.
7/26/2023 43

44. BIOPHARMACEUTICAL/ PHYSIOLOGICAL
DRUG-EXCIPIENT INTERACTION:
1. The interaction occurs between the medicine( drug and excipient) with the
body fluid.
2. The interaction have the tendency to influence the rate of absorption of drug.
3. Examples of such interaction include :
a. Premature breakdown of enteric coat.
b. Interactions due to adjunct therapy.
c. Increasein gastrointestinal motility.
7/26/2023 44

45. CONCLUSION:
1. Drug excipient compatibility study is a necessary prerequisite to the
development of drug products that are safe and stable for use.
2. Proper selection and assessment of incompatibilities between drug and
excipient during preformulation studies is of utmost importance to accomplish
the target product profile and critical quality attributes.
3. In order to avoid stability problems encountered during drug development
and post commercialisation.
7/26/2023 45

46. REFERENCE :
1. Theory and practice of industrial pharmacy, leon lachman, herbert a. Leiberman, joseph l.
Kanig.
2. Drug-Excipient Interactions: An Overview on Mechanisms and Effects on Drug Stability and
Bioavailability, Derar M. Omari, Yazan Akkam, Assayed sallam.
3. Drug-excipient interactions, Patrick Crowley, Dr Luigi G Martini.
4. www.slideshare.com
7/26/2023 46