This document discusses pre-formulation studies, which involve characterizing physicochemical properties of drug substances to provide information useful for developing stable and bioavailable dosage forms. Key aspects covered include determining drug degradation pathways, solubility, hygroscopicity, polymorphism, and thermal properties. The goal of pre-formulation is to understand factors influencing drug performance, stability, bioavailability, and dosage form development.

1. Pre-formulation
Dr. Sanjeev Kumar, Associate Professor
Guru Gobind Singh College of Pharmacy
Yamuna Nagar -135001
India

2. Z to A Approach
 Preformulation is to provide and understand
information regarding:-
 The degradation process of the drug candidate
 Any adverse conditions relevant to the drug
 Bioavailability Estimation of the drug.
 To control the Release rate
 Determination of Toxicity.

3. Z to A Approach
 Impact of approach
 It gives the directions for the development of
formulation in choice of drug form, excipients,
composition, physical structure,
 Helps in adjustment of pharmacokinetics and
biopharmaceutical properties
support for PAT (process analytical technology).
The overall objective of preformulation studies is to
generate information useful in developing stable and
bioavailable and sustained release dosage forms which
can be mass produced.

4. Pre-formulation studies
 Certain fundamental physical & chemical
properties of drug powder are determined.
 This information may dictate many of
subsequent event & approaches in formulation
development.
 This first learning phase is called as pre-
formulation.

5. Objective
 These studies focus on those physicochemical
properties of the new compound that could
affect:-
 Drug performance
 Stability Studies
 Bioavailability and
 Development of an efficacious dosage form

6. Organoleptic Properties
Color Odour Taste
Off-white Pungent Acidic
Cream-yellow Sulfurous Bitter
Shiny Fruity Sweet
Aromatic Tasteless
Odorless Tasteless

7. Bulk Characterization
 Crystallinity and Polymorphism
 Hygroscopicity
 Fine Particle Characterization
 Bulk density
 Powder flow properties

8. Difference Between Crystalline and
Amorphous Form
Crystalline forms Amorphous forms
(i) Crystalline forms have fixed internal
structure
(ii) These are more stable than its
amorphous forms
(iii) Such form has lesser solubility than
its amorphous form
(iv) Crystalline form has lesser tendency
to change its form during storage.
(i) Amorphous forms do not have any
fixed internal structure
(ii) It has higher thermodynamic energy
than its crystalline form, These are less
stable than its crystalline forms
(iii) Amorphous forms have greater
solubility than its crystalline forms
(iv) Amorphous tend to revert to more
stable forms during storage.

9. Polymorphism
 Polymorphism: the ability of a compound to crystallize
as more than one distinct crystalline species with different
internal lattices.
 e.g.: Chloramphenicol Palmitate exist in three crystalline
polymorphic forms.
 Enantiotropic Polymorphs: Which can be reversibly
changed into another form by altering the temperature or
pressure e.g. Sulphur.
 Monotropic Polymorphs: Which is unstable at all
temperature and pressure e.g. Glyceryl Sterates.
 Amorphous forms are typically prepared by
Rapid Precipitation
Lyophilisation
Rapid cooling of liquid melts

10. Hygroscopicity
 Tendency to adsorb atmospheric moisture.
Adsorption and Equilibrium moisture content can depends
upon:-
Atmospheric Humidity
Temperature
Surface Area
Exposure
Analytical methods: Gravimetry, TGA, Karl Fisher titration,
gas chromatography.

11. Powder Flow Properties
% Compressibility Flowability of
Pharmaceutical Excipients
5-10 Excellent
12-16 Good
18-21 Fair Passable
23-35 Poor
33-38 Very Poor
< 40 Very Very Poor

12. Powder Flow Properties
Material % Compressibility Flowability
Celutab 11 Excellent
Emcompress 15 Excellent
Star X-1500 19 Fair-Passable
Lactose monohydrate 19 Fair-Passable
Maize Starch 26 Poor
Dicalcium Phosphate
Dihydrate (Coarse)
27 Poor
Magnesium Stearate 31 Poor
Titanium dioxide 34 Very Poor
Dicalcium Phosphate,
Dihydrate (fine)
41 Very, Very poor
Talc 49 Very, Very poor

13. Analytical Methods for
Characterization of Solid Forms
Method Material required per sample
Microscopy
Hot stage microscopy
Differential Scanning
Calorimetry (DSC)
Differential Thermal Analysis
(DTA)
Thermo gravimetric Analysis
Infrared Spectroscopy
X-ray Powder Diffraction
Scanning Electron Microscopy
Dissolution / Solubility Analysis
1 mg
1 mg
2 – 5 mg
2 – 5 mg
10 mg
2 – 20 mg
500 mg
2 mg
mg to gm

14. Thermal Analysis
 DSC (Differential Scanning Calorimetry)
 DTA (Differential Thermal Analysis)
 TGA (Thermogravimetric Analysis)

15. Differential Scanning Calorimetry

16. X-Ray Diffraction Study

17. Solubility Analysis
Solubility analysis
Ionization constant – pKa
pH solubility profile
 Thermal effects
 Solubilization
 Partition coefficient
 Dissolution

18. BCS Classification System

19. Description of Solubility’s
Description Approximate weight of solvent
(g) necessary to dissolve 1g of
the solute
Very Soluble <1
Freely Soluble 1-10
Soluble 10-30
Sparingly Soluble 30-100
Very Slightly Soluble 100-1000
Practically Insoluble >10000

20. Partition Coefficient
 To measure the drug’s lipophilicity and its ability to
cross the cell membrane is the oil/water coefficient
(octanol/water)
 Po/w = Co/w /Cwater
 The lipophilic/hydrophilic balance has been shown to
be contributing factor for the bioavailability
 It characterizing the nature of the drug, it is lipophilic
or hydrophilic

21. Handerson- Hasselbach Equation
 For Weak Acids
pH=pKa+log Ionize Drug Conc./Unionize Drug Conc
 For Weak Bases
pH=pKa +log Unionized drug Conc./ Ionized Drug
Conc.

22. Lipophilicity and Drug Absorption
 pKa of a drug that determines the degree of ionization at a
particular pH and that only the unionized drug. If
sufficiently lipid soluble is absorbed into the systemic
circulation.
 If the drug exists in the unionized form, it will be poorly
absorbed it has poor lipid solubility or low K o/w value.
 The drug should have sufficient aqueous solubility's to
dissolve in the fluid at the absorption site and high lipid
solubility enough to facilitate the drug in the lipoid bio
membrane and into the systemic circulation.

23. Dissolution
 Dissolution: It is a process in which a solid substance
get soluble in a given solvent i.e. mass transfer from
the solid surface to the liquid phase.
 Diffusion Layer Model: This is the most common
theory for dissolution. Here, the process of
dissolution of solid particles in a liquid, in the
absence of reactive or chemical forces, consists of
two consecutive steps.

24. Diffusion Layer Model

25. Noyes- Whitney equation
dc/dt = K (Cs - Cb)
 dc/dt= dissolution rate of the drug
 K= dissolutional rate Constant (D/h)
 Cs= Concentration of drug in stagnant layer
 Cb= Concentration of the drug in the bulk of the
solution at time ‘t’.
 D = Diffusion coefficient (square cm/ sec) of the
drug in solvent (a measure of how fast the drug
molecules move or diffuse through the
solvent.
 h = Thickness of the diffusion layer ( >0.05 mm
thick).

26. Diffusion Coefficient (D)
Diffusion Coefficient (D)
Increases Value
Increase Dissolution
Decreases when the viscosity of the dissolution
media is increase

27. Surface Area of Solid Drug (A)
Surface Area of the Drug (A)
Increases in Surface Area Increase in Dissolution
Micronization Increases the Surface Area

28. Partition Coefficient (K o/w)
Partition Coefficient (K o/w)
Higher the value
Increase in the Hydrophilicity
Increase the Dissolution

29. Concentration Gradient (Cs-Cb)
Concentration Gradient (Cs-Cb)
Greater the Concentration Gradient
Increases the drug dissolution
Increases by drug solubility and volume of
dissolution medium

30. Thickness of the Stagnant Layer
Thickness of the Stagnant Layer
More the thickness
Decrease the diffusion and dissolution
Increases by agitation

31. Drug pKa and GIT pH Hypothesis
For Acidic Drugs
Very Weak Acids(pKa>8)
Unionized at all pH
Absorption is Rapid & independent of GIT pH
e.g. Phenytoin, Ethosuximide, Several Barbiturates.

32. For Acidic Drugs
 Weak Acids(pKa= 2.5-7.5)
Absorption is pH dependent
Better absorbed from acidic condition (Stomach)
largely exist in Unionized form (pH>pKa)
e.g. NSAIDS- Aspirin, Ibuprofen, Phenylbutazone,
Penicillin analogs.

33. For Acidic Drugs Stronger Acids
 For Acidic Drugs
Stronger Acids(pKa< 2.5)
Ionized in the entire pH range of the GIT
Remains poorly Absorbed
e.g. Cromolyn Sodium.

34. For Basic Drugs Very Weak Bases
 Very Weak Bases(pKa<5)
Unionized at all pH
Absorption is Rapid & independent of GIT pH
e.g. Benzodiazapines- Diazapam, Oxazepam,
Nitrazepam

35. For Basic Drugs Weak Bases
 Weak Bases(pKa=5-11)
 Absorption is pH dependent
Better Absorption from Alkaline Condition (Intestine)
Largely exist in unionized form.
e.g. Morphine Analogs, Chloroquine, Imipramine,
Amitryptiline

36. For Basic Drugs
 Stronger Bases (pKa>11.0)
Ionized in the entire pH range of the GIT
Remains poorly Absorbed
e.g. Mecamylamine, Guanethidine.

37. Solution Stability
Identification of conditions necessary to form a stable
solution.
 Effect of pH
 Ionic strength
 Co solvent
 Light
 Temperature
 Oxygen

38. Solid State Stability
 Analytic data from studies as HPLC, TLC, Florescence, or
UV/Visible spectroscopy may be required to determine
precisely the kinetics of decay product
 And to establish a room temperature shelf life for the drug
candidate
 Conditions for evaluation of solid state stability are
directly exposed the formulation to a variety of
temperature, humidities and light intensities.