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.
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
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
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.
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.
