The document provides an overview of pre-formulation, which involves determining the physicochemical properties of a drug substance prior to developing a dosage form. It discusses the goals of pre-formulation to formulate an efficacious dosage form with good bioavailability. The protocol involves characterizing the physical, chemical, solubility, stability and compatibility properties of the drug. Key aspects covered include polymorphism, hygroscopicity, particle size, solubility, dissolution, stability in solution and solid state, and compatibility with excipients. The information guides subsequent formulation development.

1. Presenter:
Amruta Balekundri
M.Pharm 1st semester,
Department of Pharmaceutical
Quality Assurance,
KLE College of Pharmacy,
Belagavi.
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2. Contents:
• Definition
• Goals of pre-formulations
• Protocol of pre-formulation
• Applications
• Conclusions
• References
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3. Pre-formulation:
• Pre-formulation is branch of Pharmaceutical science that
utilizes biopharmaceutical principles in the determination of
physicochemical properties of the drug substance.
• Prior to the development of any dosage form new drug , it is
essential that 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.
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4. Goals Of Pre-formulations:
• To formulate an elegant, safe, efficacious dosage form with
good bioavailability.
• To formulate new dosage form of already existing drug.
• Determination of all the properties of drug and the best
suitable dosage form for the drug molecule.
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5. Protocol of pre-formulations:
• Pre-formulation protocol is a plan or blueprint as how the pre-
formulation experiments/procedures are designed.
• A written plan from starting of the procedures to be conducted
till the decision points on what constitutes acceptable results.
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6. Protocol of pre-formulations:
Pre-formulations
Physico-
chemical
properties
Bulk
characterization
Solubility
analysis
Stability analysis
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7. Physico-chemical characteristic:
• Physical and chemical reactions involved in the formation of
or changes in the structure of atoms and molecules and their
interaction affecting the drug kinetics.
• Investigation of physical and chemical properties of a drug
substance - alone and or when combined with excipients is
crucial during pre-formulation studies.
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8. Physico-chemical characteristic:
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Physico –chemical
characteristics
Organoleptic
characters
Particle size & shape
Purity
Surface area

9. Organo-leptic characters:
• Organoleptic Properties are those properties which are
evaluated after an impression on the organs of sense”.
• It refers to the evaluation of drugs by properties like –color,
odors, taste, size, shape and special features like touch, texture,
etc.
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10. Particle size & shape:
• It affects the bulk flow, formulation homogeneity of the drug
particles.
• Various chemical and physical properties of drug substances are
affected by their particle size distribution and shapes .The effect is
not only on the physical properties of solid drugs but also , on their
biopharmaceutical behavior .
• In case of tablets, size and shape influence the flow and the mixing
efficiency of powders and granules. Size can also be a factor in
stability.
• Fine materials are relatively more open to attack from atmospheric
oxygen, the humidity, and interacting excipient than are coarse
materials.
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11. Purity:
• Designed to estimate the levels of all known & significant
impurities & contaminants in the drug substance under
evaluation.
• Purity test is performed in an analytical research &
development group.
• Occasionally, an impurity can affect stability.
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12. Surface area:
• Particle size & surface area are inversely related to each other.
• Smaller the drug particle, greater the surface area.
• As the particle decreases the surface area increase and in turn
the bioavailability increases up to a point after which it again
decreases.
• Specific surface is defined as the surface area per unit weight
(Sw) or unit volume (Sv) of the material
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13. Bulk characterization:
Bulk characterization
Crystallinity &
Polymorphism
Hygroscopicity
Particle size
characterization
Bulk density
Powder flow properties
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14. Crystallinity& Polymorphism :
• The crystal habit describes the outer appearance of crystals
( platy, equant, needle, bladed, etc.) and internal structure
arrangement. Compounds have several different habits,
depending on the environment for growing crystals.
• polymorphism is the ability of the compound to crystallize as
more than one distinct crystalline species with different
internal structure.
• Formation of different polymorphs depends on solvents,
temperature, pressure, rate of cooling, etc.
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15. Crystallinity& Polymorphism :
• Polymorphic transitions can also occur during milling,
granulating, drying and compressing operations.
• Different polymorphs vary in physical properties such as
dissolution, solid-state stability, compatibility, etc
• Polymorphs
Enatiotrophic :sulphur
Monotrophic : Glyceryl stearate
Transition temparature :identical free energy
Stable polymorph in room temperature with stability profile
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16. Hygroscopicity:
• Hygroscopicity: - It is the tendency of material to absorb
moisture from atmosphere & be dynamic equilibrium with
water in the atmosphere.
• Deliquescent: - It is the hygroscopic substance which absorb
moisture from air and they can be liquefied by partially or
wholly forming solution.
• Efflorescent: - A substance which loses water to form a lower
hydrate or become anhydrous is termed as efflorescent.
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18. Particle size characterization:
Powder flow:
1. Free flowing
2. Non free flowing or cohesive
• Particle size: Study of particle size give an information about
solubility, dissolution rate, absorption, etc. particle size and
surface area of a solid drug are inversely related to each
other.eg: Griseofulvin
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19. Particle size characterization:
Powder flow property:
• The flow properties of a powder will determine the nature and
quantity of excipients needed to prepare a compressed or a
powder dosage form.
• This refers mainly to factors such as the ability to process the
powder through machines.
Compressibility:
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20. Bulk density :
• Bulk density is defined as total mass per unit volume.
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21. Powder flow properties:
• Powders may be free-flowing or cohesive (Sticky).
• Angle of repose:
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22. Solubility analysis:
Solubility analysis
Ionization constant pKa
pH solubility profile
Common ion effect
Thermal effects
Partition co-efficient
Solubilization
Dissolution
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23. Ionization constant pKa:
• pKa is the dissociation constant of a drug.
• The non ionized substances is lipid soluble thus dissolve in
lipid material of the membrane and transported by passive
diffusion.
• Where as, the ionized substances is a lipid insoluble therefore
permeation is slow.
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24. Ionization constant pKa:
The percentage of ionization can be calculated as:
For Acidic compounds:
% ionized = 100/ 1+ antilog (pKa – pH)
For Basic compounds:
% ionized = 100/ 1+ antilog (pH – pKa)
Degree of ionization depends up on the pH:
• for acidic drugs pKa ranges from 3-7.5.
• for basic drugs pKa ranges from 7-11.
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25. pH solubility profile:
• The solubility of acidic or basic drug will show differences in
solubility with changes in pH.
• The solubility of an acidic or basic drug depends on the pKa of the
ionizing functional group and the intrinsic solubilities for both the
ionized and unionized forms.
• The relationship between solubility of the acidic drug and pH is
given by the equation
pH= pKa +log [Cs]/[Ca]
Where pKa =negative logarithm of the ionization constant of the acid .
[Cs]= molar concentration of the salt form in water
[Ca ] = molar concentration of free acid in water
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26. Common ion effect:
• If salt of weak acid or weak base is added to the solution of
acid or base resp. dissociation of acid or base is diminished
further.
• E.g. the addition of sod. Acetate to sol. of acetic acid
suppresses the dissociation of acetic acid.
E.g. CH3COOH-----H+ +CH3COO
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27. Thermal effects:
• The solubility of a solute in a solvent is dependent on
temperature, nature of solute and nature of solvent.
• Heat of solution represents the heat released or absorbed when
a mole of solute is dissolved in a large quantity of solvent.
• Most of the substances are endothermic, absorbing heat in the
process of dissolution.
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28. Partition co-efficient:
• It is an ratio of Unionized drug distributed between organic &
aqueous phase at equilibrium.
• Po/w = (Coil/C water)equilibrium
• Partition Coefficient study is useful in the A.D.M.E
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29. Solubilization:
• Solubilization an important property of association colloids in
solution is an ability of the micelles to increase the solubility
of material that normally insoluble or only slightly soluble in
the dispersion medium used this phenomenon known as
Solubilization.
• Some techniques like :
Solubilization by Surfactants,
Solubilization by Co-solvents.
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30. Dissolution:
• DISSOLUTION It is controlled by several physicochemical
properties- chemical form, crystal habit, particle size,
solubility, surface area and wetting properties.
• Noyes-Whitney eqn.
dC / dt= AD (Cs-C)/hV
Where, dC = Dissolution rate dT
A = surface area of dissolving solid
D = diffusion coefficient
H = diffusion layer thickness
C = solute concentration in the bulk medium
V = volume of dissolution medium
Cs = solute concentration in diffusion layer
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31. Stability analysis:
Stability analysis
Solution stability
Solid state stability
compatibility
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32. Solution stability:
• As compared with the dry form, the degradation is much rapid
in solution form. It is important ascertain that the drug doesn’t
degrade when exposed to GI fluid.
• The pH based stability study, using different stimulator GI
condition can be designed.
• A poor solution stability of drug may urge the formulator to
choose a less soluble salt form, provided the bioavailability is
not compromised .
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33. Solid state stability:
• For identification of stable storage condition .
• Also for identification of compatible excipient for a
formulation.
• Extent a product retains within specified limits and through its
period of storage and use.
• Stability studies conducted in the pre-formulation phase:
Solid-state of the drug alone
Solution phase
With the expected excipients
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34. Compatibility:
• The knowledge of drug excipients interaction is useful for the
formulation to select appropriate excipients.
• The described pre-formulation screening of drug excipients
interaction requires only 5mg of drug in a 50% mixture with
the excipients to maximize the likelihood of obscuring an
interaction.
• Mixtures should be examined under nitrogen to ultimate
oxidation and paralytic effect at a standard heating rate on
DSC, over a temperature range, which will encompass any
thermal changes due to both the drug and appearance or
disappearance one or more peaks in themogrames of drug
excipient mixtures are considered of indication of interaction.
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35. Applications:
Pre-formulation studies begins or shall be updated:
• Immediately after the synthesis and initial toxicity screening
of a new drug.
• When a newly synthesized drug shows pharmacological
evidence that requires further evaluation in man.
• When formulation and dosage form changes are required.
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36. Conclusion:
Pre-formulation studies have a significant part to play in
anticipating formulation problems and identifying logical path
in both liquid and solid dosage form technology.
By comparing the physicochemical properties of each drug
candidate with in a therapeutic group, the pre-formulation
scientist can assist:
• The synthetic chemist to identify the optimum molecule,
• Provide the biologist with suitable vehicles to elicit
pharmacological response .
• Advise the bulk chemist about the selection and production of
the best salt with appropriate particle size and morphology for
subsequent processing.
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37. References:
• Leon Lachman, Liberman. The theory and practice of
Industrial pharmacy, Edn 4. CBS publishing house, New
Delhi.2013 p:217-307.
• Brahmankar D.M, Jaiswal BS. Biopharmaceutics and
pharmacokinetics a Treatise, Edn 2. Vallabh Prakashan,
Nagpur. 2009; p: 37-45.
• www.authorstream.com
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