Preformulation

PreformulationPreformulation 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 preformulation.

DEFINITION:-Investigation of physico-chemical properties of the new drug compound that could affect drug performance and development of an efficacious dosage form.Characterization of physical, chemical Characterization of physical, chemical

and mechanical properties of new drug and mechanical properties of new drug molecule in order to develop safe, effective molecule in order to develop safe, effective , and stable dosage form., and stable dosage form.

GOALS OF PREFORMULATIONTo 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.

Outline of principal areas of preformulation research

Principal areas

Physico-chemical

propertiesBulk

characterisation

Stability analysis

Solubility analysisOrganolepti

c propertiesParticle size and shape

Purity

Surface area

Crystallinity and polimorphism Hygroscopicity

Particle size characterizationBulk densityPowder flow properties

Ionization constant pkaPH solubility profileCommon ion effect Thermal effects

solubilizationPartition co-efficient

Dissolution

Solution stability Solid state stability

Bulk stability

Compatibility

PHYSICOCHEMICAL PROPERTIESBULK PROPERTIES

Bulk properties of the solid form such as crystallinity, polymorphism, particle size, powder flow property, and surface characteristics are likely to change during process development.

CRYSTALINITYThe 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 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.

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

PolymorphsEnatiotrophic :sulphur Monotrophic : Glyceryl stearate Transition temparature :identical free energy Stable polymorph in room temperature with

stability profile

HYGROSCOPICITYThe tendency of a solid to take up water from the atmosphere, as it is subjected to a controlled RH program under isothermal condition i.e. hygroscopicity.

Classified based on the amount of rate of water uptake when a solid is exposed to controlled RH value at a specified temperature. Deliquesent material : NaCl

Particle CharacterizationPowder Flow The pharmaceutical powders are classified as --- FREE FLOWING COHESIVE OR NON FREE FLOWING

The powder flow are affected by the changes in – Density Particle Size Shape Free flowing drug may become cohesive and Electrostatic Charge necessitates an entirely new formulation strategy Adsorbed Moisture

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

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.

Several rates of flow (g/sec) determinations at each of variety of orifice sizes (1/8 to ½ inches) should be made.

Greater the standard deviation between multiple flow rate measurements greater is the weight variation in products produced from the powder.

It was found that the dependence of flow rate (w) on the true particle density(ρ),gravity(g), orifice diameter(D) by

D= A (4w/60πρ√g)^1/n A and n are constants dependent upon material and particle size

Other measures of free flowing powders is COMPRESSIBILITY. %compressibility=(ρ1-ρ0)/ρ1 Angle of repose is not much useful as lack of precision

Solubility analysis The solubility of every new drug must be

determined as a function of pH over the physiological pH range of 1 - 8

Preformulation solubility studies includepKa determinationpH solubility profile Temperature dependenceSolubility productsSolubilization mechanismsRate of dissolution

Determination of Solubility Semiquantitative determination:

Solvent(fixed volume)

Adding solute in smallincremental amounts

Vigorously shaking

Undissolvedsolute particles ?

Examinevisually

YesNo

Total amountadded upEstimated solubility

Accurately Quantitative determination:

Excess drug powder150 mg/ml (15 %)+ solvent

Ampul/vial(2-5 ml)

Shaking at constant temperature (25 or 37 oC)

2 - 8 oC ?

Membrane filter0.45 m

Determine the drugconcentration in the

filtrate


filtrate


filtrate



Sameconcentration ?

The first few ml’s of the filtrates should be discarded due to possible filter adsorption

Solubility

48 hr

72 hr

? hr

Drug pKa / Ionization at physiological pH pKa is the dissociation constant of a drug.

The nonionized 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.

The percentage of ionization can be calculated as …

For Acidic compounds:

For Basic compounds:

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.

% ionized = 100/ 1+ antilog (pKa – pH)

% ionized = 100/ 1+ antilog (pH – pKa)

pH-Solubility ProfileExcess drug

powder

Stir in beakerwith distilled

water

Continuousstirring of

suspension

Addacid/base

MeasurepH of

suspension

Determine theconcentration

of drug in the filtrate

SOLUBILITY pH

Common Ion Effect

Effect of TemperatureThe 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.

Applications:

Pharmaceutical solutions must be administered at or near

room temperature. So, it is more important factor for

product storage than the formulation.

To increase the solubility of sparingly soluble solute.

To increase the stability by reducing the moisture content.

Preformulation

Science

Transcript of Preformulation