Kinetics and Stability Studies I Flashcards
Dr. Salako
Define pre-formulation studies.
These are the studies done to determine and understand certain fundamental physical and chemical properties of the drug molecules prior to formulation.
What are physical properties?
These are characteristics that distinguish one substance from another which can be observed without any change to the sample’s chemical identity.
Physical properties can be divided into three:
i. Organoleptic characterisation
ii. Bulk characterisation
iii. Solubility properties
What are the properties involved in bulk characterisation
i. Solid state characteristics: Particle size, particle size distribution, particle shape etc. Particle size affects bioavailability (e.g. Griseofulvin) When there are large differences in size between active ingredients and excipients, de-mixing effects can occur making thorough mixing difficult
ii. Density: Bulk density, tapped density, granule density. The density of granules may affect compressibility, tablet porosity, disintegration
iii. Flow properties: The relative movement of particles along neighboring particles or along the surface of container.
Powder flow characteristics are essential for a successful tableting process, effective mixing and satisfactory weight uniformity.
iv. Crystallinity: The crystal habit and internal structure of drugs can have an effect on bulk characteristics and physicochemical properties of drug molecules.
Crystal habit describes the external shape of a crystal, whereas internal structure refers to the definite arrangement of molecules inside the crystal lattice. The degree of crystallinity can affect the hardness, density, diffusion and absorption of drugs
v. Polymorphism: This property is refers to drug substances which can exist in more than one crystalline form with different space lattice arrangements. e.g. Chroramphenicol A, c and B(most stable)
vi. Hygroscopicity: refers to a substance’s tendency to adsorb atmospheric moisture. Adsorption and moisture content is dependent on the atmospheric humidity, temperature, surface area, exposure and the mechanism of moisture uptake.
vii. Drug-excipient compatibility: The physical interactions between the API and excipients may lead to changes in the organoleptic properties, polymorphic forms, crystallization behavior, or drug-release and stability profiles.
Solid Dense Flowing Crystals Pollute High Drug-excipient compatibility
What are the factors that affect the flow properties of a powder?
i. Particle size:Very fine particles have attractive forces like Van Der Waals, surface tension and electrostatics which results in cohesion of powder and poor powder flow properties.
ii. Density: The higher the ratio between tapped and bulk density (Hausner ratio), the more cohesive is the powder, and the lower the flowability.
iii. Particle surface and shape:Smooth surface particles have high flowability and rough surface particles have poor flowability. Flat and elongated particles raise the porosity and has low flow property. High density and low porosity of particles give good flowability to powder.
iv. Moisture content:If the powder has higher amount of moisture, it increases the risk of cohesion or adhesion.
v. Flow activators: Flow activators improve flow property by reducing the adhesion and cohesion of particles. They also known as glidants. E.g. talc, maize, magnesium stearate.
What are the methods to determine the flow properties of a powder?
i. Carr’s compressibility index
ii. Hausner ratio
iii. Angle of repose
Classify the flowability of a powder based on Carr’s index values.
5 - 15% Excellent flow- Free flowing granules
12 - 16% Good- Free flowing powdered granules
18 - 21% Fair- Powdered granules
23 - 35% Poor- Fluid powders
33- 38% Very poor - Fluidised cohesive powders
>40 Extremely poor - Cohesive powders
Mention 2 methods of determining angle of repose.
i. Static angle of repose method
-Fixed-funnel method
ii. Kinetic or dynamic method
-Rotating cylinder method
-Tilting box method
Classify the flowability of a powder based on AOR values.
25 - 30 —– Excellent
31 - 35 —– Good
36 - 40 —– Fair
40 - 45 —– Passable
46 - 55 —– Poor
56 - 65 —– Very poor
>65 —— Extremely poor
Mention 5 different crystal shapes
i. Cubic
ii. Tetragonal
iii. Hexagonal
iv. Monoclinic
v. Triclinic
vi. Orthombic
Differentiate between crystalline and amorphous substances.
i. Crystalline solids have a three-dimensional repeating lattice structure while amorphous solids do not have a regular structure and have a more random arrangement of particles.
ii. Crystalline solids have well-defined edges and faces while amorphous solids have irregular or curved surfaces.
iii. Crystalline solids diffract x-rays while amorphous solids do not give well-resolved x-ray diffraction patterns.
iv. Crystalline solids have sharp melting points while amorphous solids melt over a wide range of temperatures.
v. Crystalline solids have lower solubility, dissolution rate and absorption while amorphous substances have higher solubility, dissolution rate and absorption.
(Amorphous Novobiocin is much better absorbed than the crystalline form)
Classify hygroscopicity.
i. Increase in weight >=0.2%w/w - <2%w/w ——Slightly hygroscopic
ii. Increase in weight >=2%w/w - <15%w/w ——Hygroscopic
iii. Increase in weight >=15%w/w——Very hygroscopic
iv. Sufficient water is absorbed to form a solution ———– Deliquescent
Give 2 instances of drug-excipient incompatibility
i. The conversion of chloramphenicol acetate from polymorphic form B to form A after grinding with colloidal silica
ii. The adsorption of finely divided hydrophobic magnesium stearate on acetaminophen can lead to decrease in the dissolution rate and bioavailability.
What are the solubility properties?
i. Wettability: Wetting is a precursor to dissolution and so the wettability of a drug particle has a significant influence on the dissolution rates and the release characteristics in an oral pharmaceutical delivery. It also influences the interactions with other particles during formulation.
ii. Solubility profile: The solubility of a drug is an important physicochemical property because it affects the bioavailability of the drug, the rate of drug release in dissolution medium, and consequently, the therapeutic efficacy of the pharmaceutical product.
iii. Dissolution rate: Dissolution rate in the fluids at the absorption site is the rate limiting step in the absorption process. This is true for the drug administered orally in the solid dosage forms as well as drug administered I.M. in form of pellets or suspension.
iv. Partition coefficient: The ratio of unionised drug distributed between the organic and aqueous phases at equilibrium. It is a measure of drug’s lipophilicity and an indication of its ability to cross the cell membrane. Drugs with extremely high partition coefficient (i.e. very oil soluble) readily penetrate the membranes. While drugs with very low partition coefficient (excessive aqueous solubility) cannot penetrate the membrane.
k = Co/Cw
where Co = organic phase concentration, and
Cw = aqueous phase concentration
v. Ionization constant (Pka): refers to the extent to which a drug is ionised or unionised in the body, which affects its ability to cross lipid membranes and be absorbed.
The unionised drugs are lipid soluble thus dissolves in lipid material of the membrane and transported by passive diffusion. Where as, the ionised substance is lipid insoluble and thus therefore permeation is low.
pKa=−log[Ka]
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.
PWIDS
____________ is used to measure the wettability of a powder.
A tensiometer
