W1.4_Pre-formulation Flashcards
Briefly explain the process of pre-formulation considerations.
- Determination of physical/chemical/molecular/material characteristics of drugs
- ≈ Considerations before developing the medicine
- Decide most appropriate drug candidate/dosage form, issues with manufacturing -> optimise administration route and dosage form
How can we increase solubility of a drug compound? What is the caveat in solubility? How can we measure solubility (3)?
- Change in chemistry and salt formation can increase solubility
- Caveat: common ion effect (high pH and high [ions] induces salting out)
- Measurement: Gravimetrically (measured weight of evaporated volume), UV-vis spectroscopy, HPLC assay
Give out examples of pre-formulation considerations regarding solubility (6).
- Solubility high enough for solid oral dosage form?
- GI absorption high enough for oral delivery?
- Solubility in water high enough to make a solution for injection?
- Safe co-solvent for all patient populations, including children?
- Would pH change cause precipitation/injection pain?
- pH appropriate for eye drops?
Explain how partitioning is important in drug formulation. Define the unit for partitioning.
- Distribution of a dissolved molecule between aqueous and organic environment
- Important for absorption, movement through biological membranes (GIT, BBB)
- logP=log^(o/w) (in octanol/water)
Give out examples of pre-formulation considerations regarding partitioning (5).
- If the drug is more soluble in water than oil, will it diffuse through membranes?
- If the drug does not partition into oil, any active transporters through membranes?
- Very high logP and does not dissolve in water?
- Possible use of co-solvent?
- Will it be released from oily formulations, such as emulsions?
What are the factors affecting chemical/physical stability (4/1) of a drug compound? Explain the relationship of that with purity and give out examples of assay for purity (3).
- Chemical stability: organic molecules undergoing oxidation/hydrolysis/dimerisation/photolysis, or others undergoing decomposition
- Physical stability: change of crystal forms
- Purity: high purity needed (toxic by-products?)
- Assay for purity: UV-vis spectroscopy, HPLC, NMR chromatography, Mass spectroscopy
Give out examples of pre-formulation considerations regarding stability (6).
- Drug stable enough for formulation?
- Toxic decomposition products?
- Can the medicine be packaged to stabilise the drug?
- Solid formulation generated to slow down degradation kinetics?
- Stored at low temperatures to slow down degradation kinetics?
- Anticipated shelf life sufficient for transport chain?
What is the assumption made in dissolution of drugs? Compare the dissolution rate in capsules and tablets. What are the factors that can affect dissolution? Are there any other considerations worth mentioning that may relate to dissolution?
- Assuming good absorption in GI tract and dissolution in stomach/small intestine
- Capsule > tablet for fast dissolution
- Factors: crystal form/amorphous, granulation, addition of surfactants…
- Drug palatable? Dispersed tablet/chewable tablet/solution…
- Other routes of administration?
What are the other important pre-formulation considerations (3)?
- Solid state: amorphous/crystalline (polymorphs/co-crystals (hydrate/solvate))
- Melting point
- Hygroscopicity (ability to obtain water from environment)
Define viscosity and rheology. Relate them to injectables. Define newtonian fluid.
- Viscosity: resistance to flow (opposite to fluidity) vs Rheology: study of flow and deformation properties
- Injectables: low viscosity needed to flow through a small opening
- Newtonian fluid: moves more when more force is applied (ex. plasma)
Give out and explain the equations for dynamic viscosity, kinematic viscosity, relative viscosity, and specific viscosity
- η=σ/γ η: (dynamic) viscosity (Nm^-2*s or Pas) σ: shear stress (Nm^-2) γ: rate of flow (s^-1)
- Kinematic viscosity: υ=η/ρ ρ: density of fluid
-> useful to look at different grades of polymers or different densities of solutions - Relative viscosity: η(r)=η/η(0) η(0): viscosity of pure solvent
- Specific viscosity: η(sp)=η(r)-1
-> for colloids (such as suspensions, emulsions, or colloidal solutions like blood)
According to the reduced viscosity (η(sp)/C) over concentration (g*dL^-1) graph, explain the indications of the y-intercept and slope.
- [η] (intrinsic viscosity): determines approximate molecular mass of polymer in colloidal solution
- Slope: Huggins constant (kH) that indicates interaction between polymer molecules and solvent/determine interaction between polymers and added drug compound in solution to estimate drug release from solution
How is viscosity measured (4)? Explain Stoke’s Law.
- Measurement of viscosity: U-tube viscometer (simple, for low viscosity), suspended level viscometer, falling-sphere viscometer (for very high viscosity)
- Stoke’s Law: v=d^2g(ρ-ρ0)/18η η=k(ρ(sphere)-ρ(liquid))t
v: sedimentation rate d: particle diameter g: gravity constant ρ: density of particle
ρ0: density of suspending medium η: viscosity of suspending medium k: constant t: time taken - Modern measurement: rotational viscometry (not limited to liquids, can get more rheology information)
Explain the boundary layers in terms of viscosity. Define laminar and turbulent flow.
- Lower velocity when closer to surface of tube (boundary layer)
∵ Drag forces from friction on confining surfaces - Higher viscosity -> larger boundary layer
- Laminar flow: all layers flow in same direction, highest mass transfer
- Turbulent flow: unparallel flow, lower/stagnant in boundary layer
Explain the Renylod’s number and its application. Relate it to the mixing of liquids and clotting cascade. What is its drawback?
Reynold’s number: Re=ρud/η u: velocity of mobile phase d: pipe diameter
- Inversely proportional to kinematic viscosity equation
- Re < 2000: laminar flow Re > 4000: turbulent flow
- Ex. turbulent flow -> orthogonal motion in fluid supports mixing of liquids
- Ex. obstruction in blood vessels -> clotting -> turbulent flow -> reduce in velocity in boundary layer -> initiate clotting cascade
- Drawback: does not take surface roughness into account, thus Re < 4000 can still lead to turbulent flow and ensure mixing
