L32, 41, 42 protein binding and suspensions Flashcards
(24 cards)
32
How do proteins and ligands interact structurally during binding?
Proteins and ligands are flexible and adopt conformations that allow the lowest energy binding. Binding is often via induced fit or hand-in-glove models, not rigid “lock and key”.
32
What is the ‘induced fit’ model in protein-ligand binding?
The ligand can induce a conformational change in the protein, and both adjust shape to achieve optimal binding.
32
What are enthalpic contributions in ligand binding?
Unfavourable: Breaking ligand-water and protein-water interactions
Favourable: Forming new ligand-protein bonds
32
Why do ligands bind to proteins at all?
Binding must result in net energy gain (negative ΔG), achieved through a favourable balance of enthalpic and entropic changes.
32
How does binding differ between hydrophilic and lipophilic compounds?
Hydrophilic ligands: Rely on specific bonding (enthalpic) interactions.
Lipophilic ligands: Driven more by desolvation (entropic) effects.
32
Why do hydrophilic ligands require precise binding?
They pay a high energetic cost breaking strong water bonds, so high-quality bonding with the protein is essential to compensate.
32
Why can lipophilic ligands bind with less specificity?
They are pushed out of water (hydrophobic effect) and do not form strong water bonds to begin with, so less specific interactions may suffice.
32
What is the significance of Kd in binding?
Kd is the dissociation constant. Lower Kd = stronger binding. At [L] = Kd, the protein is 50% bound.
41/42 - double lesson
What is a pharmaceutical suspension?
A coarse dispersion of insoluble solid particles in a liquid medium, used to deliver drugs that are poorly soluble or unstable in solution.
Why formulate drugs as suspensions?
Prevent drug degradation
Mask taste
Alter absorption profile
For ease of administration in populations like children or elderly
Offer flexible dosing
What are key quality attributes of suspensions?
Uniform dose on shaking
Easy redispersibility
Adequate viscosity
Small and uniform particle size
Physical and chemical stability
Microbial stability
Acceptability and deliverability
What makes suspensions thermodynamically unstable?
High surface energy
Tendency for aggregation, settling, or crystal growth (Ostwald ripening)
What is sedimentation in suspensions?
Downward movement of particles under gravity, described by Stoke’s Law.
Reducing sedimentation involves altering particle size, density, and viscosity.
What are the limitations of Stoke’s Law?
Applies only to dilute, spherical particles
Assumes no Brownian motion
Only valid in polar solvents with <2% solid concentrations
What is caking in suspensions?
Formation of a hard, compact sediment that is difficult to redisperse. It occurs due to aggregation at the primary minimum in DLVO theory.
What is flocculation and how does it help stability?
A controlled aggregation of particles into loose “flocs” at the secondary minimum. Flocs settle rapidly but are easily redispersed, preventing caking.
What are flocculating agents and examples?
Substances that reduce repulsive forces between particles
Examples:
- Polymers (e.g. xanthan gum)
- Electrolytes (e.g. NaCl, AlCl₃)
- Surfactants (ionic or non-ionic)
How do electrolytes affect suspension stability?
Reduce zeta potential
Allow particles to enter the secondary minimum
Promote flocculation (if optimal concentration used)
Too high = caking zone due to charge neutralisation
What is Ostwald ripening?
Growth of large crystals at the expense of small ones due to solubility differences. Promoted by temperature changes and some surfactants.
Which excipients are commonly used in suspensions?
Wetting agents: lower contact angle (e.g. surfactants like polysorbate)
Suspending agents: increase viscosity (e.g. carbomers, gums)
Preservatives: parabens
Buffers, flavourings, antioxidants
What are ideal rheological properties for suspensions?
Pseudoplastic + thixotropic behaviour:
Thins under shear (e.g. shaking or pouring)
Recovers thickness at rest (reduces sedimentation)
What role do wetting agents play?
Help disperse hydrophobic drug particles
Reduce interfacial tension and contact angle
Prevent powder clumping or floating
Why is particle size important?
Affects settling rate, Ostwald ripening, syringeability, taste
Ideal: <10 μm for oral suspensions
