Drug Physiochemistry Flashcards
1st Law of Thermodynamics
Energy is transferred, not created, or destroyed.
- conservation of energy
2nd Law of Thermodynamics
Entropy of an isolated system increases in a spontaneous change.
- spontaneous change increases entropy = micelle formation increases entropy
3rd Law of Thermodynamics
At 0K, a pure crystal substance has 0 entropy, meaning greatest possible orderliness.
Pharmacodynamics:
What the drug does to the body.
Fick’s 1st Law of Diffusion
The flux, at any point in the system, is proportional to the potential energy gradient.
Pharmacokinetics:
What the body does to the drug.
Pharmacogenomic:
Role of genome upon drug response.
MTC and MEC
MTC = Maximum Toxic Concentration - highest conc. before drug is toxic.
MEC = Minimum Effective Concentration - Lowest concentration to produce desired effects.
Log P
Octanol-water partition coefficient, used to characterize a drug’s lipophilicity.
A drug that is 10x more lipid-soluble than water-soluble has P = 10, log P = 1
A drug that is 100x more lipid-soluble than water-soluble has P = 100, log P = 2
Log P determination:
Mixing of known drug mass with water & octanol in equal volume, allowing the phases to separate. Then measure the [drug] in each phase.
Optimum is 1-3 Log P
If drug’s are too lipophilic they may be stored in fatty tissues.
Supersaturation
Max flux of drug across membrane achieved when applied at max chemical potential. This occurs with a saturated solution. When Cdrug/Sdrug > 1, it is supersaturation.
These are generally unstable.
How can Supersaturation occur?
- addition of a poorer solvent for drug in a ‘good’ solvent
- evaporation of a solvent or co-solvent
- uptake of water into a formulation (water = anti-solvent)
- cooling a warm saturated solution
Electrolyte
Compound ionised in solution, yielding ions when dissolved in water, meaning can conduct a cur-rent.
Strong Electrolyte
100% ionised in (aq) solution. E.g. Strong Acid/Bases & salts
Weak Electrolyte
Incompletely ionised in (aq) solution. E.g. Weak acid/bases
Non - Electrolytes
Substances that don’t yield ions when dissolved in water, so don’t conduct charge.
E.g. Sucrose, Glycerine, Naphthalene, Urea, Steroids
Buffer Capacity
Magnitude of the resistance of a buffer to pH changes
pH & pKa Relation
pKa= pH at which 50% of species are ionised
- The acidic drug is 100% unionized at -2 below its pKa & 100% ionized at pHs +2 above its pKa.
- The basic drug is 100% ionized at pHs up to -2 below its pKa & 100% unionized at pHs greater than +2 above its pKa
Lipinski’s Rule of 5 & reliability:
Rule of thumb, predicts good oral bioavailability is likely when:
* MW ≤ 500
* log P ≤ 5
* No more than 5 hydrogen bond donors
* No more than 10 hydrogen bond acceptors
* All units are multiples of five
Lipinski’s is not absolute, & many drugs which don’t meet this are not poor drugs, as bioavailability issues can be fixed with altered form, delivery route or modifying the polarity (polar functional groups needed to bind to fat, hence more makes them more lipophilic).
Solubility
If a drug has an ionisable group, when the drug’s pH changes, the drug’s solubility will change as a function of pH
Solubility Improvements
- cosolvents
- salts (changes physiochemical properties)
- surfactants
- cyclodextrins
- particle size reduction
- polymorphs
- lipid-based systems
- co-crystals
- amorphous solid dispersions
Biopharmaceutical Classification System (BCS)
Class 1 - High Solubility & Permeability
Class 2 - Low Solubility, High Permeability
Class 3 - High Solubility, Low Permeability
Class 4 - Low Solubility & Permeability
Pros & Cons: Pharmaceutical Salts
Adv:
enhanced solubility, dissolution rate, bioavailability & M.PT, easier synthesis & better taste
Dis:
decreased % of drug, increased toxicity, decreased stability, increased number of polymorphs. No change in solubility at different pH in GI tract.
Properties effected by Crystal Structure:
- Solubility & dissolution rates
- Crystal hardness ( tablet compressibility)
- Chemical stability (enthalpy, hygroscopicity, melting & sublimation temperatures)
- Others: e.g. Colour & refractive index, heat capacity, conductivity, volume, density.
Saturated Solvent
Solute is in equilibrium with the solid phase (solute).
Diffusion Layer
During dissolution, drug molecules in the surface layer dissolve to form a saturated solution around the particles.
Salt form can modify the pH of the diffusion layer.
Weak acid salt increases diffusion layer pH
Weak base salt decreases diffusion layer pH
Unsaturated/Subsaturated solution
Dissolved solute is below [the] necessary for complete saturation at a definite temp.
Solubility (Quantitative & Qualitative)
- Solubility (quantitative) -The [solute] in a saturated solution at a given temp.
A.K.A the max mass/vol of solute that dissolves in a given mass/vol of solvent at a given temp.
e.g. The solubility of ‘nitrofurantoin’ in water at 37oC is 174mg dm-3. - Solubility (qualitative) - spontaneous interaction of 2 or more substances to form a homogenous molecular dispersion.
pH in the GI
- A weak base has a high dissolution rate in the stomach, but the rate falls as the pH of the GI tract rises.
- A weak acid has minimal dissolution in the stomach, but its dissolution rate increases down the gut.
pH of the Diffusion Layer
The pH of the diffusion layer will be:
1. the bulk solution if we use the free acid
2. That of the salt or the salt form
The use of the salt form results in a controlled pH of the diffusion layer independently of the position of the GI tract, which usually improves the dissolution rate.
Helpful for controlled release.
Micellization & Hydrophobic effect
- Micellization: permits the hydrophobic effect which was preventable if the surfactant was in solution as single molecules between water molecules:
- Hydrophobic effect: the tendency of non-polar substances to aggregate in (aq) & to be excluded by water
Factor’s affecting CMC
*CMC may increase with:
– Increase in polarity of head group as it’s better able to bring more hydrocarbon chains into the solution
*CMC may decrease with
– Temp. – cloud point
– pH (surfactants are weak electrolytes)
– A second surfactant
– Addition of electrolytes & organic matter
– Greater carbon chain length
Kraft Point
Kraft point - Temp where the solubility is equal to the C.M.C
* At Temp. < Kraft point, the C.M.C > solubility & micelles cannot form
* At Temp. > Kraft point the micelles form.
Disassociated surfactant has a limited solubility, whilst micelles are highly soluble & can accommodate a large amount of surfactant.
The Cloud point
Heating non-ionic surfactants causes the solution to become cloudy through a reversible process.
The Temp increase results in dehydration, decreasing water solubility (lowering the C.M.C) & forms large visible micelles, hence cloudy.
To reverse this, the substance must be cooled, where small micelles form & the solution becomes clearer.
Critical Micelle pH
If the ionised form is surface active & has CMC > unionised (or is surface inactive), then a pH change can induce micellization.
HLB (Hydrophilic Lipophilic Balance)
The HLB scale:
* High HLB = surfactant exhibiting mainly polar or hydrophilic properties.
100% hydrophilic HLB 20
* Low HLB = lipophilic or non-polar properties.
100% lipophilic HLB 1
* Sometimes a mix of high & low HLB surfactants give greater stability
Lundelius’s rule & PIT
- Lundelius’s rule - factors that tend to decrease solubility of the surfactant promotes surface activity
- PIT (Phase Inversion Temp.) - PIT of an emulsifier is the T it changes from O/W emulsifier to a W/O emulsifier.
At the PIT, the hydrophilic & the lipophilic nature balance
Ampholytes (electrolytes) & Polyprotic (acids & bases)
Amphoteric electrolytes (ampholytes) = electrolytes which function as either acids or bases (amino acids & proteins). e.g.
*ACID: +NH3CH2COO- + H2O -> NH2CH2COO- + H3O+
*BASE: +NH3CH2COO- + H2O -> +NH3CH2COOH + OH-
Polyprotic - acids or bases able to donate or accept two or more protons
Each stage of the dissociation may be represented by an equilibrium expression & hence each stage has a distinct pKa or pKb value. e.g.
H3PO4 + H2O H2PO4- + H3O+ K1 = 7.5 x10-3
H2PO4- + H2O HPO42- + H3O+ K2 = 6.2 x10-8
pH partition hypothesis
pH partition hypothesis: Drug accumulates on the side of the membrane where pH favours ionization.
pH partition Limitations: Doesn’t consider:
- Type of epithelium
- SA of the absorption site
- Ionized drugs will be absorbed to a small extent
- Active transport of drugs
- Residence time of drug at delivery site
- Mass transfer of fluids
- Charged drugs may form ion pairs with oppositely charged species
Leaving Tendency
The degree of saturation (Coil/ Soil or Cwater/Swater) can be thought of as the drug’s “leaving tendency” from the solution.
The leaving tendency is maximised (& equal to 1) when: Coil = Soil or Cwater = Swater
Therefore, to drive drug absorption across a membrane (barrier), the closer the concentration in the formulation is to Sformulation, the better the rate of delivery.
Degradation routes:
+ Direct: A to B
+Dynamic Equilibrium: A back & forth with B
+Competitive: A to B or C
+Sequential: A to B to C
First order, (Pseudo) Zero order, Zero order and Second order
- First order: Difficult to determine rate of reaction for a particular time point, so gradient is measured continuously over small-time intervals (dt). Curve must be integrated as a function of time
- (Pseudo) Zero Order Kinetics: In a 1st order reaction, the rate decreases throughout the reaction, as A is consumed, if A could be replenished to initial values, the rate would be a constant.
- Zero order: Rate based on a constant solution & independent [of], thus has a constant rate.
- Second order: Two possibilities exist:
1. Rate is proportional to the product of two [equal], either involving a single reactant or two differ-ent reactants:
2. Rate is proportional to [two different]:
The passage of the drug from the absorption site to the systemic site of measurement (blood):
Absorption usually modelled as first order process as rate of absorption is proportional to the [drug] at absorption site (Fick’s Law) and the amount of drug at absorption site, if the transporters are not saturated (Michaelis-Menten Kinetics).
