Before a drug can act, it has to dissolve, cross membranes and survive the body. Solubility, lipophilicity, ionisation, size and stability decide whether that is possible — and which carrier is needed when it is not.
- Key descriptors
- Solubility, log P, pKa, MW
- Poorly soluble drugs
- ~70–90% of pipeline candidates
- Carrier size window
- 10–200 nm for systemic use
Every delivery decision starts with the molecule. A drug's physicochemical profile — how well it dissolves in water, how readily it partitions into lipids, whether it carries a charge at body pH and how large it is — determines how it is absorbed, where it distributes and how quickly it is cleared.
Most new small-molecule candidates are poorly water-soluble, while biologics such as peptides, proteins and nucleic acids are large, charged and fragile. Both extremes fail to reach their targets on their own. Drug delivery systems exist to correct these weaknesses: they solubilise, protect, shield charge and change apparent size so that the active molecule behaves the way the therapy requires.
The same principles apply to the carrier itself. Particle size, surface charge (zeta potential), hydrophobicity and the strength of drug–carrier interactions govern loading, stability on the shelf, behaviour in blood and release at the target.
The properties that matter most
Aqueous solubility
A drug must be in solution to be absorbed. Below roughly 100 µg/mL, dissolution often limits bioavailability and formulation help is needed.
Lipophilicity (log P / log D)
Balances membrane permeation against solubility. Values around 1–3 favour passive absorption; very high log P drives poor solubility and tissue accumulation.
Ionisation (pKa)
Charged species dissolve well but cross membranes poorly. pKa versus local pH — stomach, intestine, endosome, tumour — sets the charged fraction.
Molecular size and shape
Small molecules diffuse freely; above ~500 Da permeability falls and above ~40–60 kDa renal filtration stops, changing circulation time.
How it works
- 1
Profile the molecule
Measure solubility across pH, log P/log D, pKa, solid form, melting point and chemical stability to find the limiting property.
- 2
Classify the problem
Use the Biopharmaceutics Classification System (BCS) or developability classification to see whether solubility, permeability or both limit exposure.
- 3
Choose a strategy
Salt or co-crystal, amorphous dispersion, micelle, liposome, nanoparticle or conjugate — matched to the dominant weakness.
- 4
Characterise the carrier
Confirm size, PDI, zeta potential, loading, encapsulation efficiency and release so the formulation behaves consistently.
Biopharmaceutics Classification System
The BCS groups oral drugs by solubility and permeability and points to the most useful delivery approach.
| Class | Solubility | Permeability | Typical delivery approach |
|---|---|---|---|
| Class I | High | High | Conventional tablet; delivery rarely limiting |
| Class II | Low | High | Particle-size reduction, amorphous dispersions, lipid formulations, nanocrystals |
| Class III | High | Low | Permeation enhancers, prodrugs, alternative routes |
| Class IV | Low | Low | Nanocarriers, conjugates or parenteral delivery |
Carrier properties and their effect
| Property | Typical target | Why it matters |
|---|---|---|
| Hydrodynamic size | 50–150 nm | Avoids renal loss (<10 nm) and rapid capture by liver and spleen (>200 nm) |
| Polydispersity index | < 0.2 | Uniform particles give predictable biodistribution and release |
| Zeta potential | Near neutral in blood | Strongly cationic surfaces bind proteins and damage membranes |
| Drug loading | As high as stable | Reduces excipient burden and injection volume |
| Encapsulation efficiency | > 80–90% | Free drug causes off-target exposure and burst release |
| Surface hydrophilicity | PEG or zwitterionic coat | Reduces opsonisation and extends circulation |
Strengths
- Predictive. A small set of measurements forecasts absorption and formulation risk early.
- Rational design. Links each formulation choice to a measurable molecular weakness.
- Rescues candidates. Solubility-enabling technologies revive potent but poorly soluble molecules.
- Quality control. The same parameters become release specifications for manufacturing.
Challenges
- In vitro ≠ in vivo. Biorelevant media and protein coronas can shift solubility, size and charge in the body.
- Trade-offs. Improving solubility can reduce permeability, and vice versa.
- Physical instability. Amorphous forms recrystallise and nanoparticles aggregate without careful design.
- Biologics are different. Large molecules need protection and transport, not just solubilisation.
Where it is used
Oral bioavailability
Lipid-based and amorphous formulations for BCS Class II drugs.
Injectable nanomedicines
Liposomal doxorubicin and albumin-bound paclitaxel solve solubility and toxicity together.
Nucleic acid delivery
Ionisable lipids neutralise charge so RNA can cross membranes.
Peptides and proteins
PEGylation and lipidation increase size and stability to extend half-life.
What comes next
Physicochemical profiling is becoming faster and more predictive, linking molecular structure directly to formulation choice.
In silico prediction
Machine-learning models estimate solubility, log P and carrier compatibility before synthesis.
Biorelevant testing
Media and models that mimic gut fluids, plasma and endosomes give more realistic data.
High-throughput screening
Automated formulation screens test hundreds of excipient combinations in days.
Corona-aware design
Engineering surfaces with the protein corona in mind to control fate in blood.
Understanding the molecule's physicochemical weaknesses is the first and most important step in delivery design — the right carrier is the one that fixes the property that limits exposure.