solution 4

Crystalline vs Amorphous drugs

Crystalline = ordered repeating 3D lattice, sharp distinct melting point

amorphous = random disordered arrangement, glass transition temperature (Tg); lacks a sharp mp

Polymorphism

Ability of a drug to form multiple crystalline structures with different dissolution rates, solubility and storage stability

Advantages and disadvantages of crystalline drugs

Advantages:

• thermodynamic stability: resistant to moisture absorption and recrystallisation during storage

• batch uniformity: high purity, reproducible processing, and reliable ,mechanical flowability

• standardised manufacturing: straightforward compression for oral tablets and capsule filling

disadvantages:

• low solubility: high lattice energy acts as an energy barrier to dissolution

• reduced bioavailability: suboptimal absorption rates

• risk of polymorphism: unintended conversion between different crystal forms during processing

Advantages and disadvantages of amorphous drugs

Advantages:

• apparent solubility boost: lacks a rigid crystal lattice, enabling rapid hydration and dissolution

• enhanced bioavailability: dramatically increases systemic absorption of poorly water soluble APIs

• faster onset of action: dial for therapeutic applications requiring rapid drug absorption

Disadvantages

• thermodynamic instability: high free energy drives spontaneous recrystallisation over time

• hygroscopic sensitivity: readily absorbs atmospheric moisture, lowering Tg and hastening degradation

• complex processing: requires stabilising polymer matrices (amorphous solid dispersions)

Six main solubilisation strategies

Choose suitable solvent

use cosolvent

change drug salt

adjust pH

use cyclodextrins

select another formulation type

Types of pharmaceutical water

Potable = drinking-quality water, useful in oral medicines but may contain mineral salts/ other substances

purified = by distillation, reverse osmosis or deionisation of potable water. if stored before use it must be freshly boiled and cooled to remove any microbial contamination

water for injections = by sterilisation of pyrogen-free distilled water. water meeting stringent parenteral quality requirements

Non-aqueous solvents

Examples: ethanol, propylene glycol, vegetable oils, esters and DMSO. Useful for lipophilic drugs but may cause toxicity, irritation or poor taste

Cosolvency

Dissolve a poorly water-soluble drug in a water-miscible organic solvent, then mix with water to increase solubility

Limitations of cosolvents

Excess dilution or solvent evaporation may cause precipitation

solvent toxicity, pharmacological effects and miscibility must be considered

Examples of cosolvents

Ethanol, propylene glycol, glycerol and polyethylene glycols (PEGs)

ethanol can have unwanted pharmacological effects

Polyethylene glycols (PEGs)

Polyether excipients classified by average molecular mass

PEG 400 is a liquid cosolvent, while higher-molecular-weight PEGs are used in semisolid/solid formulations

Salt selection for solubilisation

Changing counterion can increase drug polarity and aqueous solubility

overly strong ion pairing can prevent dissociation and solvation

pH adjustment for solubilisation

Add acid or alkali to alter drug ionisation and solubility

uncontrolled pH drift may cause degradation or precipitation

Buffers and buffer capacity

Buffers resist pH changes caused by added/generated acid or base

buffer capacity is the limited amount they can neutralise before pH changes substantially

Cyclodextrin structure

Cyclic glucose-based molecules with hydrophobic interior and hydrophilic exterior

α = 6, β = 7 and γ = 8 glucose units

Cyclodextrin inclusion complexes

Lipophilic drug fits inside cyclodextrin cavity, increasing apparent aqueous solubility

drug must dissociate before exerting its effect

Alternative formulations and excipients

If a safe effective solution is impractical, use a suspension or emulsion

add only necessary preservatives, antioxidants, buffers, viscosity modifiers or other excipients