Table 5.

Liposomal drug loading.

Loading Method		Localization	Drug Properties	%EE	Pros	Cons	References [91, 97–104]
Passive	Thin film hydration	Aqueous core	Hydrophilic small molecules Proteins	<5%	Small batch Good for lab scale	Low encapsulation Small internal volume Not scalable High drug leak	[67, 105]
		Lipid bilayer	Lipophilic small molecules	<5%
	Freeze/thaw-extension of TFH	As above	As above	5-20%	Increased internal volume Improved PDI	Not scalable High drug leak	[91, 106–108]
	Reverse phase evaporation	Aqueous core	Hydrophilic drugs	≤50%	Increased loading Useful for protein drugs	Solvent contamination	[65, 91, 107] [109]
Active	pH/salt gradient	Aqueous core	Weak base small molecules	≤100%	Increased loading	Limited to weak bases Potential resistance to drug release at target site	[91, 110, 111]
	Ionic gradient	Aqueous core	Weak acid small molecules	≤100%	Increased loading and retention	Limited to weak acids	[100, 112, 113]
	Cyclodextrin pre-encapsulation	Aqueous core	Hydrophobic or poorly soluble/non-ionizable drugs	≤95%	Enables active loading of non-ionizable drugs	Limited utility	[114–116]
	Dehydration-rehydration	Aqueous core	Proteins, other large molecules	20-52%	Increased loading of large molecules	Potential protein denaturation	[91, 108, 117, 118]

Abbreviations: EE-encapsulation efficiency; TFH- thin film hydration, PDI-polydispersity index