Beyond the Simple Solution
The simplest injectable drug product is a solution: the API is fully dissolved in a compatible aqueous vehicle, the solution is sterile filtered, and it is filled into vials or prefilled syringes. A significant proportion of the injectable pipeline, however, cannot be formulated as simple solutions. Poorly water-soluble APIs, APIs that are unstable in solution, molecules that need to be targeted to specific tissues, and biologics that require depot-forming formulations for sustained release all require more complex formulation architectures.
Suspensions, emulsions, and liposomal systems are the three most clinically established complex injectable formulation platforms. Each offers distinct advantages for the right molecule, and each brings formulation challenges and manufacturing complexity that require specialist expertise to navigate.
Pharmaceutical Suspensions for Injection
A parenteral suspension consists of solid drug particles dispersed in an aqueous vehicle. Suspensions are used when the API has poor aqueous solubility, when a depot effect is desired (slowly dissolving drug particles at the injection site providing sustained release), or when the drug is more stable in solid form than in solution.
The critical quality attributes for injectable suspensions include particle size distribution (which affects both syringeability and dissolution rate at the injection site), resuspendability (the ability to achieve a uniform dispersion after settling with minimal shaking), viscosity (which must be low enough to allow injection through the intended needle gauge), and physical and chemical stability over shelf life.
Particle size control in injectable suspensions requires either micronisation of the API before suspension, or controlled crystallisation in the suspension medium. The final suspension must be sterilised, which for crystalline suspensions rules out sterile filtration and typically requires either terminal sterilisation (if the product is stable to autoclaving) or aseptic processing of each component followed by aseptic blending. ICH Q6A provides the quality standards framework for suspension characterisation.
Pharmaceutical Emulsions for Injection
Injectable emulsions are thermodynamically unstable two-phase systems in which one liquid is dispersed as droplets within another immiscible liquid, stabilised by an emulsifier. For pharmaceutical applications, oil-in-water (O/W) emulsions are most common, used to solubilise lipophilic APIs in the oil phase and deliver them via intravenous or intramuscular injection. Propofol, the widely used anaesthetic, is the most familiar example of an injectable O/W emulsion.
The critical attributes of injectable emulsions include droplet size (typically below 500 nanometres for intravenous emulsions, to prevent embolism risk), zeta potential (which governs colloidal stability), and drug distribution between the oil and aqueous phases (which affects dose uniformity). Physical stability, particularly resistance to droplet coalescence and Ostwald ripening over the product shelf life, is the primary formulation challenge and is addressed through emulsifier selection, oil phase composition, and processing conditions.
Liposomal Drug Products
Liposomes are spherical vesicles formed from phospholipid bilayers that enclose an aqueous core. The bilayer structure allows hydrophilic drugs to be encapsulated in the aqueous interior and lipophilic drugs to be incorporated into the bilayer membrane, making liposomes versatile carriers for a wide range of APIs. Commercially approved liposomal products include liposomal doxorubicin (Doxil/Caelyx), liposomal amphotericin B (AmBisome), and the COVID-19 mRNA vaccine lipid nanoparticles, which are closely related to classical liposomes.
| Formulation Type | API Suitability | Key Stability Challenges | Primary Clinical Advantage |
| Injectable suspension | Poorly water-soluble crystalline APIs; sustained release depot | Particle size growth; physical instability; syringeability | Sustained release at injection site; suitable for low-solubility compounds |
| Injectable emulsion | Lipophilic APIs requiring IV or IM delivery; propofol-like molecules | Droplet coalescence; Ostwald ripening; API leakage from oil phase | Solubilisation of lipophilic APIs; IV administration possible |
| Conventional liposome | Hydrophilic APIs (aqueous core) or lipophilic APIs (bilayer) | Aggregation; drug leakage; phospholipid oxidation and hydrolysis | Extended circulation time; reduced systemic toxicity vs free drug |
| PEGylated liposome | As above; particularly cytotoxic oncology agents | As above; PEG shedding over time | Stealth effect; avoids rapid clearance by mononuclear phagocyte system |
| Targeted liposome | APIs requiring cell-specific delivery; ADC-like specificity | As above; ligand stability; targeting efficiency in vivo | Active targeting to tumour or specific cell type; improved therapeutic index |
Manufacturing Considerations for Complex Injectables
Each of the formulation types described above requires a different manufacturing approach, and all share the requirement for aseptic processing to produce a sterile final product. Liposomal products are typically manufactured by thin-film hydration or microfluidics-based approaches, with size reduction by extrusion or high-pressure homogenisation and remote loading of the API after vesicle formation for ionisable drugs. Injectable emulsions are prepared by high-shear homogenisation followed by high-pressure homogenisation to achieve the target droplet size.
For all three formulation types, sterilisation is a particular challenge. The physical structures involved (crystals, droplets, vesicles) cannot withstand terminal steam sterilisation, so aseptic manufacturing, with the stringent environmental controls and validated processes that entails, is the standard approach.
Ardena’s Complex Injectable Capabilities at Ghent
Ardena’s development and manufacturing team in Ghent has formulation and manufacturing experience across injectable suspensions, emulsions, and liposomal products. The facility’s aseptic fill-finish capability supports GMP manufacturing of these complex dosage forms for clinical supply, with analytical support for the particle size, drug content, and stability testing required for regulatory filings.
