- API properties (e.g. particle size and size distribution, propensity to agglomerate, amorphous regions in drug particles, particle surface roughness)
- Product formulation
- Inhaler device and metering system (capsule, reservoir, multi-dose device)
- Patient lung function
- Patient inhaler technique
In order to achieve penetration into the deep lung it is generally accepted that particles of API should ideally have an aerodynamic morphology and a particle size between 1µm and 5µm. Developing such micron sized particles using a conventional ‘top down’ process, like micronisation (also known as milling), results in particles with high surface energy, rough surfaces, amorphous hotspots and defects in the crystal lattice. This causes particles to ‘stick together’, resulting in poor flowability and aerosolation performance. Additionally, particle size is less controlled from such processes, meaning that particle size distributions are wider, which can lead to more drug hitting the back of the throat upon inhalation and being swallowed, or simply being too small and so inhaled and then exhaled immediately with no therapeutic effect.
Crystec’s mSAS® supercritical fluid (SCF) technology, on the other hand, is an appealing alternative when generating powders for inhalation. It is classed as a ‘bottom up’ technology and as such, ‘grows’ particles of the correct size and shape from an organic solution, rather than mechanically grinding larger chunks of material down to the correct size. Particles generated through mSAS® processing are highly crystalline with low levels of electrostatic charge, almost molecularly smooth surfaces and fewer amorphous hotspots. The particle precipitation is thermodynamically controlled and as such particle size is targeted and the particle size distribution very narrow. This means that a greater percentage of the dose emitted from an inhaler upon inspiration reaches the desired site of action in the deep lung, rather than being swallowed or exhaled without therapeutic effect.
An added advantage is that inhaled formulations can be kept very simple because of the ‘in-particle formulation design’ (IPFD) approach taken with mSAS®. Essentially, mSAS® allows Crystec to design particles with inherent performance characteristics (e.g. size and shape for inhalation) to meet a TPP. This ultimately means that complicated formulations aren’t required to overcome the challenges of conventionally prepared powders (e.g. valve lubricants and suspending agents).
Crystec mSAS® Case Study
The focus of this project was to develop an inhalable form of the API with a target particle size of less than 5µm. The aim was to improve the in-vitro Fine Particle Fraction (FPF) as a percentage of Total Emitted Dose (TED) of the API, compared to the micronised starting material. Efficacy was evaluated in-vitro using an Anderson Cascade Impactor (ACI), a mechanical model of the human lung.
The target product profile (TPP) was:
- Particle size of less than 5µm diameter with a tight size distribution
- Powders with good flowability and aerodynamic properties
- High yields (typically once optimised yields are >90%)
- Acceptable chemical and physical stability
- Low residual solvent levels adhering to strict ICH guidelines
Product Development
- A feasibility study to determine if the API was compatible with the mSAS® process.
- Testing the solubility of the API in supercritical carbon dioxide (scCO2).
- Evaluation of solvent systems to ensure high product yields and low levels of residual solvent.
- Development of a research program to study the effects of thermodynamic and kinetic variables on the product.
- Study of the critical control parameters to finely tune supersaturation, nucleation and crystal growth.
- Analysis of the product to determine particle habit, size and morphology, as well as physical and chemical stability.
- Development of an in-vitro method (ACI) and formulation of the product for use with a dry powder inhaler.
- Accelerated stability studies on the formulated product (mSAS® drug powder:lactose blend).
Product Analysis and Performance
Sympatec laser particle size analysis (PSA) data showing three repeat batches of SCF product. Image shows both a tight distribution of particles in the inhalable size range and a highly reproducible product.
