Particle Size Modification

Controlled Crystallization

The particle size distribution of the product of a crystallization process can be controlled by ensuring a well defined procedure has been developed and implemented. Understanding of growth kinetics alongside the correct seeding protocols allow a growth dominated crystallization to be guided to forming particles with the desired particle size.

Milling and Micronization

We offer a range of different micronization services to suit a variety of customer needs:

• Increase the apparent solubility of the API and maximize bioavailability
• Rapidly supply multi-gram quantities of micronized material for early formulation and pre-clinical work
• Generation of seed material with desired PSD for optimized crystallization processes
• Improve processability and properties of bulk API materials such as filtration, compressibility and handleability

Bioavailability

A prominent issue with a large number of API candidates in the development pipeline is poor aqueous solubility limiting bioavailability. Micronization provides a route to increased apparent (kinetic) solubility by offering a vastly increased surface area to the media for dissolution to occur.

Jet Milling

Jet milling is a powerful solvent free technique typically used to reduce particle size to between 1 and 15 µm. The API material is fed via a venturi into a chamber where high pressure nitrogen jets cause collisions between particles which fracture giving a reduction in particle size. The particle size of the output material can be fine-tuned by controlling the feed rate as well as the gas pressure.

We can offer small scale jet milling on our FPS 1″ mill at our R&D facility in Cambridge, UK. If GMP material is needed for clinical work, we have jet milling capability on our production sites, ranging from 2″ to 8″ mills, servicing batch sizes from 50 g to >100 kg. Our mills are well characterized and with the help of modelling, procedures can rapidly be scaled-up to kilogram quantities.

Milling operations are known to generate fine dusts, an explosive hazard, so we operate in an isolator under a nitrogen atmosphere; this also reduces material degradation and eliminates personal exposure allowing handling of highly potent material.

 

Jet milling offers a route to micronized material for use as seeds in crystallisation development work. A key component of control and optimization of a crystallization procedure relies on the implementation of effective seeding. In many processes, having access to small seeds is necessary to keep seed loadings low whilst still providing sufficient surface area for growth. In combination with an understanding of growth kinetics, final material particle size distributions can be targeted by selection of the correct seed size and loading.

Wet Milling

Wet milling is the process of reducing the particle size (typically between 10 and 100 μm) of an API suspended in a solvent by shearing, impact and crushing. Wet milling is commonly used to improve the aspect ratio of troublesome particles obtained after crystallization. This allows more facile filtration, improves the handleability of the material and can facilitates downstream processing such as tabletting.

We have an Ultra-Turrax dispersion unit allowing feasibility and solvent system assessment at small scale. The selected system can then be implemented on a larger scale using our Magic Lab. Optimisation of the particle size is carried out using different milling heads and varying the distance between the rotors and stators. The magic lab can also be used for in-line milling as part of a crystallization methodology, allowing for a more streamlined process.

Production scale processing can be carried out at our Devens site, boasting a non-GMP IKA mill servicing up to 50 L scale and a larger GMP IKA mill allowing production on 400 – 3000 L scale. Our scale-up work flow is supported by modelling, allowing for judicious experimentation, reducing experimental load and streamlining production.

Ball Milling

Ball milling utilizes the impact between metal or ceramic grinding balls with the API within a grinding jar to cause particle breakage. We can utilise both an oscillating shaker mill or planetary mill to generate the forces needed to facilitate this method of milling, allowing access to particles bellow 1 µm in size. Carrying out this process on multi-gram scale can provide samples with very low PSD for dissolution studies and other pre-clinical work.

Characterization

Our micronization services are complimented by our complete on-site characterization suite as well as the expertise of a world-leading solid state and particle engineering team. The wealth of expertise allows for a holistic approach to determine the optimal particle size range and evaluate and select the best milling technology for your API.

• X-ray powder diffraction (XRD)
• Particle size analysis by laser-diffraction (PSD)
• Rapid particle size distribution by image processing analysis
• Thermal analysis: differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)
• Scanning electron microscopy (SEM) and optical microscopy
• Dynamic vapor sorption (DVS)
• HPLC and GC
• NMR, FT-IR and Raman spectroscopies
• Dissolution studies (free power and disk) by Inform and Distek apparatus
  Karl Fisher titration
• Tap bulk density and other powder properties
• Quantification of amorphous content (modulated DSC, XRPD, DVS)

Spray Drying

Spray drying is a single step precipitation and particle engineering technique which plays a crucial role in the pharmaceutical industry. Spray drying works by atomising a solution into droplets and then drying those droplets to form particles. A tight droplet size distribution leads to a tight particle size distribution. Spray drying is a powerful particle engineering tool, by altering the different spray drying processing parameters, it is possible to control the properties of the resultant particle including size, shape and density.

Spray drying can be used to generate spherical shaped particles of amorphous or crystalline agglomerates, typically in the size range of 1-200 µm depending on the experimental parameters employed. As well as being a valuable isolation and processing step the particles formed particularly lend them selves to use in nebulised formulations.