CMC

Nanotechnology Capabilities

Nearly 40% of new chemical entities currently being discovered are poorly water soluble Active Pharmaceutical Ingredients (APIs). The aqueous dissolution rate of the drug substance is critical as it governs bioavailability. One technique to improve dissolution rate is to reduce particle size. 

Development and Manufacture of Nanosuspensions

A nanosuspension is a suspension of API particles in the nanometre (10-9 m) range. The particle size can be represented in different ways and the precise definition may vary, for example, average particle size < 1μm; 90% of particles < 1μm, but in all cases it can be regarded as a range of very small particles on the tens to hundreds of nanometre scale.

Because of the increased surface area available, a drug delivered as an oral nanosuspension may exhibit an improved dissolution rate in the gastro-intestinal tract and consequently, improved absorption. This approach can be tested pre-clinically or clinically when other approaches are not feasible or, in combination with other approaches, to test their relative merit.

The combination of a well designed formulation and process are critical to achieving a high quality product in terms of particle size, and physical/chemical stability. Formulation variables to be considered include drug morphology and crystalline properties, drug concentration, selection of stabiliser and its concentration. Processing variables to be considered depend on the manufacturing technique to be used but include bead selection (their type, diameter, proportion versus container size/volume and batch size), milling time, rotation speed and pressure used in the case of high pressure homogenisation. The same principles apply whether the material is radiolabelled or non-radiolabelled although, in the former case and to save material, some of the development work will be conducted with unlabelled material.

Manufacture of a nanosuspension typically involves preparing a concentrated mixture of API/suspending/stabilising agent(s) and water prior to the size reduction stage. This is followed by dilution to the required API concentration. Three approaches to size reduction available within Arcinova are described below:

  • Roller milling: This is a low-shear ball milling (100 rpm) process which uses collisions between 1mm diameter Zirconium Oxide beads to reduce the API particle size. Concentrate volumes of between 5 and 300 mL are prepared using this technique with a typical sample processing time of 2 to 3 days.

  • Vertical milling: This is a high-shear ball milling (2000 rpm) process, again using 1mm diameter Zirconium Oxide beads to reduce the API particle size but with a reduced processing time. Concentrate volumes of between 5 and 15 mL are prepared using this technique with a typical sample processing time of 1 to 2 hours.

  • High pressure homogenisation: Here particle size reduction is achieved by recirculating a concentrated API suspension through a very narrow orifice under extremely high pressure (up to 30000 psi). In this environment collisions between the API particles lead to the reduction in particle size. Using this technique, batches between 30 mL and 1 L can be manufactured with an average processing time of 1 to 2 hours. 

Nanosuspension Characterisation

In-process analyses are performed to confirm that particle size distribution and drug content of the concentrated suspension product are within appropriate specifications and unless further milling is required, the suspension is diluted to the required product concentration.

The final product can then be fully analysed initially and following storage to determine an appropriate shelf-life. Analysis typically includes the parameters mentioned above but also the product’s appearance, impurity level, radiochemical purity (if relevant), specific activity (if relevant) and its microbiological characteristics.

 

Summary

Nanosuspension products can bring advantages in terms of dissolution rate/absorption. Arcinova has the capability to develop, manufacture, fully characterise and administer these products in both preclinical and clinical settings using either radiolabelled or non-radiolabelled materials to assist pharmaceutical development programmes.