Monitoring Granulation Processes using in-line Near Infrared Spectroscopy
27/04/2017 14:36

Granulation is an important step in pharmaceutical solid dosage form processing. The flow and compression characteristics of a formulation are improved through granulation. A common method of pharmaceutical granulation is top spray granulation, where the powder is fluidized in a fluid bed dryer and liquid binder solution is sprayed onto the product layer from the top counter-currently to the fluidizing gas. After spraying the liquid into the formulation and forming the granule the product must be dried to the proper moisture level. If the granules are over-dried the action of the fluid bed can cause the fracture of granules creating undesirable fines and can damage the formulation due to hydration changes in some actives and excipients. If the granules are not dry enough the product will not flow properly and can cake and cause problems with subsequent processing, including product sticking to the faces of the tablet press punches and problems with product stability during storage.

Samples typically are withdrawn from the fluid bed with a thief during processing and analysed off-line in a laboratory for moisture content. Commonly there is a delay before analysis results are available to the operator that causes processing decisions, like end-point determination, to be made without optimal product moisture information. Top spray granulation end point is often based on time or product temperature and not moisture content. Near-infrared (NIR) spectroscopy is a rapid non-destructive technique often used for in-process analysis of moisture in the manufacturing environment. Real-time measurements can be made with no sample preparation and the data can be analysed and stored automatically. NIR fits in well with the Process Analytical Technology (PAT) initiative as developed by FDA. One of the elements of the PAT initiative is to use in-line analysis to increase process understanding and control to verify product quality and release it for subsequent processing without delay. Using NIR the process can be monitored for low levels of residual moisture and alcohols and other process constituents to yield better process control and end-point determination.

The Metrohm Process Analytics XDS Analyser with Fibre Optic interface can be used with a special probe design to fit typical Single Pot Granulators. The probe has an angled face that forces the powder sample to divert in a quasi-laminar flow over the measurement window. This maintains a more constant sample density at the window interface.

As such the whole process can be monitored accurately for multiple components and typically moisture levels, solvent levels and average particle size can be monitored in real time to provide information to make rapid process decisions improving product quality, consistency and saving money. 

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