David O'Connell, PCI highlights the company’s expertise via an overview of its granulation service
Pharmaceutical granulation is a common technique for solid oral drug production, whether as tablets, capsules or granules for use in bottles or sachets. PCI offers multiple granulation methodologies addressing requirements of a range of Active Pharmaceutical Ingredients (API), irrespective of potency.
Granulation combines individual formulation components (API, diluents, binders, disintegrants) into a single uniform particle. The various techniques include wet granulation; dry granulation; fluid bed granulation and hot melt granulation.
Granulation is of benefit in overcoming challenges such as active content uniformity; densification of formulation; powder flow properties; compression properties; controlled API release profiles and API bioavailability.
PCI’s granulation is performed by aqueous-based solutions with investment in granulation equipment including high shear mixers, one pot processors, roller compactors and fluid bed processors.
PCI has the additional capability to produce high potent products (OEL down to 0.01 µg/m3) utilising high shear granulation and fluid bed processing. Containment performance is proven using Standardised Measurement of Equipment Particulate Airborne Concentration (SMEPAC) testing. PCI’s granulation suites include totally contained engineering systems with no open powder handling. The suites include small-scale (1-5 kg) (Figure 1) and large-scale (20 – 120 kg) equipment. Traditional physical assessment of the granule from the operator is not required as end-point of granulation is determined reliably from data obtained. Data is converted into user-friendly batch reports (Figure 2): the figure graphically indicates the power and torque of the impeller blades which, with relevant training, can determine the end-point of granulation prior to product over massing. The figure also demonstrates the granulation fluid addition rate.
Figure 1: Small-scale granulation suite
Figure 2. Example of wet granulation report from high potent HSM
The granulation bowls are geometrically similar with similar design of impeller blades meaning products developed at small-scale can be scaled up to large-scale. PCI uses precise mathematical scale-up modelling to ensure successful larger batches (Figure 3). Modelling includes the scale-up of the speed of the impeller blade, the granulation fluid addition, mixing times and bowl volumes. The impeller blade speed can be altered by choosing the most appropriate model to obtain a similar physical granule (tip speed, Froude number or constant shear stress).
Similar models can be performed for fluid bed granulation assessing the required air flows and spray rate calculations. This can be used to deliver a low API concentration within the formulation via the granulation fluid. Other elements of fluid bed granulation include low porosity density (particles remain more spherical) and end product bulk density that is similar to the starting material. This process is also utilised for pellet and tablet film or modified release coating.
One pot processing is another granulation technique where product drying is performed using a jacketed bowl. The bowl’s insulated water jacket is used to raise the temperature, evaporating the aqueous media drawing moist air away using a vacuum system with a condenser. During the drying phase, the impeller blade is rotated incrementally moving the colder material to closer proximity of the heated jacket wall. The Collette U600, PCI’s newest and largest one pot processor, also includes a heated bowl lid to aid drying, an in-bowl camera and a sample chute which prevents heat loss when taking samples or visualising the product.
PCI has a range of one pot processors; from small laboratory to large-scale equipment. Scale-up models can provide a faster path to large-scale manufacturing with the similar physical and chemical properties as the developed granules.
Both the high shear granulators and one pot processors can be used to perform hot melt granulations. This type of granulation introduces a waxy bioavailability enhancing excipient to poorly soluble APIs. This granulation assists in the dispersion of the granules into a fine particulate suspension aiding absorption within the patient.
Roller compaction is a process that provides a granulation method for materials that are heat and moisture sensitive by compressing powder blends between two rollers under pressure with the resulting material sized by dry mill. The granule produced is densified with a larger particle size and better powder flow in relation to the starting material.
PCI’s latest investment in a Gerteis Mini-Pactor provides fully contained roller compaction for the processing of highly potent APIs with the ability to perform small development batches at 10g/hour and scale-up to 100 kg/hour. This provides a distinct advantage in executing scale-up activities from development through clinical trial manufacture and subsequent commercial production. In line with the other state-of-the-art equipment, the PLC systems perform feedback loops for optimal control of ribbon thickness produced from the rollers.
PCI will continue to invest in granulation methods offering clients maximum flexibility in drug development and manufacturing.