Better wet granulation: development, scale-up and manufacture

Transcription

1 Better wet granulation: development, scale-up and manufacture By Tim Freeman, Freeman Technology Wet granulation is a common unit operation in the pharmaceutical industry yet accurate endpoint detection remains a challenge. Here we examine the contribution that dynamic powder rheometry can make, highlighting its ability to detect the transition from wet mass to granulate with the required sensitivity. Quantification of this transition point, with a measure that is independent of process scale, accelerates development and scale-up and improves manufacture. Introduction Wet granulation converts very fine powders into granules with a much larger particle size. This yields benefits that include: Improved flow properties Reduced segregation (especially of active ingredients relative to excipients), and hence - Better content uniformity Reduced dust hazard Increased density and lower packed volume (since larger particles can pack more closely than smaller cohesive ones that tend to trap air). Improved properties during compression One of the most widespread applications of the process is in tablet production. Here the challenge is to formulate active pharmaceutical ingredients (API), which are often very fine crystalline powders, with generally much coarser excipients, to give a blend that tablets successfully. Frequently the properties of a raw blend are incompatible with direct compression tableting. This may be due to poor flow properties, undesirable compressibility characteristics or unacceptable risk of segregation, so intermediate processing becomes essential. A successful wet granulation step converts the diversely sized blend into larger, more mobile particles of more consistent size and composition. These granules are then milled and dried to give a powder with the composition of the finished product, and properties that permit the efficient manufacture of good quality tablets. In this example, wet granulation decreases the likelihood of segregation, something that is more prevalent with a broad particle size distribution. It also reduces the dusting hazard associated with handling blends containing small particles. The feed to the tablet press then has the content uniformity required for the end product, and processability improves as a result of enhanced flow properties. It is for these reasons that wet granulation is used, according to estimates, in the formulation of up to 70% of all tablets 1. Examining the process Wet granulation is usually carried out in either a fluidized bed or a high shear mixer. The underlying mechanisms of agglomeration are the same in each, but high shear mixing gives rise to denser, more mechanically stable granulates. As a result this is the more usual process. In high shear granulators an impeller, or rotor, dominates agitation but is often supplemented by an additional chopper that breaks up larger agglomerates, aiding rapid and effective processing. The first step is initial blending of all the dry constituents, potentially including the binder, in the mixer. A solution or suspension is subsequently added to wet the blend, and granulation then continues until the desired endpoint is reached. Often the liquid added is water which dissolves the dry binder to form a solution that coats the particles, making them adhere to one another. Better wet granulation: development, scale-up and manufacture Page 1 of 5

2 Steering the granulation to a desirable endpoint depends on effective control, with the most commonly manipulated variables being: amount of granulation solution added, the rate of addition, processing time and impeller speed. Critically, it relies on recognizing when the granulation has reached an optimal point. This can be difficult as the process is usually an intermediate step - i.e. the granulate is not a final product. Determining an endpoint therefore often involves product work up and assessing performance in subsequent process steps. Simply measuring variables such as particle size distribution does not provide sufficient information to predict downstream processing behavior, which may be influenced by properties such as permeability, compressibility and flowability. Returning to the example of tableting, the aim is to produce a granulate that when milled, dried and lubricated, delivers a blend that flows and compresses to give stable tablets that meet QC standards. These specifications are typically defined in terms of: dose consistency, hardness, dissolution and disintegration characteristics. Developers scope the correlations between granulation control variables and tablet quality by producing a series of small-scale batches in a lab granulator, processing each through to tablets, and assessing the product using standard techniques for release. This approach produces a set of conditions for granulation but if these are fixed then the process will be unresponsive to feed variability. Furthermore, these established conditions will not necessarily scale-up. For example, a large scale unit may need a water addition of 22% instead of 26% to reach the same endpoint as a smaller unit, because of differences in geometry and/or process dynamics. Having a more direct measure of granulation endpoint is hugely beneficial. Tracking wet granulation with a powder rheometer Powder rheometers provide dynamic characterization of a sample by measuring it in motion. A particularly useful parameter is basic flow energy (BFE), which is the energy required to induce a specific flow pattern in a conditioned powder bed 2. During BFE testing the blade of the rheometer pushes downwards through the material in a compacting motion. Figure 1 shows BFE as a function of water content for a series of lab-scale granulation experiments conducted with all other process variables kept constant. Figure 1: Tracking a wet granulation process with basic flow energy measurements (FT4 Freeman Technology) Better wet granulation: development, scale-up and manufacture Page 2 of 5

3 At low water contents BFE remains approximately constant, but at a concentration of between 40 and 45% it begins to rise sharply. Figure 2 shows images of material from granulations at 30 and 50% w/w water respectively. (a) (b) Figure 2: Images of a granulation blend containing a) 30% w/w water and b) 50% w/w water These images suggest that the sharp rise in BFE corresponds with the transition from wet mass (a) to granules (b). Hard and stiff particles have a much higher BFE than finer more cohesive powders because they pack closely together entraining little air. With the granules the compressing force of the rotating blade transmits very effectively through the sample bed, and the flow zone, the amount of material that begins to move, is consequently large. Also the adhesive properties between granules are considerable, further increasing resistance to flow. BFE values are therefore relatively high. With the wet mass, which behaves like finer more cohesive materials, air pockets in the bed absorb the movement of the blade; the flow zone is much smaller and BFE values lower. Figure 3: Permeability as a function of water content for a granulation process Permeability data also reflect the changes (see figure 3), thus supporting these ideas. Granules allow air to flow through the bed, the wet mass exerting much greater resistance to air flow. As granules reach their maximum size, bed resistance falls to a minimum and permeability approaches zero. However, using permeability measurements the changes are essentially linear with water content, as the blend goes from under- to over-granulated. Better wet granulation: development, scale-up and manufacture Page 3 of 5

4 This work shows that BFE measurements are a useful way of detecting the transition from wet mass to granule, a critical point. This transition will often mark the end of the process although granulation may continue further. It is clear from the plot that BFE is highly sensitive to changes in water content, more so than the bulk property permeability, both around and just beyond the transition point. Process development using BFE measurements The measurement of BFE uses wet samples, direct from the granulator; analysis is quick, and tracking of the process highly effective. The way this technique characterizes the granulate is akin to using power drawn by the impeller motor to monitor the process, a common practice during full scale operation. However, powder rheometers are very much more accurate. Precision engineering and well-established methodologies combine to give exceptional reproducibility. Tracking a lab scale granulation in this way immediately narrows the range of interest in terms of control variables, in this case water concentration. For tableting, making batches around the transition point and slightly beyond, and processing them through to tablets, pinpoints an optimal granule. Now, however, the optimum granulate is associated with a BFE value rather than simply a set of processing conditions. Working to the endpoint defined by this BFE will consistently produce the desired product. Importantly, the relationship between BFE and product performance is independent of scale. This means that linking BFE with tablet quality is a one-off exercise, rather than something that must be repeated every time the scale of the process is changed. Moving the granulation from the laboratory to development and/or pilot scale and through to full production will simply demand the manipulation of control variables to ensure that BFE remains the same. This is much quicker than testing conditions with reference to final product properties. Furthermore operating the process to a BFE endpoint rather than with preset parameters introduces the potential for adaptive control. Batch-to-batch variability is common and will simply translate through to granulate quality, and downstream processing, if the granulating conditions are fixed. Granulating to an endpoint specified on the basis of a variable that reliably correlates with product performance is a more intelligent approach, consistent with Quality by Design (QbD). It allows the operator to change control variables to maintain a consistent output even when feed varies. In conclusion Detecting the optimum endpoint for granulation is a challenge. Typically, the process is an intermediate step so optimization can be a lengthy iterative task based on full work-up of the product. Optimal processing conditions vary with scale complicating the transition from development to full-scale production. The dynamic powder property, basic flow energy (BFE) is proving to be a valuable parameter for wet granulation since it sensitively detects the transition from wet mass to granulate. Characterizing the endpoint in terms of BFE provides a target for processing that is independent of scale. It accelerates process scale-up since at each stage control variables are simply manipulated to reach the same BFE. Furthermore, processing to an endpoint defined in this way gives the operator scope to vary conditions in response to a changing feed. This is a more intelligent, flexible approach, consistent with QbD, which protects downstream units from the batch-to-batch variability upstream. Better wet granulation: development, scale-up and manufacture Page 4 of 5

5 The FT4 from Freeman Technology The FT4 is a universal powder tester for the measurement of dynamic, shear and bulk properties that provides comprehensive, process relevant characterization. The reproducibility of the instrument is second to none giving excellent sensitivity. These capabilities make the FT4 a uniquely powerful tool for identifying correlations between powder properties and specific aspects of process and product performance. Such understanding is extremely valuable for formulation, development, scale-up and troubleshooting July 2009 Tim Freeman, Director of Operations Freeman Technology tim.freeman@freemantech.co.uk Better wet granulation: development, scale-up and manufacture Page 5 of 5