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Process line- Wet Granulation. According to (Bennett and Cole, 2003), wet granulation is undertaken in the pharmaceutical industries for the production of tablets and other products in order to increase their bulk density, uniformity and to prevent isolation between drug particles. Figure 1 represents a typical wet granulation process line, in which the drug particles are mixed with lubricants, binders, colouring materials and other substances throughout the process line to produce drugs with specific appearance and properties. Wet granulation is the process which is most often used for granulating drug substances and also most importantly the granulation step is the critical stage in the process line.
The overall stages involved in the process are as follows:
The dispensed materials from the dispenser is added with suitable wetting agents and flows into the wet mill where they are mixed together, the wet mass then passes through coarse screening in the sieve and is passed to the mixer granulator.
At the mixer granulator, multiple operations such as powder mixing, wetting, wet massing and cutting operations takes place and they are described stepwise below:
The wet mass is rotated between impeller and chopper at high speeds to achieve good mixing.
Liquid binder is added to the system, and is rotated and mixed well by the rotating choppers and impellers
Finally wet massing takes place with the help of high speed impellers and cutters.
This wet mass then undergoes further processing by drying, blending and milling before they can be tablet compressed.
These wet granules then passes through a wet mill, where redistribution of particle sizes takes place, and this then enters the fluidised bed dryer where drying to a particular moisture level is achieved.
Finally, the dried granules pass through fine sieve where reduction in particle size occurs, and undergoes final blending where addition of lubricants occurs to produce tablet compression mix with good initial mix and these are stored in intermediate bulk containers. The granules will now be ready to be compressed into tablets.
The advantage of this process compared to dry granulation is that it possesses low amount of dust emissions because the mixer granulator consists of a single unit, where a number of granulations steps are enclosed within the unit, and thus reduces the emissions of dust and these are also fairly rapid in action. This type of granulator offers a wide range of flexibility in the granulation process as the properties of the granules can be easily controlled by altering the binder addition rates and step times. Moreover, granulating drug substances in a mixer granulator also uses low volumes of binders.
Figure : Typical Wet Granulation Process (Dr. Rachel Bridson, 2010)
Fluidised Bed Dryer
In this report, a design space is developed for the fluidised bed dryer (as shown above in figure 1) in where moisture content of the granules is being continuously monitored. According to (Buschmuller et al.,2007) real time determination of the moisture content of the granules was performed using relevant PAT tools such as the microwave resonance technology. In this equipment and process, it is important to identify the critical process parameters (CPP) and critical quality attributes (CPQ), so that they can be monitored and evaluated during the resonance technology. Therefore, the CPP's for the dryer will be the residual water content of the granules, and the CPQ's will be stability of the active pharmaceutical ingredient, homogeneity and the hardness of granules. In addition, these properties will have an adverse effect on the flowability of the granules thus will affect tabletting properties.
Critical Process Parameters and Critical Quality Attributes
Residual Moisture Content
Development of Design Space
(Burggraeve et al.,2010) stated that the PAT(process analytical tools) were introduced and implemented by the FDA(American food and drug administration). Its main aim was to optimise and alter the process in order to maintain a constant end product quality by identifying the critical process and formulation parameters. Implementation of PAT in pharmaceutical industries has lead towards a manufacturing side with better understanding of the process, efficient process control, reduction in production cycle time, reduces the amount of rejects and reprocessing.
Methods to characterise moisture content
In pharmaceutical wet granulation, generally there are three practices in which moisture content are measured, and they are as follows: discontinuous sampling with discontinuous drying operation, continuous sampling with discontinuous operation and continuous operation with continuous sampling. The four main techniques which are already implemented for this purpose are Karl Fischer titration, loss on drying (LOD), and loss on drying using infrared (LOD/IR), nuclear magnetic resonance (NMR). But unfortunately these techniques do not comply with the PAT regulations as they fail to produce real time analysis of drying and also are time consuming since analysis is done by sample withdrawal. Therefore microwave resonance technology was developed for real in time moisture measurement in fluidised bed dryers so that they meet FDA's PAT approach.
Microwave Resonance Technology
According to (Buschmuller et al.,2007) this newly developed technique produces continuous measurements that are not density dependant and gives two parameter measurements. Further, this also enables us to obtain the total molecules of water present and the solids density in a single measurement. This works in the following principle, the water molecules tend to re-arrange when an electromagnetic field is applied. The frequency of the applied wave causes the water molecules to arrange in accordance to the polarity of the field. Provided that the electromagnetic field alters its polarity quickly, only water molecules and other small masses can move around with it due to their large dipoles. Due to this movement this causes loss if energy in the field and this loss in energy correspond to the total amount of water present in the granules in the dryer. Therefore, MRT allows for the determination of the total energy loss due to the presence of water and its response to the frequency of the applied microwave, and also the powder density from the shift of the applied microwave wavelength. Furthermore, from this research paper this technology has been implemented in Glatt fluidised bed dryers for in -line moisture measurement in accordance to the current good manufacturing practice (cGMP).
Investigation of MRT sensors
The working principles and practical applications of the sensors are tested using real process conditions in order to be used in pharmaceutical industries. The materials required for the investigations are: Microcrystalline cellulose was used in Vivapur, and Avicel, a-Lactose monohydrate, Povidone 90 (Kollidon 90F), Hydranal Coulomat AG, Hydranal Coulomat EG, dried methanol, sodium tartrate dehydrate and pure nitrogen.
This technology exploits the interactions between the water molecules and the frequency of the electromagnetic waves. The frequency that is measured from the stray sensor corresponds to resonance wavelength of the microwave inducing resonator, and also the frequency is dependent on the geometries of the sensors. Increase in storage of electrical energy will cause a decrease in the resonance frequency if the resonator is over-loaded with materials; this also causes the permittivity of the resonator to change. Furthermore, wet contents in the dryer will emit energy of the resonator which in turn causes an increase in width of the resonance bands. In addition, due to the decreasing resonance frequency an increase in water content is obtained, which then leads to broadening of the frequency band. This effect takes place due to material load in the resonator and the product moisture content. Moisture and density can be obtained by measuring the frequency and the width of peak broadening, and comparison of these values to the resonator in air yields a relationship between the product moisture and the density, as shown in equation 1, where is the total amount of water molecules.
This equation can be altered by eliminating the dependence on solids density by calculating the ratio between band width magnification and decrease in resonance frequency.
This relationship accounts for the measurement of physically bound water molecules and ignores any crystal water, since different types of wavelengths are required for this purpose. From literature it has been concluded that the frequency of MRT is dependent on temperature due to the thermal expansion of the resonator itself, and they are un-affected by UV absorption by the products, conductivity and heterogeneous distribution of water molecules.
Stray field resonators
This stray field resonator Hydropharm, is an open type sensor consisting of an external electric field which protrudes into the space containing products. It is made of ring shaped ceramic wave guide which are soldered into a titanium disc. An electronic unit which generates an electromagnetic wave is incorporated within the sensor, and these work at 2.5 GHz which is said to be equivalent to ISM (industrial, scientific and medical) band. These sensors are mounted on two types of fluidised bed dryers; GPCG 15 and WSG 60 for investigation purposes. Both these types of dryers are from Glatt GmbH as mentioned in (section 4.2.1). It is important that the test material and the surface in which the resonator makes contact with should comply with cGMP regulations. When the resonators exploit the surface, the response and behaviour of water molecules is as shown in figure 3. As we have discussed above the temperature affects the microwave signals, thus these are measured by the installation of PT 100 thermo sensor just beneath the surface. Therefore, the measured values for moisture content, temperature and density are processed and appraised further by software known as MWF-Standard (Doscher & Doscher, Hamburg, Germany).
Figure : (Buschmuller et al.,2007)
Experiment with Placebo Granules
The experimental sample from the high shear mixer contains the following materials; 33 % MCC and 67% a-lactose monohydrate and 1.7 kg of aqueous solution containing 10% of Povidone 90 with an overall weight of 6kg. This is then transferred to the hydropharm sensor installed GPCG 15 fluidised dryer. The sensor is installed at the lower end of the product container. The drying process takes place without any interruptions and is continuously monitored with the help of this sensor. Samples of 4 g were regularly withdrawn at certain time periods for moisture analysis by LOD/IR, and these were then compared to the offline moisture content of the sample.
Figure : (Buschmuller et al.,2007)
LOD/IR: analysis in this is carried out in a heat balance, LJ16 moisture analyser from Germany at temperatures around 70 C.
Experiment with Verum granules
In this case, the sample is prepared according to the following mixture constituents; 16% API water free crystals, 84% MCC, and these were mixed until it reaches a temperature of approximately 38 C in the granulator. Later, 17.4 kg of aqueous solution of 7% Providone 90 was added, producing an overall batch with 53 kg in weight. This WSG 60 dryer incorporated with hydropharm sensor operates with single drying chamber. Just as the above experiment, the drying was interrupted because of withdrawal of samples at certain time periods for analysis using LOD/IR. In addition, Karl Fischer method was also implemented to measure the moisture content and the MRT signals were also measured concurrently. These values were then compared to the offline measurements on water content. Simultaneously, an experiment where continuous monitoring using the MRT sensor is carried on another batch of Verum granules without disrupting the process for sample withdrawal. This process is continuously run until the specific moisture content is reached, and then it is stopped
Figure : (Buschmuller et al.,2007)
Karl Fischer Method: Analysing moisture using this method is achieved using moisture meter CA05 along with dry heating oven VA05 from the manufacturers (Mitsubishi Chemical Industries Limited, Tokyo). This is used alongside with an analytical weighing balance Mettler AT261 from Germany. In this technique, the sample is heated around 170 C and passed over to the measuring cell by the help of nitrogen.
LOD/IR: This was carried out using a heat balance, MA 45 Moisture Analyzer from Germany at temperatures approximately 100 C due to the high presence of MCC in the verum granules.
Results and Data Obtained
Validation of sensor using Placebo granules: It is important to calibrate these sensors in accordance to the reference methods since they are in direct measuring methods. Thus, from the above experiment with placebo granules, it can be deduced that the flow pattern of the granules were not disrupted and they followed a uniform pattern. Moisture content was then determined by LOD/IR, and the results obtained were used to calibrate the MRT sensor by determining the specific correction factors with the help of calculations and the delivered software.
The percentage moisture decrease throughout the whole drying process monitored by the MRT sensor is given in figure 5. It represents a decrease from 18% to 0.4 % in 37 mins, and these results were compared to the offline moisture measurement by LOD/IR. It was found out to be that the both methods i.e offline by LOD/IR and inline by MRT, corresponded well below a moisture content of 10%.
To check for repeatability and accuracy of the data obtained different batches of placebo granules were tested under the same processing conditions. Results obtained by repeating the experiments are shown in figure 6, it can be deduced that there is a slight variation at the start of drying because of unconditioned air, but the curves seem to superimpose at the end of the drying cycle. This suggests that the MRT sensor can be applicable for inline moisture measurement in fluidised bed dryers. For further confirmation a plot of LOD/IR versus against MRT values were plotted(Figure 7), thus the graph yields a linear regression coefficient of 0.976. Therefore, absolutely promising results were obtained at lower moisture content which is very important in monitoring the end point moisture content of the granules.
In addition, MRT sensors are not dependant on the density and these are confirmed by investigating with pre-dried granules. These are fed into the GPCG 15 dryer, and then the inlet air volume was set and increased regularly at certain timings, and any change in output signal was observed for any deviations for change in air volume. It was found out to have no changes in the output signal therefore it can be concluded that the sensor is not dependant on the air volume thus the density.
Validation of the sensor using Verum granules: Just as the above case, the MRT sensor is re calibrated using two reference methods in here to check for the accuracy of the MRT for moisture measurements. Two methods are used because Karl Fischer titrations methods are generally considered more effective than LOD/IR. Samples at regular intervals were collected and measured using titration methods, and as same the values were calculated to product specific correction factors using software and this were compared to the inline MRT moisture measurement. Validation in verum granules takes place by two experiments. For both cases the end point for drying is set according to the drug product. In the first experiment the moisture content is being observed by continuous sample withdrawal for LOD/IR and on the other hand there is continuous monitoring by MRT. The relationship of moisture percentage of the inline and the offline measurements are shown in figure 9.
In the second experiment, the process was not disrupted for any sample withdrawal but MRT analysis takes place continuously and the process is paused at the residual water content end point. These products from the dryer were then tested by LOD/IR and Karls Fischer titration. Therefore, from all these results obtained it can be concluded that the MRT sensor complies well with results obtained from offline methods.
Therefore by performing the above experiments using in-line and offline moisture measurements, it is very well understood that offline moisture measurements produce less reliable moisture content as it is difficult to obtain the actual real moisture measurement using techniques such as LOD/IR and titrations. This is because for discontinuous sampling, the fluidisation has to be stopped and this causes the granules to rest at the bottom of the container where some tend to get dry, the ones closer to the walls and some appears to be wet especially the ones in the middle. Therefore this does not give reliable real time measurements for moisture. Therefore, MRT accounts for any changes in the physiochemical properties of the granules involved. Furthermore, this technology has been proven to be more efficient ensuring high quality of the products due to the numerous benefits they serve from the experiments that were conducted on fluidised bed dryers. They provided high accurate and precise moisture measurement for in-line determination and also is time saving. Moreover, this technology abides well with the FDA's PAT approach for in-line moisture measuring and also offers fewer risks involved in sampling and allows for inhomogeneous moisture measurements.