Prueba

3.5.1 Filtration

Following the completion of each experimental run, the crystal slurry from the crystallizer was transferred into a pre-warmed beaker, before being taken to a temperature controlled box for filtration and washing. To recover the crystals from the mother liquor, the crystal slurry was filtered using a Büchner filter which was attached to a vacuum pump. This was completed in the specially built ‘temperature controlled box’, which delivers precise and constant temperature throughout the filtration and washing process. The box as shown in Figure 3.7 was fitted with a standard heat lamp and thermocouple, as well as a fan connected to the temperature controller so that the final crystallization temperature can be maintained. The main purpose was to minimise any additional nucleation which may occur due to any fluctuation of room temperature varying from 10 °C in winter, to 25 °C in summer during the filtration and washing processes. Any additional nucleation after the end of the experiment is problematic, as the mother liquor attached to the crystal surface could crystallize prior to washing, lowering the purity.

Figure 3.7: Diagram of filtration system and temperature controlled box

To ensure no ‘extra’ crystallization occurred during the slurry transfer, the beaker used was also pre-warmed to the box temperature and removed just before the slurry was to be

Vacuum Pump Filtration

Set-Up

Fan

Heat Lamp Control Box for Temperature Control

Door

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transferred. This transfer was completed as quickly as possible. In addition, the flow in the jacket of the crystalliser was left on throughout the transfer procedure in order to maintain the final temperature within the vessel. All due care was also taken to avoid any spillage or loss of slurry. Once the slurry had been moved to the box it was immediately and carefully poured into the Büchner filter with the vacuum pump already turned on, drawing the solution through the filter paper and into the collection vessel. It should be noted that all glassware used for the filtration was pre-warmed to the box temperature and was thoroughly cleaned after each use and replaced in the box to maintain its temperature.

3.5.2 Washing

Following the initial separation of mother liquor, the crystals collected were washed. The washing step is to remove any mother liquor which is adsorbed onto the crystal surface as well as within the voids of the filtration cake owing to capillary attraction (15). Traditionally washing is carried out using solvents of varying concentrations in several stages in industry (15). As a result, the selection of washing solution/solvent and the establishment of the washing protocols are important. Due to the high solubility of urea in water and many other readily available organic solvents (82), isopropanol (purity > 95 %) was identified as the most suitable wash liquor.

Several possible solvents and washing arrangements were identified and trialled, see Table 3.6.

Each trial was carried out as three replicate experiments to establish the statistics.

Table 3.6 Possible washing methodologies

Trial Number

Washing temperature

(°C)

Wash solvent used Number of washes

4 (step 2) 24 Isopropanol/Water

mix 1 127

5 (step 1) 24 Saturated urea

solution 1 100

5 (step 2) 24 Isopropanol 2 50

To allow comparison between the different washing protocols, a base run was carried out with no washing. The purity was determined using the off-line FTIR solution analysis system (Section 4.1.3) and the yield calculated was related to the expected mass of solid recovered at

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the final temperature. Table 3.7 shows the yield and purity results corresponding to the washing methodologies listed in Table 3.6.

Table 3.7: Results from washing trials

Trial

As can be seen in Table 3.7, the application of washing has opposite effects on the purity and yield, when any washing is applied, the average yield obtained from the crystallization falls while the purity increases. This is likely due to a combination of the removal of any extra mother liquor present on the crystal surface and the probable loss of solid due to the solubility of urea in isopropanol (3.17 g/100g at 25 °C (82)). Note that the Trial 4 was only carried out once due to the heavy loss of solid, this was because of the high solubility (47.6 g Urea/100 g solvent at 25 °C (82)) of the urea in the isopropanol/water mix (2/3 IPA to 1/3 H2O). Subsequently this solvent mixture was disregarded.

In Trial 5 where the saturated urea solution and isopropanol were used to wash the crystals in sequence, the best results of yield and purity were obtained. However the preparation of the saturated urea solution was done batch wise, not only was this time consuming, but it was also difficult to ensure the consistency of the solution. To make up the solution, high purity urea (99.5 % pure) must also be used. In order for the solution to not dissolve the crystal samples, excess urea was added into the solution which was then left for one hour at the set box temperature for full dissolution. The solution was then filtered to remove any undissolved urea and then kept in the box for a further 20 minutes until use.

Unpredictability could occur where sometimes the solution would re-crystallize or the solution would dissolve the sample crystals during application. On balance it was decided to discard this method.

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This left the two ‘pure’ isopropanol washing systems to be considered. As can be seen from Table 3.6, the only difference between these two systems is how the 100 ml of isopropanol was delivered. Trial 2 just had one isopropanol wash of 100 ml, while Trial 3 split this volume into two 50 ml washes. It was decided that the Trial 3 method gave more control over the even dispersion of the solvent across the surface of the filter cake and was consequently adopted as the washing methodology and applied to the rest of the work. It should be emphasized that the purities of washed and unwashed crystals, as well as of both the mother liquor and the wash liquor were also analysed to ascertain that the mother liquor and impurity from the wet cake were washed away as thoroughly as possible. The results indicated that the impurity was contained within the mother and washing liquors and that the amount of impurity left on the crystals was negligible. This justifies the methodology that was established and is also in line with the GMP operation in GSK.