Informal and subjective reports from various production departments involved in the filling of fine grade cefuroxime sodium have been collected over a period of several years in an attempt to identify 'good' and 'poor' filling batches. Such reports have generally proved inconclusive in identifying batches which can be classified as being of consistently 'good' or 'poor' performance. Individual batches processed on different occasions by different production departments have been reported by some as being 'good' and by others as 'poor' fillers. Environmental variables and storage times and conditions may, in part, account for such variation.
However, it can clearly be seen from Figures 8.1 to 8.34 that machine-dependent variables have a considerable influence on the relative behaviour of different batches of this material. The fill weight required determines the port depth at which filling takes place. This parameter in turn imposes limits on the dwell times which can be used if an acceptable fill weight variation is to be achieved. Optimisation of the dwell time, and hence the rate of production, depends upon the selection of an appropriate paddle speed (where this parameter can be independently controlled).
The classification of a particular batch with respect to its filling performance will therefore depend indirectly on the required fill weight and the limits of weight variation which are deemed acceptable, and directly on whether conditions of dwell time and paddle speed are optimal for the required fill weight.
Historically, batches have been assessed prior to filling, on the basis of the plug density which can be achieved under 'standard' conditions using a single-dose hand-held vacuum/purge gun (Section 2.1). The data generated by such a technique frequently indicate differences between batches under these conditions and usually show acceptable reproducibility. Correlation of density differences with subsequent relative filling performance has generally been poor.
Reference to Section 8 on the relationship between plug density and various filling parameters suggests that two materials which may behave in a similar way with respect to plug density under a particular set of conditions, especially of port depth (Figures 8.33 and 8.34) behave very differently from each other when these conditions are changed.
Assessment of filling performance potential prior to actual production filling must therefore be performed with caution. Any method used must be carefully standardised and should be closely related to filling conditions used in routine production filling.
Filling performance might usefully be judged on the maximum rate of production (which will depend on the type of machine used) or the shortest dwell time (which will not) at which a specified mean fill weight can be achieved within defined limits of variation, when other influential variables, particularly paddle speed, have been optimised. Other factors may then be introduced which have been used subjectively to assess filling performance. These include 'dustiness' of the powder plugs produced and the length of time a machine will run without adjustment of port depth and other parameters, and without cleaning. These factors have not been considered in this work.
8.6
Effect of vacuum on plug density and coefficient of fill weight
variation.
The machine was set up with the lower paddle speed at 66rpm and a dwell time of 0.75s. This yields a value for Q of 0.83 revs, at which the bulk density of the powder plugs produced for all batches approaches the maximum value at all port depths investigated (at a vacuum of 20"Hg). The CV for all batches approaches a minimum at this value of Q for each port depth (see Section 8.4 above). Powder plugs were collected and weighed as before for a range of port depths. The maximum vacuum reading at each port depth was varied over the range 2 to 20"Hg.
The mean values of plug density for batch A recorded under each set of conditions are presented in Figure 8.35 as a graph of plug density vs vacuum for four port depths. Plug density increases with vacuum over a range which depends upon the port depth. Plug density generally decreases with increasing depth for each port depth investigated.
Figure 8.36 illustrates the effect of increasing the applied vacuum on the CV for a range of port depths. There is, generally, a small decrease in CV at each port depth when the vacuum is increased from 10"Hg to 20"Hg, although this decrease is negligible for a port depth of 23mm.
The change in CV is also illustrated for a port depth of 5mm as the vacuum is increased from 10 to 20"Hg. At 10"Hg most of the material is ejected from the port. At 15"Hg coring of the plug sometimes occurs, when a significant portion of the material in the filled port is retained beyond the ejection stage and the CV is therefore very high. At 20"Hg, coring occurs at each ejection stage so that, although the mean fill weight is reduced, the CV falls back to a level close to that observed
P l u g d e n s i ly ( g e m F i g u r e 8. 35 Pl ug (lenslty vs a p p l i e d v a c u u m at f o u r p o r t d e p t h s ( c e f u r o x i m e h a t c h A, Q = 0.83 revs) 10 IT) V a c u u m (" Ilg) 2 0 d e pIII ( m m ) 0 . 54 - 0 . 5 0 . . 0 . 4 8-- 0. 4 () — f ♦ 25
C V t 8 - . 7. . 2. . L -
l<^igiire 8.36 Co ef fi c ie n t of fill weiglit v a r i a t i o n (CV) vs a p p l i e d v a c im i n ( c e f n r o x i i n e hatcli A, 0 = 0.83 revs) ( i e p l i i (injn) 5 . 0 7 . 5 10 4 — 1 T) 2 0 25
when coring does not occur. Coring is likely to occur when the adhesive forces between the plugs of powder and the inner surface of the port, particularly at the edge of the piston mesh, which, along with frictional forces, oppose the ejection of the powder plug, exceed the cohesive forces within the formed plug, close to the piston mesh (see Section 8.2). It appears that, at lower values of applied vacuum, the adhesive and frictional forces between the plugs and the port are reduced to an extent which is greater than the reduction in the forces of cohesion within the plug, associated with a lower packing density, and the powder plug is ejected complete. It may therefore be possible to reduce the degree of coring where this is a problem, particularly with very shallow ports, by manipulation of the applied vacuum. However, port depths usually associated with coring i.e. less than about 7mm, are not relevant to production filling.
Figures 8.37 and 8.38 illustrate the effect of increasing vacuum on plug density and CV respectively for batch B at a value of Q of 0.83 revs. From Figure 8.37 a pattern of increasing plug density with vacuum is apparent which is similar to that observed for batch A (Figure 8.35). However, plug densities are higher for port depths below 15mm for this batch than for batch A. Such a difference is consistent with that observed in Section 8.2 for these batches under conditions of constant vacuum.
From Figure 8.38 it can be seen that the CV is generally reduced with increasing vacuum for batch B at port depths greater than 7.8mm. At a depth of 7.8mm the CVs at vacuum readings greater than 5"Hg are higher than those for depths of 10 and 15mm. The values of CV at a depth of 23mm across the range of applied vacuum investigated are significantly higher and change over a wider range than those for shallower ports. In this respect batch B differs from A in which values of CV are more closely similar for each port depth when the applied vacuum is above
10"Hg.
Generally, the applied vacuum should be set to the highest value possible to achieve a relatively high bulk density and low coefficient of fill weight variation. This value should be at least 20"Hg to minimise the resulting CV for a wide range of port depths. If the applied vacuum is reduced to less than 20"Hg then CV is likely to be increased to an extent which is more significant for deeper ports.
When lower values of vacuum are applied to deeper ports, particularly with ports of depth 23mm and vacuum less than 10"Hg, the material within the filled port gradually sinks away from the wheel's surface into the port, between the filling and ejection stages of the cycle. In all cases the calculated values of plug density are determined from the mean weight of material discharged from the port divided by the calculated port volume and reflect the actual density within the port immediately after the filling stage is complete. Clearly, where material sinks within the port, the