Fill Depth

6 Adjustable Parameters Formulation, Concentration and Fill Depth 

Setting the product composition of a pharmaceutical preparation, so as to effect an efficient and economical drying cycle, will probably always be beyond the remit of the process engineer. However, bearing in mind the complexities of the freeze-drying process, its optimisation should be given due consideration even by those responsible for product development. 

The important role played by the solution fill depth in determining the sublimation rate has already been touched upon and can hardly be overstated. It depends on the shape of the containing vessel in relation to the fill volume. Ideally, a fill depth of 5 mm is to be recommended. Freeze-drying of chemically labile products at fill depths in excess of 20 mm is to be avoided. Where for pharmacokinetic or other reasons e.g. solubility) a certain volume is prescribed for the administration of the reconstituted solution, the limitation of fill depth has to be achieved by other means. This often involves the use of a vial with a larger-than-ideal diameter. For reasons of cost and suboptimal utilisation of freeze-drier 

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Figure 2 The rate of water loss and residual water content during freeze drying. Moxa-lactam disodium formulated with 12% mannitol in aqueous solution at 30% solids 10 mL tubing vials with a solution fill depth of 1 cm. The chamber pressure was 0.05 torr (6.6 Pa). (From Ref. 2.)...

Modern systems combine one of these control systems with automatic weighing of tablets. Weight control will automatically adjust the filling depth in order to keep tablet weight within specified tolerance limits. 

Fig. 3 Calculated primary drying times for a typical product as a function of product temperature. Open circles = 0.5-cm fill depth filled circles = 2.0-cm fill depth.

Fig. 10 Examples of the kinetics of secondary drying. Triangles = mannitol (crystalline) squares = poly (vinylpyrrolidone) circles = moxalactam di-sodium (amorphous). All solids were prepared by freeze-drying a 5% aqueous solution from a 1-cm fill depth, followed by hydration to a uniform moisture level of 7%. The quantity, F, is the fractional attainment of equilibrium, which corresponds to near zero water content. The secondary drying conditions were product temperature = 18°C chamber pressure = 200mTorr. (From Ref °l)...

Online, force-loop-feedback systems are used for weight control on most production tablet presses. Upper and lower punch forces as well as mean punch force can be monitored by load cells for each station on the tablet press. Deviations between the target and actual compaction forces are measured, and adjustments to the punch filling depth are automatically made to bring the mean force back into the target range. In some cases, the speed of the force feeders on the press is adjusted by reducing the observed variability of the compression force data. 

During tablet compression, the distance between the rollers remains constant unless a machine adjustment is made to change tablet hardness or thickness. Additionally, all tooling dimensions (tooling length and die cavity size) are constant within established standards. Under these conditions, for a specific material of uniform density, if the same volume of material is delivered to each die, the maximum measured compression force for each punch station is the same. If, on the other hand, different volumes of material are delivered to each die, the maximum measured compression force for each punch station is different. On this basis, adjustment of fill depth (fill volume) to maintain a constant compression force should result in a constant tablet weight. This concept is the general basis of all rotary tablet press force control systems. 

As an alternative to performing regression analysis, fill depth can be adjusted to achieve each average weight requirement and the resultant compression force can be recorded and set. 

During normal production with the force control system in operation as specified above, the tablet press will operate to maintain the constant compression force of 10 kN by adjusting the fill depth (Fig. 9). Most force control systems do not require the user to input the upper and lower force control limits for average compression force that are typically set by the manufacturer within tighter tolerances than those demanded by the weight requirements. The control system typically calculates the average compression force every revolution and compares it to the force set point. If the average measured compression force varies from... 

While in the automatic mode, the machine tablet edge thickness is increased or decreased to increase or decrease the tablet weight, respectively. For example, by increasing the machine tablet edge thickness, the measured compression force is decreased. The force control system will then increase fill depth to return the compression force to its previous value thus increasing tablet weight. 

The best fill cam size is that where the fill depth is centered in its range. 

If large tablets are being produced requiring deep fill depths, then insertion depth should be increased. Otherwise, as the punches pass from a deep fill to a shallow insertion depth, the uncompressed granulation will be pushed out of the die cavity resulting in material loss. 

If the insertion depth is too shallow relative to the fill depth, material will be pushed out of the die and lost to the dust extraction system. 

It is most desirable to compact the entire fill depth. Therefore D is taken as 30 feet, 9.14 meters, in equation 3.1, to see if energy requirements are reasonable and attainable. (Assume no surface mat is needed.)... 

Figure 4 illustrates an experimental test performed on 5% solutions of KCl and polyvinyl pyrrolidone (PVP), both at 10-mm fill depth. The inverse relationship between and T is clearly shown and, interestingly, takes a very similar course for both products, despite their marked physical differences, i.e. KCl is crystalhne and PVP is amorphous. To a first approximation, the sublimation rate increases 3-fold for every 10° rise in temperature. It must, however, be remembered that for a wholly or partly amorphous product, the temperature of the subliming ice front must not be allowed to exceed the glass transition temperature Tg. It follows that the product composition also plays an important role in determining... 

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