Tableting and Granulation of Pharmaceutical Materials

Granulating processes of pharmaceutical materials can be broadly classified into dry and wet processes. In the dry process, materials are densified and compressed in a confined space by application of external force, while in the wet process, they are agglomerated by coagulative force between particles. The performance of the former is significantly affected by the stress distribution in the compacts and that of the latter by the packing structure of solid and liquid, that is, the ratio of liquid to solid sup~ plied and their distributions. The author has been developing a tableting machine which can effectively reduce capping in actual product_ion and a powder coating granulator which can provide comparatively uniform distribution of solid and liquid. By using these equipments, capping phenomena and solid-liquid packing structure have been investigated and analyzed. This paper describes the essentials of these results.


Introduction
Granulating processes of pharmaceutical materials can be broadly classified into dry and wet processes. In the dry process, materials are densified and compressed in a confined space by application of external force, while in the wet process, they are agglomerated by coagulative force between particles. The performance of the former is significantly affected by the stress distribution in the compacts and that of the latter by the packing structure of solid and liquid, that is, the ratio of liquid to solid sup~ plied and their distributions.
The author has been developing a tableting machine which can effectively reduce capping in actual product_ion and a powder coating granulator which can provide comparatively uniform distribution of solid and liquid. By using these equipments, capping phenomena and solid-liquid packing structure have been investigated and analyzed. This paper describes the essentials of these results.

Stress distribution in tablets and capping phenomena 1 Analysis of primary factors influencing capping
Capping phenomena have been studied by Train l), Long 2 ), Shott on 3 ), and other workers for many years. However, few of their fruits can be applied to practical production of a tablet which is performed by rotary tableting machine within such a short period of time as 0.02 to 0.1 seconds. The author has investigated the primary factors influencing capping which are listed in Table 1. A part of the results will be described below.
(a) Iterative compression Compressive strength and capping generation of tablets were determined by two different compressing methods. Two tableting machines (A and B) were used which showed different characteristics in tableting. One comprises the iterative compressing formation which was carried out by A-equipment first and then by B-equipment, while the other comprises the converse procedure. The results obtained in this test are listed in Table 2. It can be estimated that capping . would not take place in a compressing stage but in an ejecting one since the same operating conditions were employed in both stages. The difference in tableting performance between these two equipments might possibly result from the slight difference in mechanism of the ejecting stage.

(b) Ejection under pressure
The author has devised a specific rotary tableting machine with pressurized ejection mechanism, which is schematically illustrated in Fig. 1. This machine allows tablets to be discharged out of a die in keeping application of compression pressure from 1 to I 0 MPa with upper and lower punches after the main compression. The compressing force during ejection can be adjusted by sliding wedge-type pressure adjuster and by moving guide rail of the lower punch up and down. Figure 2 shows a drilling load measuring apparatus which consists of a load cell CD, a sample holder ®, elevating equipment @, a drill bit ®, and a recorder @. Typical drilling load distributions of the tablets obtained by the machine shown in Fig. 1 are illustrated in Fig. 3 where the result of the pressurized ejection is compared with that of the nonpressurized ejection. It is found that crack occurred at 2 mm depth from the surface. Summarizing the results obtained from these findings: I) The primary factors influencing capping of   the compacts produced by a rotary tableting machine are involved in the ejection stage.
2) The reduction of capping can be effectively achieved by the method in which the tablets are discharged out of a die under the remaining compression of 1 to 1 0 MPa with an upper and lower punch.     Fig. 6 Residual, compressive stress of die wall (Using concave punch) at the die wall. As can be seen from Fig. 6, the residual stress at the die wall increased as the ratio h/hE increased, that is, the radius of curvature decreased. It has been empirically known that capping increases as the curvature radius decreases. In view of these facts, it may be considered that capping is closely related to the residual stress at a die wall.

2 Stress analysis in capping generation
(b) Residual stress at die wall q r and extent of capping If the compressive stress at a die wall is different from the compressive stress of an upper punch, a shear stress is generated in the body of the tablet. The maximum shear stress in the tablet may be given by  The value of T max during decompression was examined for two materials: caffein and ethoxybeniamide, which are regarded cappingpoor and capping-rich, respectively. The results are shown in Fig. 7. T max becomes qr/2 when the compressive force of the upp~r punch is completely released. On the other hand, Fig. 8 shows the compressive stress-compressive strain curves of the cylindrical tablets of caffein and ethoxybenzamide, which have been prepared by tableting each 1 gram of the powders by a circular die of 1 cm 2 cross sectional area and a flat punch. From the curve in   Fig. 9. It is found that the specific strength varied la~gely at qr/Pb = 1. This implies that the degree of capping can be estimated by the value of qr/Pb. It is emphasized, therefore, that a practical design for a tablet requires a suitable selection of powder prescription and tablet shape.

1 Necessary condition for powder coating granulation
The conditions required for powder coating granulation are considered to be: 1) Mixing and dispersion of solids and liquids 2) Optimization of moisture content 3) Consolidation by tumbling The first is how uniformly coating liquids and powders can be dispersed in the bulk of solids; the second is the ratio of liquid to solid A configuration of the granulator which has been developed after trial and error is schematically illustrated in Fig. 10. This configuration was found to provide an excellent performance on smooth convective mixing without any local stagnation in the granulator, which was called CF equipment by the author. Typical mixing characteristics are shown in Fig. 11, which indicates that the mixing was finished within 20 to 30 seconds. The ratio of air to liquid flow rates is of great importance for spray coating liquids with concentric two-fluid nozzle system. It is because as the droplet diameter is larger, the generation rate of particle coagulation becomes larger. As can be seen from the relationship 80 ,e.  between the air-to-liquid ratio and the generation rate of coagulated particles shown in Fig  12, the decrease in droplet size requires an increase in air-to-liquid ratio.
(c) Control system of moisture content on particle surface To keep the mixture at its optimum wet condition, the granulator is required to be equipped with the specific control system which consists of measuring moisture content of particle surface and determining the feed rate of spraying liquid or powder. It is well known that powder bed becomes an electrical conductor to some extent if spraying liquid is an aqueous solution. Hence the electrical conductivity of the powder bed was used as a measure of moisture content of the particle surface. The system established is schematicall¥ indicated in Fig. 13.

3 Powder coating granulation
Experimental data with the granulation established by the author and operated under the automatically controlled conditions are listed Table 4.

4 Optimum ratio of solid to liquid
Another experiment using this granulator was also conducted to determine the optimum ratio of liquid to solid for practical operations.  The liquid used was a saturated syrup solution and the result is listed in Table 5.

5 Occupation ratio of liquid among particles and optimum ratio of solid to liquid
The specific volume of wet compact ~Po 1 was determined by gradually compressing the particulate material which had been preliminarily mulled in a 100 cm 2 container with liquid at a given liquid-to-solid ratio of 1.5 kg/cm 2 • Its porosity Eo 1 is calculated by the following form:   As seen from Eq. (2), the occupation ratio '¥ can be calculated from the specific volume <Po 1 and the Eo1 obtained from Eq. (1 ). Plots of the occupation ratio against the ratio L(l + 'JI.fpP)/ (S -'JI.L) are shown in Fig. 14, in which the optimum granulating condition is expressed as the symbol ffi. It is obvious from this figure that the optimum condition would be involved within 55 to 65% of 'IF. The author could verify this tendency irrespective of the kind of liquid or powder materials. This suggests that powder coating granulation could be optimized in actual operation for most cases if the occupation ratio 'IF is kept within 55 to 65%.