Ingredient technology: SMCC leads the way

Silicified microcrystalline cellulose has a number of advantages over the standard microcrystalline cellulose, as Sohan Paul from Penwest Pharmaceuticals explains

What can reduce production costs by 25% or more? How can production plant output be increased without additional capital expense? The answers to these questions is the application of a new high functionality ingredient, silicified microcrystalline cellulose or SMCC (such as Prosolv SMCC from Penwest, Patterson, NY).

SMCC is formed by co-spray drying 2% (w/w) colloidal (fumed) silicon dioxide (CSD) with microcrystalline cellulose (MCC), which is prepared by the standard manufacturing process for premium grades of MCC. Both CSD and MCC are generally recognised as safe (GRAS) by regulatory authorities worldwide.

The compactibility of SMCC Direct Compression (DC) formulations has been found to be two to four times greater than formulations of the same active pharmaceutical ingredient(s) with MCC. This pharmaceutical prescription product could be manufactured to a hardness of 230N with 12% SMCC, compared with only 130N with twice as much (25%) MCC PH102, and a four-fold improvement in compactibility. The harder tablet is more robust for the final coating process. Furthermore, the tablet size and weight is significantly reduced, providing a more appealing product for the patient, which could lead to increased compliance.

The ingredient cost savings are significant due to the four-fold reduction in compaction ingredient(s). Additionally, there is less negative production cost variance with the more robust product, especially in the coating process. And the tabletting speed is doubled without losing hardness of the tablets due to the low strain-rate sensitivity of SMCC 90, which leads to another production cost saving.

more force

Users of SMCC invariably report the ability to increase tablet production speeds without losing hardness or quality of the tablets. To investigate the reason for superior tabletting performance, the relative strain-rate sensitivity of MCC and SMCC was determined using a compaction simulator. The data, shown in table 1, demonstrates that SMCC requires only 4-6% more force to produce an equivalent tablet when the compaction speed is increased 100-fold, while MCC requires 16-17% more force. Most other conventional tabletting excipients require at least 30% more force to accommodate the increase in tabletting speed.

Indeed, cost savings through a reduction in the levels of compaction ingredients used have been achieved using SMCC in numerous commercialised products (table 2). The ingredient costs savings do not stop with the reduction in compaction ingredient. With the use of SMCC, other ingredients can be reduced or eliminated from the product formulation. For example, difficult to handle materials like CSD and talc can be removed, eliminating not only the cost of these ingredients, but the environmental and cleaning issues in production from such fugitive, dusty powders.

Formulations with SMCC can be developed with satisfactory flow and non-sticking properties without the use of ultra-fine powder ingredients. Such formulations at production scale frequently require less lubricant, which also reduces cost and other production issues with high lubricant levels. More importantly, it leads to an increase in the life of tablet machine tooling. Reduction in tooling wear means production benefits, not only in tooling cost savings, but less down-time and labour costs.

The consolidation and densification properties of SMCC products offer even greater production cost improvements in addition to the lower ingredient use levels and elimination of other ingredients. Consider the results for a nutritional product where SMCC 90 provided a 13% increase in the density of the formulation due to its consolidation properties. More tablets could be made from each production batch using the same equipment and avoiding additional capital expense. This consolidation/densification phenomenon, together with an 11% reduction in binder use level with SMCC 90, resulted in a 28% reduction in overall manufacturing costs. The production cost savings from consolidation/densification resulting from SMCC was, in effect, equivalent to producing every fourth batch free.

One of the key functional properties of SMCC that makes it truly effective for DC tabletting is its superior material flow. The silicification of MCC improves the material flow properties equal to or greater than doubling the MCC particle size. This was observed in flow studies (figure 1), where the flow of SMCC 90 was equal to MCC PH200 and greater than PH102. The average particle size of the 200 grades is approximately 200mg, while PH102 and SMCC 90 grades are about 110mg.

satisfactory production

Using conventional ingredients, the process of wet granulation (WG) has been necessary to allow the satisfactory production of many drug products. WG has been used to increase the compactibility of poorly compactible actives, to enhance the flow properties of micronised or aggregating powder actives, and to maintain drug content uniformity in the final dosage form.

The high functionality of SMCC for compactibility, material flow, consolidation and drug active dispersion will provide the necessary properties to allow elimination of the WG process and go to a simple blending and DC process. SMCC also enhances the effectiveness of dry granulations, such as roller compaction, to replace the need for WG, which is very costly relative to DC and takes much more processing time, which reduces production capacity.

The enhanced material flow properties of SMCC, especially its uniform, non-avalanching flow, leads to improvement in drug content uniformity. In fact, some DC formulations, which have been developed with SMCC, demonstrate better drug content uniformity than their original wet granulated formulations using conventional excipients.

Another unique property of SMCC is how well it imparts its inherent good flow properties to drugs and other required excipients. Tablet weight variation studies have demonstrated how well SMCC 90 accommodates both 20% and 25% levels of a very poor flowing acetaminophen (APAP) powder.

With MCC PH102, it was shown that increasing the load of APAP from 20% to 25% destroyed the tablet weight uniformity due to poor flow of the powder blend.

A case study on the conversion of WG to DC for acetaminophen products is documented in US Patent 5,733,578. Acetaminophen is known to be a poor flowing, poorly compactible powder, which requires WG to achieve high drug loading with conventional ingredients.

Using SMCC, high loads of acetaminophen can be processed by simple DC into tablets with good tablet hardness, tablet weight uniformity and drug content uniformity, low friability, quick drug dissolution, and faster tablet disintegration than acetaminophen products produced by wet granulation.

Utilising high density grade of SMCC (HD-SMCC), batch sizes can be increased by another 10-30% depending upon the level of compaction ingredients in the formulation without incurring capital expense. This high density grade, which also incorporates 2% colloidal silicon dioxide, has a density greater than 0.40g/ml, with a particle size of 100mg.

Additional production using high density SMCC is derived from the simple fact that higher density ingredients will occupy less volume in the production equipment. This additional capacity is achieved through high density in addition to the previously described densification and consolidation properties and the lower use levels due to high compactibility of SMCC products. The exact amount of batch size increase achievable can be determined from graphical arrays similar to that shown in Figure 2. This graph plots the potential batch size increase for formulations with the following parameters: bulk density of other components, 0.25g/ml, and density of starting MCC, 0.28g/ml. At a 30% use level of SMCC with a density of 0.42g/ml, the high density SMCC formulation would provide a 17% increase in batch size over the MCC formulation. Compared with high density non-silicified MCC, SMCC a much more spherical structure is observed.

faster flow, lower bridging

High-density spherical silicified particles lead to very fast, uniform material flow properties. Flow rates and bridging apertures for MCC, SMCC, and high density SMCC are shown in Figure 3. These data demonstrate the faster flow and lower bridging potential for the high density SMCC. Fast flow and densification are achieved with the HD-SMCC while maintaining compactibility. It also has faster disintegration in placebo tablets compared with regular MCC over a wide range of tablet tensile strength (figure 4).

The economic value in terms of production cost savings utilising the HD-SMCC is demonstrated in the reformulation of a commercial mineral supplement product (table 3).

First, the level of compaction excipients was reduced, eliminating dicalcium phosphate entirely, which reduced the production costs by $1.66 per 1000 tablets. Meanwhile, the hardness of the tablets was improved by 10% using only half of the original compaction force.

Second, the tablet size and weight was significantly reduced. The additional production cost savings from increased batch sizes was equivalent to getting every third batch production cost free.

The tablet is smaller and easier to swallow. A much smaller bottle, which costs less, can be used to package the tablets. More bottles can be put in a box. More boxes can be put on a truck. And, more bottles will fit into the shelf space.