Using excipients as binders

Excipients are essential to many pharmaceutical applications. Yeli Zhang and Sibu Chakrabarti, from National Starch and Chemical, discuss how they can be used to alter the efficacy of the active drug

Excipients are the mortar in the majority of solid dosage pharmaceutical applications, added to active ingredients to facilitate their effective functioning. They can be used to aid in binding ingredients together, disintegrate active compounds, dilute ingredients and aid tablet compression. They also have a variety of cosmetic uses, such as adding colour, flavour, preservatives and coating films.

The majority of pharmaceutical products are administered via the solid dosage form and more than 90% of drugs are applicable to it.¹ Its benefits include accurate dosing, inexpensive transportation and increased stability in comparison with liquid forms.²

For many manufacturers the preferred solid dosage tabletting technique is direct compression, where the dry ingredients are blended to a homogenous mixture and put directly into the tablet press.

This contrasts with wet granulation, where the active ingredients and excipients are mixed together and then agglomerated with a wetting solution. The mixture is then dried and granulated.

In the direct compression tabletting process, active ingredients are clearly the crucial element in any formulae, but the physical properties of many actives present a challenge to manufacturers. Some may lose potency by reacting to air and moisture, while others may not be easily compressible, which has an impact on tablet size.

Manufacturers turn to excipients to avoid such potential problems in the direct compression process, using them to bind the ingredients together and impart the desired levels of strength and compressibility. By their very nature, binding excipients are often very compressible and can impart this property to other ingredients.

The choice and selection of binder is critical. It must fulfil certain requirements, especially in terms of powder compressibility, density, moisture content and flow properties. Consequently, there are currently relatively few materials that meet the criteria to allow their classification as directly compressible excipients.^3,4 This article aims to analyse and compare the basic properties of six widely available binders. (table 1).

dosage formulations

The compact properties of the excipients were studied in an attempt to understand, characterise and compare the binding mechanism.

The powder properties of the excipients were tested in order to gain a better understanding of the binding functionality. Considering that most common solid dosage formulations are based on biphasic (two-phase or two-component) binder mixtures, an understanding of the performance and functionality of the biphasic mixture of the binders is also crucial. The bulk, tap and true densities for the powders are listed in table 2.

Compared with the bulk and tap densities, the true densities of the excipients are quite close to each other, except DC dicalcium phosphate dihydrate.

physical properties

The moisture contents for the excipients are listed in table 3. All excipients were within the expected moisture content specifications.

Good flow properties are a critical factor for excipients in the successful development of any pharmaceutical tablet. The flowability is typically determined by powder properties such as density, surface area, moisture content, particle shape, particle size and size distribution.

The Mean Time to Avalanche, or MTA, is the measure of the flowability of the powder, while the scatter value defines the regularity of the flow behaviour. A powder with good flow properties will have an MTA close to zero and a low scatter value (table 4). DC dicalcium phosphate dihydrate demonstrated the best flow property, combining the smallest MTA with a low scatter value.

The poor flowability of microcrystalline cellulose is attributed to the particle shape (rod-like particles), small particle size and low bulk density, a theory supported by the fact that silicified microcrystalline cellulose exhibited improved flow properties. The moderate flow property of partially pregelatinised starch may be attributed to higher density (improves flowability) and higher moisture content (reduces flowability). The very poor flowability of low density starch comes from its extremely low bulk density and large surface area. Finally, the spherical particle shape of spray dried DC lactose anhydrous gives it moderate flow, while the favourable particle size and high density gives DC dicalcium phosphate dihydrate its excellent flow properties.

Overall, a gradual improvement in crushing strength was observed as the compression force increased (figure 2). At the same compression force, microcrystalline cellulose, silicified microcrystalline cellulose and low density starch produced the hardest compacts, whereas DC dicalcium phosphate dihydrate produced the softest tablets. The hardness of partially pregelatinized starch and DC lactose anhydrous fell in between the two.

The hardness of a compact depends on two factors: the binding capacity and the compact porosity. Compact porosity is related to compression force. Binding capacity is generally due to material properties. For example, the extremely strong binding properties of microcrystalline cellulose and silicified microcrystalline cellulose are mainly caused by hydrogen bonds between the plastically deformed, adjacent cellulose particles. These hydrogen bonds on an extremely large surface area are brought into close contact during plastic deformation.

slippage and flow

In addition, the existence of moisture within the porous structure of microcrystalline cellulose and silicified microcrystalline cellulose acts as an internal lubricant and facilitates slippage and flow within the individual microcrystals during plastic deformation, enforcing the formation of hydrogen bond bridges.⁵

Partially pregelatinised starch showed low hardness. The low strength of starch is because plastic deformation is too slow to produce adequate interparticulate binding during rapid compression.5 In the meantime, due to elastic recovery during decompression and ejection, brittle fracture occurs, which reduce compact strength.

The extremely good binding functionality of low density starch may be attributable to rapid plastic deformation during compression instead of fragmentation.

DC Lactose anhydrous is a spray-dried anhydrous lactose, which has both amorphous and crystalline regions. Under compression, the crystalline regions undergo brittle fracture readily at lower stresses, the amorphous regions undergo plastic deformation and attribute to its binding capacity.

DC dicalcium phosphate dihydrate exhibited poor binding properties. The brittle nature of DC dicalcium phosphate dihydrate leads to considerable fragmentation during compression.

mixing excipients

Fractures create a large number of interparticulate contact points, which implies a comparatively weak type of bonding. The compact strength is therefore low compared with other binders.

Microcrystalline cellulose was mixed with each of the other excipients in turn and tested for hardness. The microcrystalline cellulose/low density starch mixture demonstrated the highest crushing strength, which was actually higher than that of its separate components. The crushing strength of microcrystalline cellulose/silicified microcrystalline cellulose mixture was lower than that of microcrystalline cellulose, but higher than that of silicified microcrystalline cellulose (figure 3).

For all the other biphasic compacts (microcrystalline cellulose/partially pregelatinized starch, microcrystalline cellulose/DC lactose anhydrous and microcrystalline cellulose/DC dicalcium phosphate dihydrate), the crushing strength was lower than that of microcrystalline cellulose and gradually decreased as the proportion of microcrystalline cellulose in the mixture was reduced.

Excipients are essential to many pharmaceutical applications. Without them, the efficacy of the active ingredients would be seriously impaired. It is not a simple matter of obtaining the excipient, adding to the process and reaping the product benefits, however.

Every excipient has different properties and in processing will exhibit characteristics unique to those properties and to the specific application it is being used in. It is therefore essential that pharmaceutical manufacturers select the most effective excipient for each of their products.

As this research indicates, microcrystalline cellulose - a widely used excipient binder - has poor flowability, excellent compressibility and extremely good compact hardness due to its inherent good self-binding property.

Silicified microcrystalline cellulose showed good flow, excellent compressibility and very good compact hardness.

Partially pregelatinised starch, one of the most popular excipients, exhibited moderate flowability, compressibility and hardness and a high dependence on moisture content, with a higher moisture content leading to poorer flowability and higher hardness.

On the other hand, low density starch displayed excellent binding functionality and hardness, even better than microcrystalline cellulose. However, per se it showed poor flowability.

DC lactose anhydrous presented moderate flowability, compressibility and hardness.

DC dicalcium phosphate dihydrate had excellent flowability, but poor compressibility and binding property.

The research also showed that the hardness of a biphasic mixture is very dependent on the component, but not necessarily dependent on compositions. Low density starch, microcrystalline cellulose, and silicified microcrystalline cellulose perform well as binders due to their plastic deformation under pressure, whereas DC dicalcium phosphate dihydrate tends to fragment. Partially pregelatinized starch and DC lactose anhydrous exhibit both characteristics, but predominantly fragmentation.