Binders are one of the critical excipients for a successful wet granulation formulation. They are used to create an ordered mixture of all the ingredients by creating a cohesive network.
Binders that are commonly used as granulating agents and these can be subdivided into three main categories,
- Sugars such as sucrose, glucose, or sorbitol for use primarily in chewable tablets
- Natural polymers and gums such as pregelatinized starch, starch, acacia, gelatin, and sodium alginate
- Synthetic polymers which include PVP, PEG, all the semi-synthetic cellulose derivatives (e.g., Hydroxypropylmethylcellulose (HPMC), Methylcellulose, hydroxypropylcellulose (HPC), sodium carboxymethylcellulose (CMC) and ethylcellulose as well as the polymethacrylates, a class of materials sold as either aqueous dispersions, dry powders, or organic solutions under the trade names Eudragit, Eastacryl, Kollicoat, or Acryl-eze.
Table 1 for a listing of common binders used in aqueous-based processes and their concentration ranges.
ALSO READ: Granulation Process in Pharmaceutical
- With the advent of newer synthetic polymers, several natural binders are no longer that popular. Gelatin usage has dramatically decreased due to health concerns over Bovine Spongiform Encephalopathy or Mad Cow Disease. Acacia or Gum Arabic, being a natural product, was found to be prone to batch-to-batch inconsistencies in its viscosity as well as having high-bacterial counts.
- Starch required an extra processing step of heating in order to form a paste. The high viscosity of the paste makes this ingredient more difficult to work with and incidentally, can lead to localized over-wetting, which generates oversized granules. Consequently, it is difficult for the starch to become homogeneously distributed throughout the powder bed and many formulators have preferred to use pregelatinized starch instead for its easier use and improved impact on product quality.
- The selection of the appropriate binder and levels for a certain application are usually empirical, involving some type of optimization and based upon previous results, functional characteristics, performance, cost, and availability.
- The ability of a binder to produce strong, non-friable granules is dependent on the binder itself and binder’s distribution in the granulation. However, the use of too much binder or too strong and cohesive of a binder will produce harder tablets which will not disintegrate easily, hence, impairing drug release, and can even cause excessive wear on the punches and dies. On the other hand, using too low a quantity of binder will produce friable granules, can generate a large amount of fines, and produce tablets with lower crushing strengths as a result.
- Binders can be added either as dry powders in the blend or prepared beforehand as solutions and added during mixing. Generally, a larger quantity of granulating liquid used will yield a narrower particle size range along with coarser, harder granules due to the formation of solid bridges as with excipients such as lactose.
- Using a low-viscosity binder solution as opposed to a dry powder requires a much lower concentration of the binder in order to achieve a certain granule hardness. This is likely due to the fact that the polymer is already fully hydrated and dissolved in the solution; which enables it to be more easily homogeneously distributed within the blend.
- In general, it has been shown that the use of a dry binder added to the powder blend results in smaller granule sizes and a high level of larger lumps. It is recommended to add a dry binder to the blend because the binder distribution throughout the powder bed cannot be assured.
- When applying the binder solution during mixing, it is best to provide a uniform liquid spray with as small a droplet size as possible as this will have the largest surface area. This spray will have the greatest coverage throughout the powder bed and will prevent localized over-wetting of the granules, which can result in oversized particles.
- The rate of binder addition is important as well since a consistent, steady rate is desired to obtain a narrower and consistent particle size distribution. Typically, finer granules with lower bulk densities can be obtained when a smaller volume of liquid is added during mixing. Moreover, these granules of smaller particle size yield tablets with faster dissolution rates and lower hardness values.
- The mechanical properties of a binder film are important as well and a good tablet binder.
- should be able to offer flexibility and plasticity and yield without rupturing in order to absorb the effects of elastic recovery.
- The type of binder selected can also affect the mechanical properties of the granules and tablets. While gelatin showed the highest granule crushing strength using the lowest binder levels during high shear granulation, PVP showed intermediate values for crushing strength.
- At the other end of the spectrum, PEG 4000, a waxy, plastic material exhibiting poor binding properties, showed not only the lowest granule crushing strength values but required the highest binder levels. Recently, it was similarly reported for lactose-based placebo granulations using aqueous binder solutions of 9% w/w in a fluid bed granulator, that the mechanical strength of PVP K30 granules was lower than that of granules prepared with either pregelatinized starch or gelatin; in fact, PVP granules were characteristically softer, more plastic, and readily deformable.
- Gelatin, now widely phased out as a binder in the pharmaceutical industry, had some interesting properties. Gelatin is a protein-based polymer that undergoes gelation when cooled to ambient temperature. It is known to provide good adhesion properties in agglomerates, produce films with high tensile strength, and yield strong granules and tablets of intermediate hardness.
- The binder selected also has implications for coating operations as it would be more advantageous to use a binder with a lower elastic recovery as this would diminish the likelihood that the common problems of tablet coating uniformity and cracking would
Tags
Production
