Are you using the right binder for granulation?
Granulation using a binder is central to pharmaceutical manufacturing. Binder addition not only increases the ease of granule formation but also aids in forming granules of desirable characteristics. A binder ensures cohesion and adhesion between the powder particles in a wet state and confers plasticity, binding ability, and compactibility in a dry state. A binder can be directly added as a dry powder to the powder blend as in the roller compaction method and hot melt granulation. Alternatively, a binder is dissolved in a suitable solvent and then added to the powder blend or mixed with the powders followed by solvent addition.
How does a binder work?
A binder aids the granulation process in many ways. It :
- Increase bonding between primary particles of the formulation thus enhancing granule strength and density and maintains integrity throughout the processing
- Provides enough thermoplasticity and toughness to increase formulation compactibility of granules that are to be compressed into tablets
- Provides necessary thermoplastic and mechanical properties to the formulation mixtures containing components that do not possess favourable compaction properties
Pharma manufacturers have been using natural polymers as wet binders traditionally which includes gelatin, gum tragacanth, gum acacia, starch, guar gum, and sugars like glucose. The other most commonly used binders are polyvinyl pyrrolidone (PVP), partially gelatinized starch (PGS), copovidone, and cellulose-ethers such as methylcellulose (MC), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC).
Selecting the right binder
When it comes to the selection of a binder, it is not an easy task and the formulator has to consider many factors. Traditionally, the selection of a binder has been based on empirical considerations. However, as the number of studies on different binders and their properties is growing rapidly, formulators are considering the scientific aspect as well.
Ideally, a binder should have a high degree of wet adhesion, good spreadability, and a high degree of surface wetting to facilitate the agglomeration process. These attributes depend upon the surface energetic, wettability, physicochemical, and thermomechanical properties of the binder. The film-forming and mechanical properties of a binder along with surface energies determine the granule characteristics.
Considerations of the following factors can help the formulator to narrow down the list of desired binders.
- Binder concentration – Depending upon the drug and formulation, binder concentration tends to vary and also may go beyond typical concentration values. Granule size and strength are proportional to the binder concentration.
- Binder efficiency – It is the minimum binder concentration required to achieve a standard tablet crushing strength and friability. It is not advisable to use maximum binder concentration to achieve granules of maximum strength as it may create challenges in drug release. Instead, it is recommended to use such a binder concentration that will allow forming granules of minimum acceptable strength or maximum acceptable friability. Not only this would lead to achieve granules of desirable strength, but it would also cut down the cost and tablet size.
- Stability and compatibility – The compatibility of a drug with its excipients is a crucial factor and needs to be checked during the pre-formulation study. Although, most of the binders designed today are considered inert; a chemical interaction may be induced in the formulation from the chemical impurities introduced by the drug itself, excipients, or packaging materials. The presence of peroxide, aldehyde, or carboxylic acid groups in the binder should be considered for stability purposes since it may interact with acid-labile drugs or with those having amine and hydroxyl free groups.
- Binder wetting and surface energetics – A binder with poor wettability and spreadability leads to the formation of weak, porous, low-density granules with non-uniform distribution and broad particle-size distribution. A binder must be able to wet a porous powder substrate, penetrate rapidly into the powder bed, spread across the particle surfaces, and distribute uniformly throughout the powder bed. A binder disperses in the powder bed through wetting and capillary action to initiate granulation and this phase is largely decided by the formulation and the selected binder. The interaction between the binder and its substrate is determined by their characteristic properties. For binder fluid, parameters such as surface tension and viscosity become crucial whereas the surface free energy of the substrate plays an important role in the interaction with the binder. The extent of binder-substrate interaction is described by parameters such as contact angles or substrate surface wetting, spreading coefficient of the binder, and the granule characteristics. Surface energetic can also be modified by the use of surfactants or less polar, organic solvents. Hydro-alcoholic solutions of ethanol, isopropyl alcohol (IPA), methanol, acetone are generally used to prepare binder solutions. Hydro-alcoholic solutions are preferred as they help to make granules less friable compared to alcoholic solutions that would give extremely friable granules.
- Regulatory compliance – To avoid issues from the regulatory bodies, it is important to choose binders that are tagged as pharmaceutical excipients or listed in pharmacopeias or inactive ingredient database. Relevant critical material attributes can also be established to facilitate compliance with quality-by-design (QbD) requirements.
The formation of free-flowing, high-quality granules requires many factors to come together and click at the same time and a binder is an important one amongst them. As the advances in material processing science and the discovery of new ingredients have increased the number of binders multifold, so the task of choosing the right binder has become more difficult and tedious for the formulation scientists. However, keeping in mind the final product characteristics and following certain simple practices can put the formulators in the right direction.