Introduction of Directly Copressible Adjuvants

The International Pharmaceutical Excipients Council (IPEC) defines excipient as “Substances, other than the API in finished dosage form, which have been appropriately evaluated for safety and are included in a drug delivery system to either aid the processing or to aid manufacture, protect, support, enhance stability, bioavailability or patient acceptability, assist in product identification, or enhance any other attributes of the overall safety and effectiveness of the drug delivery system during storage or use”5.

Solvents used for the production of a dosage form but not contained in the final product are considered to be excipients, i.e. the granulation fluids, which might be dried off later, should comply with relevant requirements of pharmacopoeia unless adequately justified. Excipients no longer maintain the initial concept of “inactive support” because of the influence they have both over biopharmaceutical aspects and technological factors. The desired activity, the excipients equivalent of the active ingredient’s efficacy, is called its Functionality.

The inherent property of an excipient is its functionality in the dosage form. Determination of an excipient’s functionality is important to the excipient manufacturer in its assessment of the proper level of GMP, and yet the drug manufacturer may withhold this information until well into the development process.

 In order to deliver a stable, uniform and effective drug product, it is essential to know the properties of the active ingredient alone and in combination with all other ingredients based on the requirements of the dosage form and processes applied. Excipients are usually produced by batch process; hence, there is a possibility of batch-to-batch variation from the same manufacturer. Excipients obtained from the different sources may not have identical properties with respect to use in a specific formulation. To assure interchangeability in such circumstances, users may wish to ascertain equivalency in final performance or determine such characteristics before use. Such tests are thus related to the functionality, that the excipient impart to a specific formulation.

 In order to manufacture any finished product with consistent quality, standardization of raw materials in the drug formulation is necessary for its acceptance by regulatory authorities and pharmaceutical formulators. Unfortunately, such performance standards have not been included in pharmacopoeia primarily because their specifications have always been based on chemical purity and because it is not possible to standardize Performance criteria. Pharmacopoeial standards do not take into account particle characteristics or powder properties, which determine functionality of excipients. Control of functionality is important as a control of identity and purity. The following reasons can be cited:

1.    Many excipients have multiple functions (e.g. microcrystalline cellulose, starch).
2.    There is lack of awareness that the excipients behave differently, depending upon the vendor (i.e. microcrystalline cellulose).
As a consequence, excipients with optimal functionality are needed to ensure smooth tablet production on modern machines. The introduction of special force feeder to improve flow of granules from hopper marked a significant advancement in direct compression technology

1.1.2 Ideal Requirements of Directly Compressible Adjuvants
1. Flowability
The directly compressible adjuvant should be free flowing. Flowability is required in case of high-speed rotary tablet machines, in order to ensure homogenous and rapid flow of powder for uniform die filling. During the short dwell-time (milliseconds), the required amount of powder blend should be transferred into the die cavities with reproducibility of + 5%. Many common manufacturing problems are attributed to incorrect powder flow, including non-uniformity in blending, under or over dosage and inaccurate filling.

2. Compressibiliy
Compressibility is required for satisfactory tableting, i.e., the mass must remain in the compact form once the compression force is removed. Few excipients can be compressed directly without elastic recovery. Hence, the directly compressible diluent should have good compressibility, i.e. relation between compaction pressure and volume.

3. Dilution Potential
Dilution potential can be defined as the amount of an active ingredient that can be satisfactorily compressed in to tablets with the given directly compressible excipient. A directly compressible adjuvant should have high dilution potential so that the final dosage form has a minimum possible weight. The dilution potential is influenced by the compressibility of the active pharmaceutical ingredient.

4. Re-workability
A directly compressible adjuvant should be capable of being reworked without loss of flow or compressibility. On recompression, the adjuvant should exhibit satisfactory tableting characteristics.

5. Stability
It is the ability of adjuvant to remain unchanged chemically and physically. The directly compressible adjuvant should not exhibit any physical or chemical change on ageing and should be stable to air, moisture and heat.

6. Control Particle Size
A directly compressible adjuvant should have a particle size equivalent to the active ingredients present in the formulation. The particle size distribution should be consistent from batch to batch. Reproducible particle size distribution is necessary to achieve uniform blending with the active ingredient(s) in order to avoid segregation.

7. Inertness
Filler-binders should not accelerate the chemical and/or physical degradation of the API(s) or excipients. It should not interfere with the biological availability of active ingredient/s. It should be compatible with all the adjuvants present in the formulation. It should be physiologically inert5. It should not interfere with the disintegration or dissolution of the active ingredient. It should be colourless and tasteless. It should be relatively cost effective and available in desired time. It should accept colorants uniformly. It should show low lubricant sensitivity. It should show batch-to-batch reproducibility of physical and physicomechanical properties. It should possess proper mouth fill, which is defined as the feel or the sensation in the mouth, produced when the excipient is used in chewable tablets.