Functionality of directly compressible adjuvants in the formulation of tablets

Over the past century, tablet manufacturers have developed materials and processes that can produce compressed tablets containing a precise amount of an active pharmaceutical ingredient (API) at high speed and at relatively low cost. The development in the field of APIs, excipients and tableting machines during the
past decades has made tablet manufacturing a science and the tablets the most commonly used dosage form. The ease of manufacturing, convenience in administration, accurate dosing, and stability compared to oral liquids, tamper-proofness compared to capsules, safety compared to parental dosage forms makes it a popular and versatile dosage form. Experts in the art of tableting are aware with the basic art of tableting by the three well-known methods, i.e. wet granulation, roller compaction and direct compression.

Prior to the late 1950s, few references on the direct compression of pharmaceuticals exist. Due to great deal of attention been given to both product and process development, the availability of new materials, new
forms of old materials and the invention of new machinery allowed the production of tablets by simplified and reliable methods. In early 1960s, the introduction of spray-dried lactose (1960) and Avicel (1964) had changed the tablet manufacturing process and opened avenues of direct compression tableting. Today, direct compression is the method of choice for granulation process compared to wet massing and fluid bed/ tray drying, wet granulation and roller compaction.

Previously, the word “direct compression” was used to identify the compression of a single crystalline compound into a compact form without the addition of other substances. Current usage of the term “direct compression” is used to define the process by which tablets are compressed directly from the powder blends
of active ingredient/s and suitable excipients. No pre-treatment of the powder blends by wet or dry granulation is involved. The simplicity of the direct compression process is apparent from a comparison of the steps involved in the manufacture of tablets by wet granulation, roller compaction and direct
compression techniques. It has been estimated that less than 20 percent of pharmaceutical materials can be compressed directly into tablets. The rest of the materials lack flow, cohesion or lubricating properties necessary for the production of tablets by direct compression. The use of directly compressible adjuvants
may yield satisfactory tablets for such materials.\

Directly compressible 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”. 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. The reasons for control of identity and purity being an important control of functionality, can be because:

* Many excipients have multiple functions.
* There is lack of awareness that the excipients behave differently, depending     upon the vendor.

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.

Ideal requirements of directly compressible adjuvants

Flowability: The directly compressible adjuvant should be free flowing, 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.

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

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. The dilution potential is influenced by the compressibility of the active pharmaceutical ingredient. A directly compressible adjuvant should have
high dilution potential so that the final dosage form has a minimum possible weight and should be capable of being reworked without loss of flow or compressibility. On recompression, the adjuvant should exhibit
satisfactory tableting characteristics and remain unchanged chemically and physically. The adjuvant should not exhibit any physical or chemical change on ageing and should be stable to air, moisture and heat.

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
components in order to avoid segregation.

Filler-Binders: should neither accelerate the chemical and/or physical degradation of the APIs or excipients nor interfere with the biological availability of active ingredients. It should be compatible with all the adjuvants present in the formulation; be physiologically inert and not interfere with the disintegration or
dissolution of the active ingredient; be colourless and tasteless; be relatively cost effective and available in desired time; accept colorants uniformly, while showing low lubricant sensitivity. It should show batch-to-batch reproducibility of physical and physico-mechanical properties and 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.

 

Advantages of direct compression

The prime advantage of direct compression over wet granulation is economic since the direct compression requires fewer unit operations – meaning less equipment, lower power consumption, less space, less time and less labour leading to reduced production cost of tablets. Direct compression is more suitable for moisture and heat sensitive APIs, since it eliminates wetting and drying steps and increases the stability of active ingredients by reducing detrimental effects. Changes in dissolution profiles are less likely to occur in tablets made by direct compression on storage than in those made from granulations. This is extremely important because the official compendium now requires dissolution specifications in most solid dosage forms.

Disintegration or dissolution is the rate-limiting step in absorption in the case of tablets of poorly soluble API prepared by wet granulation. The tablets prepared by direct compression disintegrate into API particles instead of granules that directly come into contact with dissolution fluid and exhibits comparatively faster
dissolution. The high compaction pressure involved in the production of tablets by slugging or roller compaction can be avoided by adopting direct compression. The chances of wear and tear of punches and dies are less. Materials are “in process” for a shorter period of time, resulting in less chance for contamination or cross contamination, and making it easier to meet the requirement of current good
manufacturing practices. Due to fewer unit operations, the validation and documentation requirements are reduced. Due to the absence of water in granulation, chance of microbial growth is minimal in tablets prepared by direct compression.

 

Limitations of direct compression

Direct compression is more prone to segregation due to the difference in density of the API and excipients. The dry state of the material during mixing may induce static charge and lead to segregation. This may lead to the problems like weight variation and content uniformity. Directly compressible excipients are the
speciality products produced by patented spray drying, fluid bed drying, roller drying or co-crystallization. Hence, the products are relatively costly than the respective raw materials. Most of the directly compressible materials can accommodate only 30-40 % of the poorly compressible active ingredients, which means the weight of the final tablet would be more and the large tablets may create difficulty in swallowing.

All the spray-dried directly compressible adjuvants show poor re-workability since on preparation of tablets the original spherical nature of the excipient particles is lost. API that has poor flow properties and/or low bulk density is difficult to process by direct compression. Lubricants have a more adverse effect on the filler,
which exhibit almost no fracture or shear on compression. The softening effects as well as the hydrophobic effect can be controlled by optimising the length of blending. There is a lack of awareness in some situations that the excipient behave differently, depending upon the vendor so much so that substitution from one source to that of another is not possible. Hence, there is a need for greater quality control in purchasing of raw material to assure batch uniformity.