Introduction of Tablet Manufacturing Process

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Over the past hundred years 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.

Introduction Tablet Manufacturing Process

Over the past hundred years 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 form1,2. The ease of manufacturing, convenience in administration, accurate dosing, and stability compared to oral liquids, tamper-proofness compared to capsules, safe 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. The pros and cons of wet granulation and roller compaction are well documented in the literature 3, 4, 5. Prior to the late 1950s, the literature contained few references on the direct compression of pharmaceuticals. A great deal of attention has been given to both product and process development in the recent years. The availability of new materials, new forms of old materials and the invention of new machinery has allowed the production of tablets by simplified and reliable methods 1. In early 1960’s, the introduction of spray dried lactose (1960) and Avicel (1964) had changed the tablet manufacturing process and opened avenues of direct compression tableting. Shangraw6 conducted a survey of 58 products in United States of America for the preference for the granulation process. The results were in favour of direct compression. Of the five processes listed in the survey, the average score (1.0 being the perfect score) for direct compression was 1.5 compared to wet massing and fluid bed drying (2.0), wet massing and tray drying (2.5), all-in-one (3.3) and roller compaction (3.6). About 41% of the companies indicated that direct compression was the method of choice, and 41.1% indicated that they used both direct compression and wet granulation. Only 1.7% of the respondents indicated that they never used direct compression and 15.5% indicated that the process was not recommended. Previously, the word “direct compression” was used to identify the compression of a single crystalline compound (i.e. sodium chloride, potassium chloride, potassium bromide, etc.) 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 ingredients and suitable excipients. No pre-treatment of the powder blends by wet or dry granulation is involved 5. 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 4 (See Table 1). It has been estimated that less than 20 percent of pharmaceutical materials can be compressed directly into tablets 4. 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 adjuvant may yield satisfactory tablets for such materials.

Tablet Manufacturing Process

[A] Wet granulation
Introduction
The most widely used process of agglomeration in pharmaceutical industry is wet granulation. Wet granulation process simply involves wet massing of the powder blend with a granulating liquid, wet sizing and drying.
Important steps involved in the wet granulation
i)    Mixing of the drug(s) and excipients
ii)    Preparation of binder solution
iii)    Mixing of binder solution with powder mixture to form wet mass.
iv)    Drying of moist granules
v)    Mixing of screened granules with disintegrant, glidant, and lubricant.

Advantages
(a)    permits mechanical handling of powders without loss of mix quality:
(b)    improves the flow of powders by increasing particle size and sphericity:
(c)    increases and improves the uniformity of powder density:
(d)    improves cohesion during and after compaction:
(e)    reduces air entrapment:
(f)    reduces the level of dust and cross-contamination:
(g)    allows for the addition of a liquid phase to powders (wet process only): and
(h)    Makes hydrophobic surfaces hydrophilic.

Limitation of wet granulation
i)    The greatest disadvantage of wet granulation is its cost. It is an expensive process because of labor, time, equipment, energy and
space requirements.
ii)    Loss of material during various stages of processing
iii)    Stability may be major concern for moisture sensitive or thermo labile drugs
iv)    Multiple processing steps add complexity and make validation and control difficult
v)    An inherent limitation of wet granulation is that any incompatibility between formulation components is aggravated.

[B] Dry granulation
Introduction
In dry granulation process the powder mixture is compressed without the use of heat and solvent. It is the least desirable of all methods of granulation. The two basic procedures are to form a compact of material by compression and then to mill the compact to obtain a granules. Two methods are used for dry granulation. The more widely used method is slugging, where the powder is recompressed and the resulting tablet or slug are milled to yield the granules. The other method is to precompress the powder with pressure rolls using a machine such as Chilosonator.
Roller compaction
The compaction of powder by means of pressure roll can also be accomplished by a machine called chilsonator. Unlike tablet machine, the chilsonator turns out a compacted mass in a steady continuous flow. The powder is fed down between the rollers from the hopper which contains a spiral auger to feed the powder into the compaction zone. Like slugs, the aggregates are screened or milled for production into granules.
Use: Use in the production of directly compressible excipients, the compaction of drugs and drug formulations, the granulation of inorganic materials, the granulation of dry herbal material and the production of immediate/sustained release formulations.

Processing steps:
Weighing of raw material-screening-mixing-compression to slugs-milling-mixing-compression to finished tablets
Advantages:
The main advantages of dry granulation or slugging are that it uses less equipments and space. It eliminates the need for binder solution, heavy mixing equipment and the costly and time consuming drying step required for wet granulation. Slugging can be used for advantages in the following situations:
i)     For moisture sensitive material
ii)     For heat sensitive material
iii) For improved disintegration since powder particles are not bonded together by a       binder
Disadvantages:
i)     It requires a specialized heavy duty tablet press to form slug
ii)     It does not permit uniform colour distribution as can be
iii) Achieved with wet granulation where the dye can be incorporated into binder liquid.
iv) The process tends to create more dust than wet granulation, increasing the potential contamination.

[D] The direct compression process
This method is used when a group of ingredients can be blended and placed in a tablet press to make a tablet without any of the ingredients having to be changed. This is not very common because many tablets have active pharmaceutical ingredients which will not allow for direct compression due to their concentration or the excipients used in formulation are not conducive to direct compression. Granulation is the process of collecting particles together by creating bonds between them. There are several different methods of granulation. The most popular, which is used by over 70% of formulation in tablet manufacture is wet granulation. Dry granulation is another method used to form granules.

Advantages of Direct Compression

1. Cost Effectiveness
The prime advantage of direct compression over wet granulation is economic since the direct compression requires fewer unit operations. This means less equipment, lower power consumption, less space, less time and less labor leading to reduced production cost of tablets.
2. Stability
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 granulations5. This is extremely important because the official compendium now requires dissolution specifications in most solid dosage forms10.
3. Faster Dissolution
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.
4. Less wears & tears of punches
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.
5. Simplified Validation
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

1. Segregation
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.
2. Cost
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.
3. Low dilution potential
Most of the directly compressible materials can accommodate only 30-40 % of the poorly compressible active ingredients like acetaminophen that means the weight of the final tablet to deliver the 500 mg of acetaminophen would be more than 1300 mg. The large tablets may create difficulty in swallowing.
4. Re-workability
All the spray-dried directly compressible adjutants show poor rework ability 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.
5. Lubricant sensitivity
Lubricants have a more adverse effect on the filler, which exhibit almost no fracture or shear on compression (e.g. starch 1500). The softening effects as well as the hydrophobic effect of alkaline stearates can be controlled by optimizing the length of blending time to as little as 2-5 min.
6. Variation in functionality
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.

 

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