Manufacture Of Pharmaceutical Tablet

Drug (Tablet)

Pharmaceutical production is the production of tablet or related products in pharmaceutical industries or companies. However, this is not the first stage in drug production. It takes stages for a drug to hit the market. It begins with drug discovery in school or research institution laboratories. After establishing the drug, it's design begins.

From drug discovery, it is established the type of drug, it's indication and the best route. This information is just enough for a pharmaceutical company to design a suitable dosage form. After then will drug production commence.

Pharmaceutical Manufacturing Of Tablet

This is defined as the industrial scale syntheses of pharmacological drugs by pharmaceutical companies. The process is made up of a series of unit operations.

Unit Operation

A unit operation is specialised in a single or few operations of a drug production. Some units have smaller units within a larger one. In a drug production process involving tablet, they are divided into;

1. Dispensing/weighing

2. Milling/screening

3. Blending

4. Granulation

5. Drying

6. Tablet compression

7. Coating

8. Packaging

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Liquid dosage form does not go through all these. It usually ends with blending and jumping to packaging.

Dispensing/Weighing

It is in this unit the weight required for each active pharmaceutical ingredient (API) and it's excipient is calculated and accurately weighed. The weight required determines the type of weighing machine to be used. But since it is bulk weighing, they use big machines unlike those used in the school laboratory.

To prevent contamination of the ingredients, the room is constructed to exclude microbes. They make use of three basic principles. They are;

1. Unidirectional flow of materials and personnel

2. Segregation between hazardous and non hazardous material

3. Separation of storage and manufacturing items Some designs make use of laminar airflow, broths or gloves boxes. The room is called weighing room, weight room, central weighing dispensary, dispensing, fractionation and subdivision.

Milling/Screening (Particle Size Reduction)

Since a drug is made up of both API and excipients, it is good they are of the same characteristics. When the particles are of different behaviour, the final drug will not be able to uniformize between tablet or batch. Some of the ingredients are made up of large particle powder and some small particle powder. Mixing it like this will result in segregation of the particles during production. The large particles will fall to the bottom of a container due to gravitational force leaving the small particles to float at the top. This results in excipients/API segregation. Some tablets formulated like this will not contain either an API or it's excipient. This is because the API may be the big particle and the excipient the big particle . To solve this problem, all the ingredients are grinded to attain the same particle size. This process is also called size reduction, milling, crushing, grinding and pulverization.

Advantage Of Milling

1. Improves flow properties

2. improves the colour and or API dispersion in tablet excipient

3. tablet uniformity

4. Increase surface area that enhance active dissolution rate

Disadvantage Of Milling

1. The milking process generates heat that can end up damaging the ingredients that are heat sensitive. Slow mill speed with sheet break can prevent this.

2. May end up with excessive production of fines or overly broad particles size distribution. Each powder should be mill with the right milling machine for periods that will produce the right powder size.

3. Increase in surface energy can lead to agglomeration.

Milling Equipment

There are different milling equipment and work hard on three principles. They are;

1. Shear (cutting)

2. Compression (crushing)

3. Impact (high velocity collision)

Example of mills are;

1. Screen Mills

2. Impact mills: hammer and pin type

3. Jet mill: pancake (spiral), loop/oval, opposing, fluidized bed and fixed/moving target

4. Stirred media mill

5. Energy based analysis: ball mill

6. Fluid energy mill

Blending

Hardly a drug is made only from it's API. The drug is usually added to excipients. These excipients after obtaining the same particle size are mixed together. This process can be done before or after granulation which is the next step here. Blending must follow a particular design if the drug is to achieve the desired result. The right amount of load, speed and time all contribute to achieving a good mix. This is similar to mixing sand and cement. Wrong blending can lead to segregation of particles, over mixing of lubricant, etc.

Blending is done with some pharmaceutical machines some of which are oblocone, container, tumbling and agitated machines.

Granulation

When blended products segregate or tend to be impacted by one of the machines used in tableting, the ingredients are granulated. Segregation is caused by difference in the density or size of the particles or mix. Smaller and denser particles segregate to the bottom of a container while the larger and less dense particles remain at the top. This kind of situation can cause API to stay in one place and the excipients at another place. This causes some tablets to have more API and others not to have.

Granulation is a situation whereby powder particles are made to form large particles called granules. This is achieved by adding a binding agent or compression. A granules will contain all the constituents of the mixture in the correct proportion in each granule of the same size without segregation. In some capsules, this is the final stage before encapsulation.

Properties Of granules

1. Compressibility

2. Cohesiveness

3. Flowability

4. Bulk density

Granulation Technique

There are two methods of granulation. They are the wet and dry granulation method.

Wet Granulation

When liquid is used to turn powder particles to granules, it is called wet granulation. The liquid may contain binding agents. Wet granulation is only use for compounds that are stable to moisture.

Advantage

1. Improves flow of drug particles in machine

2. Improves tablet uniformity

3. Increase bulk density

4. Enhanced resistance to segregation

Disadvantage

1. Disintegration and dissolution may be retarded due to double lubrication.

Properties Of Liquid Use In Granulation

Volatile and nontoxic

Types of liquid

Water

Is the most common use liquid

Advantage

1. Cheap

2. Available

3. Non-flammable

Disadvantage

1. Affect drug stability

2. Prolong drying time of granules

Ethanol, isopropanol

Advantage

1. Use for water sensitive drugs

2. Faster than water in granulation

Disadvantage

1. Expensive

2. Disintegration and dissolution may be retarded due to double lubrication

Process

1. First agitate the powder in a container

2. Spray the powder with the required liquid

3. The powder is mixed and kneaded until a uniform dispersion is form

Parameter

1. Amount of binder

2. Rate of addition

3. Time of granulation

4. Speed

Dry Granulation

It is a method employed for heat sensitive powders. The process invoice pressing together the powders to achieve granules.

Advantage

1. Suitable for moisture sensitive powders

2. Increase bulk density

Disadvantage

1. Disintegration and dissolution may be retarded due to double compaction.

Methods

There are many methods in dry granulation. They all have the same basic working principle.

Roller Compaction

First, the powder is conveyed from the feeding system to the compaction unit area. Here it is compressed by two counter rotating rolls to a ribbon. The last phase consists of a size reduction unit for milling the ribbons to size.

Parameters

1. Roll speed (horizontal and vertical)

2. Pressure

3. Deaeration

4. Roll diameter

5. Surface

Slugging

In this method, the powders are compressed into tablet form directly using a tableting machine. There could be weight differences between tablet and even uneven tablet particles distribution due to poor flowability.

New Methods

Steam granulation: using steam as a source of water. Their produce spherical and easy dissolution

Melt granulation/thermoplastic: meltable binder is added to the mixture at high temperature (50-80 °c) which solidifies at room temperature. No need for drying.

Moist granulation Technique (MGT): After wet granulation, a moisture absorbing material is added to remove moisture.

Drying

Drying the granules is the next stage after wet granulation. Wet granules degrade easily. Moisture provides a suitable environment for microbes. Drying removes moisture.

Types Of Dryers

There are different ways of removing moisture to avoid destroying the granules. One uses direct heat of the powder. An example is tray dryers. The other is an indirect contact of the heating medium with the powder. An example is a fluidized bed dryer.

Others are vacuum tray, microwave, spray, freeze, turbo-tray, etc. The best is the fluidized bed dryer because it is a single machine for both wet granulation and drying. This saves cost, space, time, uniformity of products and easy process.

Tablet Compression

This is the last phase of tablet formation before packaging for distribution and sales.

Process

The process makes use of machines. There are two main types of machine for tableting. They have single and multiple punches (rotary press {3-60 punches} and multi layer high speed rotary press). Single punch uses just one punch and dies to produce a single tablet per time and can produce up to 200 tablets per minute. It is slow and time consuming. Some are even bigger than multiple punches.

Multiple punches have many punches and die for producing many tablets at the same time. They can produce up to 10000 tablet per minute. It is fast and can produce many tablets in a short time.

The powder is poured into the hopper. The hopper is like a cone that can hold so many of the powder. Using gravitational force, the powder flows down into the via die. Under the die is a punch that can move upward during tableting. The die rim rolls off sealing the mouth of the hopper from allowing more powder to flow down. The lower punch in some machines moves upward as the upper die comes down to compress the powder into tablets.

After attaining a particular pressure, the upper punch leaves. The lower punch pushes upward to the same level with the die rim. A pushing device removes the formed tablet from the machine.

Core components of tableting machine

1. Die

2. Punch

3. Hopper

4. Cam tracks

5. Feeding mechanism

Properties Of Powder For Tableting

1. Compressibility

2. Flowability

Direct Compression

As earlier said, not all powders require granulation. Powders that already have the characteristics of granules can be compressed directly.

Advantage

1. These powders have over those that require granulation to reduce production cost and time.

2. Produce drugs that have faster dissolution and disintegration rate

3. Require less equipment thereby creating space and reduce learning time for newcomers

4. Products stability can be greatly improve

5. Eliminate heat and moisture hence suitable for thermal and moisture sensitive API

6. Batch to batch variation reduce

Disadvantage

1. Non-uniform distribution of colours especially in tablet of deep colour

2. Problem in uniform distribution of low dose drugs

3. Many active ingredients are not compressible

4. Large particles must be use

5. Needs direct compressible filler and are expensive eg avical

6. High dose drugs with high bulk volume, poor compressibility are not suitable for direct compressible

Coating

Not all tablets are coated. Coating is a type of material used to cover a tablet. Thia process is a small unit under compression.

Reasons For Coating

There are several reasons for coating tablets. They are:

1. Taste masking

2. Improve drug release

3. Protect the drug from moisture and air

4. Make the product stronger

5. Add colour

6. Easy to handle during package

Type Of Coating

1. Sugar coating

2. Film coating

3. Enteric coating

4. Pan

5. Fluid bed or air compression coating

Packaging

The finish tablet must be protected from the environment. This saves it for the end user and enables it to stand until the day of expiration. The type of packaging will be determined by the type of formulation of the medicine. Liquid formulation goes into bottles or softgel. Blister packs are the most commonly used in tablet packaging as they are cheap and protect the majority of drugs. It is also good as it is transparent and the patient can see the tablet. Light sensitive tablets cannot be packaged with blisters.

Types Of Packaging

a. Primary e.g. bottle, cup and sachet

b. Secondary e.g. packets, small cartons of one or few products

c. Tertiary e.g. cartons for export and bulk purchase

Table Defect

During production, the tablet may fail to meet industry standards. This could be due to a minor error in the production line. Examples are moisture, improper drying, excess binder, poor lubricant, wrong ratio of ingredients, air, wrong speed of machine, wrong temperature, size and shape.

Types Of Defect

Mottling: this is an unequal distribution of colour on the surface of the tablet. This is usually due to the different colours of ingredients. It can also result from colour change due to degradation. Another possibility is migration of dye during drying of the granules.

Solution

a. Change solvent system

b. Reduce drying temperature

c. Reduce Particle size

Capping and lamination: When the upper part of a tablet comes off, it is called capping. It can occur at any stages of the he tableting process like tableting or packaging or even before use. This is caused by entrap air. Entrap air is caused by large amounts of fines in the granulation or lack of sufficient clearance between the punch and the die or too dry granulation.

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Lamination is the same as capping. But this time, it occurs by the side of the tablet. It's cause is the same as capping.

Solution

a. Increase binder especially dry binder

b. Decrease the upper punch diameter

c. Ensure right amount of granules

Binding

It is granules adhering to the die wall. This leads to difficulty in ejecting the tablet from the machine (die). Tablets with rough and vertical score marks on the edges are the end products. It is caused by insufficient lubrication and adequate distribution and moisture.

Sticking

The whole tablet sticks to the punch surface. This leads to a full scratch or rough surface. It is caused by improper dry or lubricated granulation.

Picking

Small part of the tablet sticks to the punch face.

Filming

Slow form of sticking due to excess moisture in the granulation.

Others are;

a. Chipping

b. Weight variation

c. Poor flow

d. Hardness variation

e. Double compression

f. Cracking

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