How Granule Size Influences Tablet Stability and Bioavailability

The bulk granulation process is an essential aspect of the manufacture of tablets within the pharmaceutical industry. The purpose of this process is to convert very fine particles into larger (typically) granules which are more free-flowing than the fine powders and assist in improving the flow properties, compressibility and homogeneity of the powder prior to tablet compression.

The major variables in the granulation process have a significant impact on the properties of the finished tablet product. Granule size is one of the factors that govern how stable or bioavailable a drug will be when ingested.

The characteristics of granules, including the size and distribution, will determine how materials are compressed into a tablet, how the finished tablet will dissolve in the body and how the drug will be absorbed in the body. The regulatory guidelines established by Good Manufacturing Practices require manufacturers to have strict control over parameters related to the granulation process (e.g., granule size) in order to ensure that the product produced is of a consistent quality.

A thorough understanding of the relationship between granule size, tablet stability and drug bioavailability is crucial for pharmaceutical formulation scientists and manufacturing professionals.

What is Granule Size in Tablet Manufacturing?

Granule size indicates the particle size of the granulated powder produced during the granulation (or manufacture of granules) of tablet production. All powders generally go through one of the following methods of processing when being manufactured into tablets:

• Wet method of granulation
• Dry method of granulation
• Roller compaction
• Fluid bed granulation process

Each of these methods results in different-sized granules, which are subsequently screened and mixed to achieve a uniform mixture before being compressed into tablets.

Granule size distribution is generally determined using any of the following methods to confirm that there is consistency:

• Sieve Analysis
• Laser Diffraction
• Particle Size Analyzer

Granule size should be maintained within a defined range because if not controlled properly or out of range, it can adversely affect the quality and performance of the tablets.

Importance of Granule Size in Tablet Formulation

Granule size affects a number of critical attributes of tablet production and performance, including:

• Flowability of the powder
• Hardness and strength of the tablet
• Dissolution rate
• Uniformity of content
• Stability of the drug

Poor control of granule size can lead to several manufacturing problems, including capping, lamination, or variations in weight of the tablets, which will lead to sub-therapeutic performance of the tablets.

Influence of Granule Size on Tablet Stability

The granule size of a tablet can affect the stability of that tablet and how well they last.
The tablet’s stability is the ability of a drug product to keep its physical, chemical, and microbiological characteristics over time.
There are many ways granule size can affect the stability of a tablet:

1. Surface Area and Moisture Absorption

The smaller the granule, the greater the surface area. When there is greater surface area, tablets with fine granules are more likely to have their stability affected by moisture and oxygen in the environment than tablets containing larger granules.
Once moisture has made its way into the tablet, it may lead to:

• Chemical decomposition of the Drug Product (API) that is in the tablet
• Reduction of the shelf-life of the Drug Product
• Change in hardness and friability of the tablets

Therefore, by controlling granule size, we can prevent many problems with degradation due to environmental factors.

2. Tablet Mechanical Strength

Granule size has an effect on how the particles bond together during compression.

• Fine granulation may lead to excessive densification in tablets and produce overly hard tablets, i.e., tablets may crack or laminate because they are so hard.
• On the opposite end of the scale, too many large granules in a tablet will not uniformly densify and will therefore produce weak tablets and a poor mechanical bond.

With an optimal size distribution of granules allows the particles to pack together efficiently and form strong inter-particle bonds; thus, providing a stable tablet during handling, packaging and shipment.

3. Uniform Drug Distribution

If one or more of the granules are too coarse in size, they may become separated from the finer granules during processing or storage. This could cause uneven distribution of the active component throughout the products produced, resulting in variability in the strength of the manufactured dosage forms produced.

Maintaining a controlled granule size helps ensure all tablet dosages are uniform in composition so each tablet provides the intended quantity (dose) of the active ingredient.

Effect of Granule Size on Bioavailability

Bioavailability indicates how quickly and completely a medication enters the general circulation after being administered by the patient.

The size of the granules greatly affects both the speed and efficiency at which medications will become available for absorption through their dissolution after they have been released from the tablet.

1. Rate of Dissolution

Dissolution is an essential step when taking medications, and according to the Noyes-Whitney Equation, the amount of time it takes for a solid material to dissolve will increase proportionately with the amount of surface area present by utilizing smaller sized granules.
Increased surface area is created by utilizing smaller size granules causing:
- Faster rates of dissolution
- Faster release of medications
- Greater bioavailability
However, very fine sized particles in some cases can present formulation problems such as difficulty flowing or clumping together.

2. Rate of Disintegration

Disintegration refers to what occurs when the tablet breaks apart into small particles after the patient has swallowed the tablet.

The size of the granules has an impact on the ease with which water can move into the tablet structure.

• Smaller granules will form more compact density in a tablet and may inhibit dissolving in water due to reduced ease of penetration when compared to larger size granules.
• Larger granules promote a more porous tablet structure and will increase the speed with which water enters into the tablet, allowing for faster disintegration of the dosage form and subsequently faster release of medicine from the dosage form.

When both of these properties are in balance with one another, the tablet will not suffer from delays related to the disintegration or to delays in medication being released from the dosage form.

3. Efficiency of Absorption

Once a drug is dissolved, the solubility rate will be determined by how quickly it is dissolved; then, the best time for it to be absorbed in the GI tract.

The use of smaller particles or granules will enhance dissolution for drugs that are poorly soluble; therefore the rate of dissolution can determine the rate at which a drug is available for absorption.

For some classes of drugs in the Biopharmaceutics Classification System, dissolution rates can restrict their bioavailability.

Balanced Granule Size Distribution

Rather than concentrating on only one size of granule, companies that manufacture pharmaceuticals will try to accomplish an optimal granule size distribution instead.
Typically, a balanced granule size distribution comprises:

• Smaller granules to enhance bonding during compression
• Medium-sized granules for even flow properties
• Larger than average granules to improve capillary action, which will subsequently affect the rate of dissolution.

The combined effect of these three categories of granules will enhance the ease of manufacturing tablets without compromising the uniformity of drug release.

Methods for Controlling Granule Size

Multiple ways to control granule size exist for manufacturers of pharmaceuticals, including:

1. Controlled Granulation Processing

The growth of granules can be influenced by the proportion of binder concentration used, the speed at which raw materials are mixed, and the amount of time allowed for granulation.

2. Screening and Milling

Oversized particles can be removed from the process through sieving, and when larger granules are broken down into smaller granules through the use of milling.

3. Process Analytical Technology (PAT)

The latest technologies used in manufacturing are based upon real-time monitoring methods that measure the physical size of the particles produced in order to ensure consistency from batch to batch.

4. Optimization of Equipment

The three primary types of equipment used in the production of powders include granulators, fluid bed processors, and roller compactors. Each of these types of equipment can be optimized through design parameters to provide for the desired geographic range of the produced granules.

Regulatory Considerations

It is essential for manufacturers of pharmaceuticals to adhere to regulations set forth by regulatory agencies regarding the manufacturing process; these agencies have very specific requirements for controlling critical process parameters within a critical process control system (CPCS), as many of these parameters can impact product quality.
Granules produced during the production of pharmaceuticals are defined by guidelines such as:
- ICH Q8 Pharmaceutical Development
- ICH Q9 Quality Risk Management
Manufacturers need to show that granules are produced with variations in size that do not affect their safety, quality or efficacy.

To accomplish this, process validation studies will be performed to demonstrate that the manufacturing process consistently produces granules within the controlled range as defined.

Challenges in Controlling Granule Size

Even with advanced technologies, granule size can still be difficult to manage consistently.
Several factors that contribute to this difficulty include:

• Variation of properties of the raw materials used
• Changes in humidity/environmental conditions
• Wear and tear of equipment/poorly calibrated equipment
• Variability of the granulation parameters used for the product

By implementing strong process controls, and regularly monitoring the processes, these risks can be decreased.

Granulation size has a profound impact on the stability and bioavailability of pharmaceutical tablets in many various aspects of tablet manufacture such as tablet mechanical strength, dissolution rate, disintegration and drug absorption.

The influence of granulation size on both drug dissolution and bioavailability with respect to small granule sizes being able to promote dissolution and bioavailability by increasing the surface area of granules and larger granule sizes creating increased porosity and stability for a sustain release of the tablets requires controlled granulation processes as well as controlled granule size distributions to create uniform quality products.

By carefully monitoring granule size via established regulatory requirements during controlled granulation processes, manufacturers will have the confidence in knowing that products consistently will perform according to specified customer requirements and will meet regulatory standards. This helps maintain production quality and patient safety.

Frequently Asked Questions (FAQs) on Granule Size Influence the Stability and Bioavailability

Q1. What is granule size in tablets?

Answer: Granule size in a tablet refers to the sizing of the granulated powder particles used for the manufacturing of the tablets.

Q2. Why is granule size important in tablet formulation?

Answer: Granule size in tablet formulation impacts how well the granulated powders can flow (flowability), be compacted (compressibility), dissolve in water (dissolution rate) and how stable the finished tablet will be (tablet stability).

Q3. How does granule size affect dissolution?

Answer: The effect of granule size on how a tablet will dissolve can generally be stated that the smaller the granule, the more surface area available to dissolve the active ingredient (i.e. faster dissolution will occur).

Q4. Can granule size affect tablet hardness?

Answer: Granule size can affect tablet hardness. If too large or too small of granules are used, tablets may be manufactured with weakened structures or excessive amounts of hardness.

Q5. What is the ideal granule size?

Answer: Typically tablets of mixed granule sizes of fine, medium and coarse particles are desired.

Q6. How is granule size measured?

Answer: Common methods used to measure granule size are sieve analysis and laser diffraction.

Q7. Does granule size affect drug bioavailability?

Answer: Granule size affects both the dissolution of the active ingredient and the ability of the body to absorb the drug.

Q8. Which guidelines address granule size control?

Answer: Some examples of regulatory guidelines that discuss granule size are ICH Q8-Pharmaceutical Development and Good Manufacturing Practices.