The role of disintegrate in solid oral dosage form!

At first we have to know about disintegrate.......

WHAT ARE DISINTEGRATES?

Disintegrates are agents added to tablet (and some encapsulated) formulations to promote the breakup of the tablet (and capsule “slugs’) into smaller fragments in an aqueous environment thereby increasing the available surface area and promoting a more rapid release of the drug substance.

There are three major mechanisms and factors affecting tablet disintegration as follows:

A:    Swelling:

Although not all effective disintegrates swell in contact with water, swelling is believed to be a mechanism in which certain disintegrating agents (such as starch) impart the disintegrating effect. By swelling in contact with water, the adhesiveness of other ingredients in a tablet is overcome causing the tablet to fall apart.

B:    Porosity and Capillary Action:

Effective disintegrates that do not swell are believed to impart their disintegrating action through porosity and capillary action. Tablet porosity provides pathways for the penetration of fluid into tablets. The disintegrate particles (with low cohesiveness & compressibility) themselves act to enhance porosity and provide these pathways into the tablet. Liquid is drawn up or “wicked” into these pathways through capillary action and rupture the inter-particulate bonds causing the tablet to break apart.

C:    Deformation:

Starch grains are generally thought to be “elastic” in nature meaning that grains that are deformed under pressure will return to their original shape when that pressure is removed. But, with the compression forces involved in tableting, these grains are believed to be deformed more permanently and are said to be “energy rich” with this energy being released upon exposure to water. In other words, the ability for starch to swell is higher in “energy rich” starch grains than it is for starch grains that have not been deformed under pressure.

It is believed that no single mechanism is responsible for the action of most disintegrates. But rather, it is more likely the result of inter-relationships between these major mechanisms.

The classical example of the earliest known disintegrant is Starch. Corn Starch or Potato Starch was recognized as being the ingredient in tablet formulations responsible for disintegration as early as 1906 (even though tablet disintegration was itself not given much importance in tablet formulations until much later).

Until fairly recently, starch was the only excipient used as a disintegrant. To be effective, corn starch has to be used in concentrations of between 5-10%. Below 5%, there is insufficient “channels” available for wicking (and subsequent swelling) to take place. Above 10%, the incompressibility of starch makes it difficult to compress tablets of sufficient hardness.

Although the connection between bio-availability of drug and tablet disintegration took some time to become appreciated, it is now accepted that the role of the disintegrate is extremely important.

Other factors which affect the dissolution of Drugs from tablets are:

• Type and Concentration of Active Ingredient
• Type and Concentration of Binder Used
• Type and Concentration of Fillers Used (soluble vs. insoluble)
• Type and Concentration of Lubricant Used
• Type of Dissolution testing Used (Apparatus, Speed, Media)
• Manufacturing Process (wet granulation vs. compaction vs. direct compression)

In a direct compression process, drug is blended with a variety of excipients, subsequently lubricated and directly compressed into a tablet. A disintegrant used in this type of formulation, simply has to break the tablet apart to expose the drug substance for dissolution.

In a wet granulation process, the drug substance is combined with other excipients and processed with the use of a solvent (aqueous or organic) with subsequent drying and milling to produce granules. The resulting granules are then blended with additional excipients prior to being compressed into a tablet. {Dry compaction is similar. But compression and milling are used (rather than solvents) to make the granules}

A disintegrant used in granulated formulation processes can be more effective if used both “intragranularly” and “extragranularly” thereby acting to break the tablet up into granules and having the granules further disintegrate to release the drug substance into solution.  However, the portion of disintegrant added intragranularly  (in wet granulation processes) is usually not as effective as that added extragranularly due to the fact that it is exposed to wetting and drying  (as part of the granulation process) which reduces the activity of the disintegrant.  Since a compaction process does not involve its exposure to wetting and drying, the disintegrant used intragranularly tends to retain good disintegration activity.

The following are some of the disintegrates which were available prior to the use of the formulation.....

Pregelatinized Starch (Starch 1500)  

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Pregelatinized starch is a directly compressible form of starch consisting of intact and partially hydrolyzed ruptured starch grains. Pregelatinized starch has multiple uses in formulations as a binder, filler and disintegrate.  As a disintegrate, its effective use concentration is between 5-10%. It’s major mechanism of action as a disintegrate is thought to be through swelling.

Micro-crystalline Cellulose (Avicel)  

Like pregelatinized starch, micro-crystalline cellulose is widely used in formulations because of its excellent flow and binding properties. It is also an effective tablet disintegrant when used in a concentration of between 10-20%.

Others  
Sodium Bicarbonate in combination with citric or tartaric acids is used as an “effervescent” disintegrant.

Alginic Acid at a concentration of between 5-10% is an effective, but very expensive disintegrant.

Ion Exchange Resins (Amber-lite 88) has disintegrant properties at a concentration of between 1-5%. But this type of disintegrant is rarely used.

SUPER DISINTEGRANTS:

Because of the increased demands for faster dissolution requirements, there are now available, a new generation of “Super Disintegrates”

Three major groups of compounds have been developed which swell to many times their original size when placed in water while producing minimal viscosity effects:

1. Modified Starches- Sodium Carboxymethyl Starch (Chemically treated Potato Starch)

i.e. Sodium Starch Glycolate (Explotab, Primogel)

Mechanism of Action: Rapid and extensive swelling with minimal gelling.

Effective Concentration: 4-6%. Above 8%, disintegration times may actually increase due to gelling and its subsequent viscosity producing effects.

2. Cross-linked polyvinylpyrrolidone- water insoluble and strongly hydrophilic.
i.e. crospovidone (Polyplasdone XL, Kollidon CL)

Mechanism of Action: Water wicking, swelling and possibly some deformation recovery.

Effective Concentration: 2-4%

 

3. Modified Cellulose- Internally cross-linked form of Sodium carboxymethyl cellulose.

i.e. Ac-Di-Sol (Accelerates Dissolution), Nymcel

Mechanism of Action: Wicking due to fibrous structure, swelling with minimal gelling.

Effective Concentrations: 1-3% (Direct Compression), 2-4% (Wet Granulation)

ADVANTAGES:

• Effective in lower concentrations than starch
• Less effect on compressibility and flow ability
• More effective intragranularly

DISADVANTAGES: 

• More hygroscopic (may be a problem with moisture sensitive drugs)
• Some are anionic and may cause some slight in-vitro binding with cationic drugs (not a problem in-vivo.)

SUMMARY OF DISINTEGRANTS:

• Disintegrants are an essential component to tablet formulations. While rapidly disintegrating tablets do not necessarily ensure fast bioavailability, slowly disintegrating tablets almost always assure slow bioavailability.
• The ability to interact strongly with water is essential to disintegrant function.
• Combinations of swelling and/or wicking and/or deformation are the mechanisms of disintegrant action.
• Super disintegrants offer significant improvements over starch. But hygroscopicity may be a problem in some formulations.

If a Pharmaceuticals Company isn't following cGMP, are there drug products safe for use?

If a company is not complying with cGMP regulations, any drug it makes is considered “adulterated” under the law. This kind of adulteration means that the drug was not manufactured under conditions that comply with cGMP. It does not mean that there is necessarily something wrong with the drug.

For consumers currently taking medicines from a company that was not following cGMPs, FDA usually advises these consumers not to interrupt their drug therapy, which could have serious implications for their health. Consumers should seek advice from their health care professionals before stopping or changing medications. Regulatory actions against companies with poor cGMPs are taken as a preventive measure because the manufacturing processes do not meet FDA’s regulatory standards. By focusing on the procedures and processes used to make these drugs, FDA is working to ensure that drugs meet their quality standards and are safe and effective. The impact of cGMP violations depends on the nature of those violations and on the specific drugs involved. A drug manufactured in violation of cGMP may still meet its labeled specifications, and the risk that the drug is unsafe or ineffective could be minimal. Thus, FDA’s advice will be specific to the circumstances, and health care professionals are best able to balance risks and benefits and make the right decision for their patients.

How does FDA determine if a company is complying with cGMP regulations?

FDA inspects pharmaceutical manufacturing facilities worldwide using scientifically and cGMP trained individuals, whose job it's to evaluate whether the company is following the cGMP regulations. FDA also relies upon reports of potentially defective drug products from the public and the industry. FDA will often use these reports to identify sites for which an inspection or investigation is needed. Most companies that are inspected are found to be fully compliant with the cGMP regulations.

Why cGMP so Important?

I discussed shortly....

A consumer usually can't detect that a drug product is safe or if it will work.  While cGMP require testing, testing alone is not adequate to ensure quality. In most instances testing is done on a small sample of a batch (for example, a drug manufacturer may test 100 tablets from a batch that contains 2 million tablets), so that most of the batch can be used for patients rather than destroyed by testing. Therefore, it is important that drugs are manufactured under conditions and practices required by the cGMP regulations to assure that quality is built into the design and manufacturing process at every step. Facilities that are in good condition, equipment that is properly maintained and calibrated, employees who are qualified and fully trained, and processes that are reliable and reproducible, are a few examples of how cGMP requirements help to assure the safety and efficacy of drug products.