A Broad and Holistic Review of Nutraceutical Granules using Polyherbal

Abstract

The trend of seeking natural alternatives has triggered the invention of new products known as nutraceuticals which are health-beneficial and have an added value to basic nutrition. Multiple medicinal herbal formulations have brought their synergistic effect to the forefront and enhanced single medicinal therapy’s therapeutic potential. This study is concerned with forming and characterizing polyherbal granules as a carrier system for nutraceuticals. The polyherbal granules were prepared using extracts from several plants with antioxidant, anti-inflammatory, and immunomodulatory properties. The granules were designed and prepared to facilitate oral administration, controlled release, and increased bioavailability of the active ingredients. This included identification of the appropriate herbs, extraction of their bioactive components using suitable solvents, and standardization of the preparation of the granules with regard to granulation, drying, and sieving processes. Various physical parameters such as particle size, flow ability, and compressibility were assessed in addition to the kinetics of in vitro release studies of the nutraceuticals incorporated into the granules. The granule formulation was evaluated for its stability under different storage parameters to provide assurance on its effectiveness for a longer period. The preparation of the polyherbal nutraceutical granule has shown good and favourable results within the time period of the study regarding the components used.

Introduction

“Nutraceutical” means nutrition plus medicine and was coined by Dr. Stephen De Felice, founder of the Foundation for Medical Innovation. “Nutraceutical” is the trade name for any product, dietary supplement, or preparation that contains instructions to help detect, treat, or prevent a seemingly endless number of diseases (e.g., nutraceuticals are essentially taken as or incorporated into food to achieve therapeutic and health effects and to mitigate or reverse the onset of a wide range of diseases)¹. The Latin word “granulatum,” which names a granular mixture, comes from the same root as the English word “granulated.” The word “granules” refers to the aggregation of small, fine particles in the pharmaceutical granulation process, which are subsequently developed into a bigger and more complex material. Among these structures, the average size is around 0.2 to 0.4 mm. “Usually, particles that are in the 0.2 to 0.5 mm range are created and then they are most effective for binding or pressing together during compaction. Pharmaceutical granulation which is in a way, disperses the particles efficiently, already mentioned above, and is the key factor in the improvement of the medicine quality².

Nutraceuticals, which are functional foods or dietary supplements that provide health benefits aside from very basic nutrition, have received considerable attention in the past few decades. Granules, which are only one of the several types of nutraceuticals, have been in the spotlight for being the best choice so far because of their comfort of being used, being stable, and their possibility of controlled release of active drugs. Polyherbal formulations, which use several plant extracts with combined effects to create synergy, are now being used in growing numbers of research projects as such formulations are expected to have diverse healthcare benefits e.g. immune support, anti-inflammatory, and antioxidant properties. Oxidative stress is a major factor in disease onset and progression. Successful formulations lead to improved health outcomes and reduced risks of side effects associated with single herb treatment or the use of synthetic drugs.

Granulation is the technique by which particle size is increased using the granulation process. It is one of such important operations in solid dosage forms manufacturing, such as tablets and capsules.

The defined granules from granulation technology ensure that the target drug and excipients will be mixed to achieve an appropriate distribution of particle size; this is followed by a subsequent dosage form processing. For good material homogeneity, flow ability, and compressibility for the tablet compression process, as well as excellent stability for transport in the storage process³.

POTENTIAL ROLE OF NUTRACEUTICAL

Nutraceuticals are beneficial in a multitude of therapeutic areas such as cough and cold, treatment of arthritis, digestive disorders, sleep disturbances, cancer therapies, depression, diabetes, cholesterol, hypertension, and analgesics. The nutraceutical research and development sector is buzzing with activity to explore how different nutraceuticals will turn out to be beneficial in future medicines. Science is indeed demanding standardization of constituents for nutraceuticals as well as cautious formulation of protocol and undertaking clinical studies that might core to benefit consumer health and impact nutraceutical companies⁴.

NUTRACEUTICAL IN VARIOUS DISEASES

They’re good as adjuncts in disease prevention and management, addressing the original blocks such as oxidative stress, inflammation, and nutrient deficiencies. Appeal value aside, their potential is dependent on proper dosing, bioavailability, and particular health conditions. Always consult a medical professional before using nutraceuticals to complement any disease management program. Most of the nutraceuticals available in the world can be safely taken by people, with only a few cases where nutraceuticals have caused harm or injury in humans, as some nutraceuticals have toxic effects on human health. Studies have shown that a number of these nutraceuticals consumed by people, when taken in the correct controllable amounts, are highly beneficial with little toxicity⁵.

Nutraceuticals help us improve our health and well-being and modulate immunity, thus preventing and treating various diseases and health issues. Many diseases are treated with the help of nutraceuticals, some of which are discussed below.

IDEAL PROPERTIES OF GRANULES:

In the best scenario, the granules should have spherical morphology, narrow size distribution, and a relatively small amount of fines, to guarantee proper filling of space between the granules, proper moisture level (1-2%), good flow ability, and good compactibility and adequate hardness⁴.

The effectiveness of granulation depends on the following properties.

• Drug and excipients particle size,
• Type of binder (strong or weak),
• Volume of binder (less or more),
• Wet massing time (less or more),
• Drying rate (Hydrate formation and polymorphism).

Difference in Nutraceutical Granules and Synthetic Granules:

REASONS FOR GRANULATION:

1. Segregation Prevention
2. Improved Flow Characteristics
3. Optimized Compaction
4. Safety
5. Dust Reduction
6. Consistent Medicine Distribution
7. Mechanical Toughness
8. Compressive Qualities
9. Hygroscopic Risk Reduction
10. Aesthetic Enhancement
11. Space Efficiency

1. To prevent the segregation of the constituents in the powder mixture:

Segregation or de-mixing is a phenomenon that depends on differences in quantity or surface packing of the mixture, where smaller particles “bearings” or denser particles concentrate at the bottom of a container and larger particles “pins” or less dense particles concentrate in the top. To achieve a perfect granulation all the ingredients of the mixture are in ideal proportions in each granule and ingredient segregation is not permitted. It is important to be able to control the range of particle size for the granules, since although the individual constituents do not have to distribute themselves if there is a large range distribution in particle size, the granules will segregate. If there is such a phenomenon in the hopper of advanced devices like sachet-filling, capsule-filling, or tablet-filling machines, the products will have high weight-changed characteristics. This is because equipment is filled by volume rather than weight, assuming for instance, that different zones within the hopper consist of granules of varying sizes (and thus bulk density), a certain volume in those zones will have various connotations of weight for the granules contained therein. This leads to an unacceptable distribution of the drug content within the batch of the finished product even if the drug has been evenly distributed, weight by weight, through the granules.

2. To improve the flow properties of the mix:

A large number of powders, because of their small size and irregular shape or surface characters, are cohesive and do not flow well. Low flow leads to a large weight variation in the final product as a result of variations in filling tablet dies, etc. Granules made from this coherent system will be bigger and have greater diametric value.

3. Improvisation of the compaction characters of the mixture:

Most of the underlying primary powder particles are extremely refractory to compressing even though the powder mixture is as compactable as possible. Still, powders can be mixed to yield somewhat compressible granules that have the highest binder strength found in the existing literature. Mostly the solute migration which occurs during the post-granulation drying stage results in a binder-rich outer layer to the granules. This leads to direct binder-binder bonding that enhances the adhesion of the bonded weak materials.

4. Other reasons:

The granulation procedure is also helpful in minimizing the risk of toxic dust particles under powder handling, and powder transportation, and so therefore precaution should be made. Granules are nearly filling space with less volume per unit weight but more density than their mixture powder, so easier for storage and transportation purposes. Adhesion and cake development are convenient to obtain in hygroscopic materials utilizing the granulation method. It is because in size 3 the granules will be able to adsorb some amount of water and keep flow-ability, that is, they cannot be too wet because of the size.

METHODS FOR PREPARATION OF  GRANULES:

1. Dry granulation
2. Wet granulation
3. Granulation incorporating bound moisture
4. Steam Granulation
5. Melt Granulation
6. Moisture Activated Dry Granulation (MADG)
7. Foam Granulation
8. Thermal Adhesion Granulation
9. Pneumatic Dry Granulation Technology (PDG)
10. Freeze Granulation Technology

Dry Granulation:

Dry granulation is the process of granule formation in the absence of the addition of any liquid solution because the product can be moisture and heat-sensitive. In this course, dry powder particles can be mechanically agglomerated by compression into slugs or roller compression into flakes⁶.

Types of Dry Granulation:

Dry granulation is a process that can happen without water in two ways, as generally accepted:

1. Roller compaction
2. Slugging.

Roller Compaction:

Roller compaction is a growing process in the manufacturing using dry granulation method. This compacts dried powders into a solid mass, which is called ribbon and is broken up into the intended sizes using a milling system. This enables the powder particles to adhere to each other for granulation.
The roller compaction process brings the powder mixture to the counter-rotating roller pair, either by gravitational means or via an auger feed system. The powder is then run into the gap, which is a decreasing volume between rollers by reducing the gap diameter.
To develop the bulk density and consistency, it is necessary to control the gap between the rollers and compact the powder blend with the given force. In brief, powder feed, the compression pressure applied, and gap diameters in the roller compaction process are critical features.
Basically, the powder feed, the applied compaction pressure, and the gap diameters are the most critical process parameters in roller compaction.

Figure 3: Roller Compaction

Procedure for Roller Compaction:

• The bulk mass of the material passes into a funnel with an agitator, feed auger, and tamp auger that thereafter convey the material toward the rotating rollers.
• Afterward, a certain force is applied to compact the material passing through the rollers.
• High pressure is applied onto the material forming a ribbon-shaped compacted mass.
• Then, the ribbons are passed through a rotor sieve mill which produces the final granules of the desired particle size.
• Fine particles smaller than the desired size have an increased chance of sticking together again, hence they are sent back to the funnel for another round of granulation. Thus, losses of material are avoided.

Slugging:

Slugging is one of the forms of dry granulation. It is also referred to as pre-compression or double compression. This cost-effective dry granulation technique is applicable for most raw materials sensitive to heat and moisture.

Uniform blending of powdered solids is done, and these are then pressed into flat-faced slugs of larger-than-usual size on a conventional tablet press. It is a procedure devoid of heating or the use of solvents. The slugs obtained are milled into granules. Nevertheless, the slug weights vary as solids having small particles with low bulk density tend to flow into the tablet press poorly; this results in major variations in the force applied to each slug. Granule properties from slug milling are oftentimes not properly controllable.

Procedure for slugging:

• In this process, a blended powder is put into a tablet press.
• The blend is compressed into extra-large tablets or slugs (typically about 25mm in diameter and 10-15mm in thickness) utilizing flat-faced punches.
• The slugs themselves are subjected to screening both before and after the slugging.
• Then the slugs are ground to the desired particle size employing a hammer mill or an oscillating granulator.
• The granule obtained is subjected to screening for the final granule separation.

Advantages of the Dry Granulation Technique:

• Economical: Compared to wet granulation, dry granulation costs less and demands minimum energy and resources.
• Suitable for sensitive drugs: Dry granulation is a good choice for drugs sensitive to heat or moisture.
• Better yield: Dry granulation will enhance the production yield.
• Better control of particle size: Dry granulation offers better control of the particle size.
• Preserves drug structure: Dry granulation does not alter the structure of the drugs.
• No special equipment: Dry granulation does not require any key machines or equipment.
• Saves floor space: Dry granulation needs less space on the floor.

Wet Granulation:

Wet granulation is undoubtedly the most widely used granulation process in pharmaceutical pharmacy. It is characteristic of adding liquid formulation (with/without binder) or binder to powders, thus obtaining the wet mass or preparing granules, by adding the powder plus adhesive instead of compaction. The dried damp mass is granulated to get granules. The entrained liquid enwraps the particle powder partially by capillary and viscous forces in the wet state. Subsequent drying produces more stable links that result in the aggregation of the film forming the agglomerates. It is by far the most practical agglomeration process mostly practiced in the pharmaceutical industry. It includes the granulating liquid mixing with the powder, wet-sizing, and drying⁹.

Important steps involved in the wet granulation include:

• Mixing of the drug(s) and excipients
• Preparation of Binder solution
• Mixing of binder solution with powder mixture forming wet mass.
• Drying the moist granules
• Mixing screened granules with disintegrates, glidants, and lubricants.

Advantages of Wet Granulation Technique ⁹:

• Improved throughput rate
• Reduced inventory and storage space
• Clean-up time is reduced
• Involvement of reduced operator
• Less application for air, water, and power
• Minimal process footprint

Challenges:

• Modulating flow level and control
• Real-time in-process quality
• Real-time quality control
• The need for personnel training
• Superfluous controls and instrumentation
• Fast corrections in a variety of operational conditions
• Advanced process control

Granulation incorporating bound moisture¹⁰:

Bound moisture-wet granulation is a routine process in the field of pharmaceuticals and industry, especially for granule manufacture and tablet production. It is concerned with moisture in association with the granule material or introduced under controlled conditions and not with free water.

Bound Moisture:

Bound moisture is defined as molecular water species chemically or physically bound to material constituents (e.g., surface adsorbed, pore trapped, or hydration bonding to the molecule).In contrast to free moisture where there is no structural locking the moisture can move (and evaporate).

Granulation:

Granulation is the fabrication of granules by agglomeration of fine particles. It has a functional impact on performance parameters, including flow-ability, compressibility, and uniformity of the material, which are of major significance for manufacturing tablets, capsules, etc.

Incorporating Bound Moisture:

In controlled granulation, moisture is added to allow consolidation without compromising product integrity, i.e., excessive wetting and/or caking and/or excessive drying time. Approaches such as fluidized bed granulation or spray drying/extrusion can be adopted.

Advantages of Using Bound Moisture in Granulation:

• Enhanced Stability: Entrapped free water makes roundly moist materials less prone to damage.
• Controlled Release: Bounded moisture is known to affect the release profile of the active ingredients, particularly in pharmaceutical formulations.
• Improved Physical Properties: Depending on the moisture state, granules can be made mechanically stronger and homogeneous.
• Energy Efficiency: As bound (or) moisture content is usually lower; the dehydrating process is usually less energy intensive than when water-free content is used as a criterion¹².

Applications:

• Pharmaceuticals: Creating uniform, compressible granules for tablet production.
• Agriculture: Formulating controlled-release fertilizers,
• Food Industry: Developing powdered products with consistent rehydration properties.

Steam Granulation:

It looks like a wet granulation; however, the intent here is for the binder to exist as a pure vapour instead of in the liquid form. Moreover, it is estimated that one gram of steam will occupy roughly 1600 times the volume of an equal mass of liquid at standard temperature and pressure. The primary process in steam granulation consists of the injection of the required molten mass of steam. Steam injection provides enough heat to wet the particles, thus forming agglomerates in the granulated product. The advantages of steam granulation include uniform distribution throughout the powder particles. Formation of optimal spherical granules saves time and enhances the dissolution of granules due to the larger surface area created. This process has drawbacks such as a need for special machines to generate steam thermolabile products are not recommended and not all binders are suitable for this method^13,11.

Melt Granulation:

Melt granulation is a process of mounding powder particles together in the presence of a molten binder or a binder capable of melting within a certain temperature range (50-80⁰C). Lowering the temperature of the agglomerated powder allows the temperature of the molten binder to be dropped and turned into a dry granulation, to get final dry granules. Melt granulation has advantages over wet granulation; it is suitable for moisture-sensitive materials because it saves time and money since there is no addition of liquid to dry out. However, a great disadvantage is that due to this method, heat-sensitive drugs won’t be able to be granulated properly^14,11.

Moisture Activated Dry Granulation (MADG):

The MADG process is such that it doesn’t apply direct heat to dry granules but only uses heat in the form of steam to promote granule formation. There are two stages in the MADG: the first stage being the agglomeration of the required powder. In this stage, the binder and diluents are mixed with the drug to make a uniform mixture. During the mixing process, a small amount of water is sprayed on the powder to wet the binder and make it tacky. The presence of the binder in the formulation helps in the mixing of the drug and the excipients when mixed with the circular motion of the mixer blades. An average particle texture of agglomerates falls within the ranges of 150-500μm. Then, the second stage is moisture absorption. This is where the microcrystalline cellulose or silicon dioxide is added to the mix so that it absorbs the moisture during the mixing process. The moisture absorbents assist in moisture absorption so that moisture can get redistributed within the mixture; as a result, this leaves the whole mixture at low humidity. A certain level of moisture acts as an internal binder to prevent the granules from being too brittle and crumbling. This technique ensures that granules of consistent size can be obtained¹⁵.

Foam Granulation:

Foam granulation is a technology that uses the liquid binder, i.e., aqueous foam, in place of sprays or poured liquid on top of powder particles. It compares favourably with wet granulation because it requires less binder than spray granulation, less water than wet granulation, shorter processing time due to reduced water requirements, and elimination of the need for spraying nozzles with its attendant clogging and over-wetting problems. This method is suitable for moisture-sensitive materials, namely, reduced drying and manufacturing time overall. It provides for more even distribution of binder throughout the powder bed, with less being used for the solid dosage form^16,6.

Evaluation of Granulation¹⁷:

Granules have descriptive morphological features. The granules’ morphology could conveniently be analysed using a computer-supported imaging system. A good correlation exists between the compressibility of granules and their shape, flow property, packing property, frictional property, and coat ability. Some of the correlations would include volume shape measures, shape factors, and morphological descriptors. The following parameters are used for the characterization and evaluation of the granules:

1)       Determination of particle size and shape.

The size of granules affects average weight, weight variation, friability, flow capacity, and drying rate. The size and shape depend on the applied processing factors during granulation. The following techniques are usually employed to evaluate size and shape:

• Sieving and rate of sedimentation.
• Light scattering with microscopy (SEM).

2)       Density:

Density might affect compressibility, porosity, and dissolutions. For cohesive compacts of dense, hard granules, a larger load may be required to minimize the number of loose grains present at the tablet surface.

Tools = Density Calculators

Pyknometer -Mercury-infused liquid (any low-surface-tension solvent)-Granules’ solution in liquid and absorption action in the pores should not cover this point the granulation’s mass is used to compute density from the amount of volume that was intruded fluid into the pycnometer

Density (D) = M/Vp- Vi

Where Vp=Total volume of pycnometer Vi= Volume of intrusion fluid containing mass (M) requirement to fill pycnometer.

3)       Strength and friability of granules:

The strength and friability of granules are important because they will affect:

• Changes in the particle size distribution of the granulations.
• Ability to compress into cohesive tablets.
• Compressive strength acts as a determinant to ascertain the strength and friability of the granules in the friability measurements.

4)       Flow Properties:

Uniform tablet production necessitates free flow of the granulations from the hopper to the die cavity. The flow properties of granules depend on many forces.

• Frictional
• Mechanical forces resulting from particle colliding
• Electrostatic forces

Van der Waals/cohesive forces:

The forces also affect the shapes of the granules’ surface area, surface texture, roughness, and particle size distribution. With particle size around 150 m, frictional and van der Waals forces would dominate.

5)       Moisture content:

Moisture content refers to the amount of moisture found on granules. The typical moisture content of granules is 2%. The powder or grains must stick together during compression in the die cavity. The moisture is measured by IR balance or moisture balance. Simple balance is constituted by IR Balance. The sample was then taken from the oven to obtain the moisture level and placed in the moisture balance.

The first reading must be recorded. Grains’ moisture is evaporated under the influence of heat and we start with the IR light again. The final reading is recorded.

% Moisture = Initial weight – Final weight.

6)       Percentage Fines:

Fines represent the percentage of “powder” still present in the granules, and this is typically around 15% of the fine amount. When 100% of granules are employed, it may reduce the hardness of the tablet as there would be a void after compression in the die cavity, which due to air could cause the tablet to crumble. The sieve method can be employed to determine the percentage of fines. However, it should not exceed 15%¹⁷.

Conclusion

Nutraceuticals hold in store that much nutrients containing all of the essential nutrients, necessary for humans, to be consumed within a healthy diet. From the above study, it can be established that many chemical constituents from natural sources can be procured and prepare into various optimized, safe, stable formulations for the treatment and diagnosis of diseases. Granulation is an important step in drug discovery and formulation of solid dosage forms. These contribute more than 75% to any dosage form which is further compressed to form tablets. Unlike pellets, here they appear to look similar to each other; however, there are some critical parameters by which they can be differentiated. Technical and technological advances on existing procedures are beneficial for a process and for product formulation quality, which would ease and improve the process.

Read more

Srushti S. Gode, Aniket S. Gudur, Neha S. Ghosalkar, Mukul S. Malpure. A Broad and Holistic Review of Nutraceutical Granules using Polyherbal. Asian Journal of Pharmacy and Technology. 2025; 15(1):66-2.
doi: 10.52711/2231-5713.2025.00011