A Practical Guide to Pelletizing Technology

I. Concept of Pelletizing Technology

Granulation technology: A technology for processing materials in powder, molten, aqueous, and other states into granular products of specified shape and size.

Purpose of granulation:

① Improves flowability, facilitating portioning and tableting;

② Prevent segregation of the individual components due to differences in particle size and density.

③ Prevent dust from becoming airborne and adhesion to the vessel walls;

④ Adjust the bulk density to improve dissolution performance;

⑤ Improve the uniformity of pressure transmission during tablet manufacturing;

⑥ Easy to take, convenient to carry, and enhances product value.

Granulation method: Wet granulation, dry granulation, one-step granulation, and spray granulation are all employed; among these, wet granulation is the most widely used.

Application of Granulation Technology: It is most widely used in solid dosage forms, particularly in granules and tablets.

II. Pelletizing Method

(1) Wet Granulation Method

Wet granulation: A binder or wetting agent is added to the drug powder to form a soft mass, which is then passed through a sieve to produce wet granules. After drying, the wet granules are further size‑sorted to obtain the final product. Granules produced by wet granulation exhibit advantages such as improved surface characteristics, attractive appearance, enhanced abrasion resistance, and excellent compressibility, making this method the most widely used in the pharmaceutical industry. The mechanism of wet granulation involves the liquid in the binder first wetting the surfaces of the drug particles, thereby generating interparticulate adhesion. Subsequently, under the action of liquid bridging and external mechanical forces, particles of a defined shape and size are formed; following drying, these particles are ultimately consolidated via solid bridges. Wet granulation typically comprises several steps: preparation of the soft mass, formation of wet granules, drying of the wet granules, and size‑sorting.

1. Preparation of soft material: The accurately weighed fine powders of the raw and excipient materials are thoroughly blended, then an appropriate amount of a wetting agent or binder is added and mixed until a soft mass is obtained. Points to note when preparing the soft mass:

(1) The type and dosage of the adhesive shall be determined according to the properties of the material.

(2) The concentration of the adhesive and the stirring time should be adjusted flexibly according to the specific variety.

(3) Soft material quality. Due to variations in raw and auxiliary materials, it is difficult to establish a uniform standard; generally, this is assessed empirically: when firmly squeezed by hand, the material should form a compact mass, yet it should readily crumble apart with gentle pressure from the fingers.

(4) The duration of wet mixing significantly affects the consistency of the granules; the longer the wet-mixing time, the greater the viscosity, and the harder the resulting granules.

2. Preparation of moist granules: The soft material is forced through a sieve to form granules. If the granules fall through the sieve in long strips, it indicates that the soft material is too moist and contains an excessive amount of binder or wetting agent. Conversely, if the soft material passes through the sieve as a powder, it suggests that the material is too dry and should be adjusted accordingly. Commonly used equipment includes oscillating granulators and high-speed mixer‑granulators; sieves are available in four types: nylon wire, galvanized iron wire, stainless steel, and plate‑type.

3. Drying of wet granules: The wet granules obtained by sieving should be dried immediately to prevent caking or deformation under pressure. This can be achieved by spreading the prepared wet granules on stainless steel trays and turning them periodically to address caking and deformation during storage. Drying temperature depends on the properties of the raw materials, typically ranging from 50–60°C; for certain drugs that are stable to moisture and heat, the drying temperature may be raised appropriately to 80–100°C. The degree of dryness is controlled by measuring the moisture content: granule preparations must have a moisture content not exceeding 2%, while tablet granules retain an appropriate level of moisture—generally around 3%—which varies depending on the specific formulation. Common drying equipment includes cabinet-type systems (such as drying chambers or ovens), fluidized‑bed dryers, microwave dryers, and far‑infrared dryers, among other heated drying methods.

4. Whole-grain: After wet granules are dried, they must be screened and sized to break up any agglomerates, thereby meeting the particle-size specifications for granules or the compression requirements for tablets.

(1) Granules: A sieve with a mesh size smaller than that used for preparing wet granules—specifically, one with a mesh count of 10 or finer (No. 1 sieve)—may be employed to appropriately break up any material that fails to pass through the sieve openings. Subsequently, the material is graded according to particle-size specifications, passing through a 60‑mesh or 80‑mesh sieve (No. 5 sieve) at the lower limit of the desired particle size range, and only the granules within the 10–80 mesh range are collected.

(2) Tablets: Granules may be screened through a sieve with a mesh size larger than that used for preparing wet granules.

5. Blank Particle Method: For drugs that are unstable to moisture and heat and are administered in small doses, the excipient granules and other moisture- and heat‑stable ingredients may first be processed by wet granulation; after drying and size‑grading, the moisture‑ and heat‑sensitive drug is then blended uniformly with the granules. The method of preparing dry granules solely from the excipient, followed by blending the drug with these granules prior to tableting or portioning, is known as the blank‑granule method.

(2) One-step granulation

One-step granulation: Raw and excipient materials are blended, a binder is sprayed and mixed in, causing the binder to atomize and come into contact with the powders to form granules. Drying and other processing steps are carried out sequentially within a single piece of equipment, hence the name “one-step granulation,” also known as fluidized‑bed spray granulation. Characteristics: Mixing, granulation, and drying—all performed in one unit—can also be followed by coating. The process is simple, time‑saving, and involves low labor intensity. The resulting granules exhibit low bulk density, uniform particle size, and good flowability and compressibility, though their mechanical strength is relatively low.

(3) Spray Granulation

Spray granulation: This method involves mixing the active and excipient ingredients with a binder, stirring continuously to prepare a drug solution or suspension containing approximately 50%–60% solids, and then using a pump to atomize the mixture through a high-pressure spray nozzle into a hot air stream within a drying chamber. The rapid evaporation of moisture directly yields spherical, dry fine particles. Characteristics: It converts liquids directly into solid powdered particles; the spray droplets have a large specific surface area, the hot‑air temperature is high, and the drying rate is extremely fast. Particle heating time is very short, and the temperature of the dried material remains relatively low, making it well suited for heat‑sensitive materials. Drawbacks: High equipment costs, substantial energy consumption, and elevated operating expenses. In recent years, spray‑drying granulation has been widely employed in the production of antibiotic lyophilized powders, the preparation of microcapsules, the study of solid dispersions, and the drying of traditional Chinese medicine extracts.

(4) Dry Granulation

It can be divided into the heavy‑pressing method and the roller‑compaction method. The heavy‑pressing method, also known as the large‑tablet method, involves first compressing solid powder into billets 20–25 mm in diameter using a heavy‑duty tablet press, followed by crushing these billets into particles of the desired size. The roller‑compaction method uses a roller compactor to form sheet‑like masses from the drug powder, which are then milled into particles of a specified size. Characteristics of dry granulation: This technique is commonly employed for heat‑sensitive materials, drugs that are unstable in the presence of moisture, and substances that readily form compact tablets upon compression. It is simple to implement and saves both labor and time. However, care should be taken to avoid potential issues such as polymorphic transformations or reductions in potency caused by the compression process.

(5) Granulation of Traditional Chinese Medicine

Granulation of traditional Chinese medicine: Wet granulation is generally preferred.

1. Granulation of fine medicinal powder: When the formulation contains a small dosage, the herbal materials may be ground into a fine powder passing through a 100-mesh sieve, then mixed with an appropriate wetting agent or binder to form a soft mass, which is subsequently sieved to produce granules.

2. Granulation by mixing concentrated herbal extract with fine herbal powder: Some of the medicinal materials are processed into a thick extract, while the remaining portion is ground into a fine powder; the two are blended to form a soft mass, which is then screened, granulated, and dried. This method allows the use of a thick extract as a binder, helping to reduce tablet bulk and making it widely employed. If the thick extract alone does not provide sufficient binding strength, other binders may be added.

3. Granulation of dry extract: All the herbal ingredients in the formula, except those containing volatile constituents, are extracted and converted into dry extracts. The dry extracts are then crushed into granules; alternatively, they may be milled into a fine powder, mixed with an appropriate wetting agent—such as ethanol of suitable concentration—to form a soft mass, which is subsequently granulated.

III. Factors Affecting Wet Granulation

1. Properties of raw and auxiliary materials

(1) The powder is fine and loosely structured, with poor dryness and adhesiveness, and low solubility in water; therefore, a binder with stronger adhesive properties should be selected, and the binder dosage should be increased.

(2) When the substance has high water solubility and the excipients themselves exhibit strong viscosity, select a wetting agent or a binder with lower viscosity, and reduce the amount of binder used accordingly.

(3) It is moisture-sensitive and readily hydrolyzed; water should not be used as the solvent for the binder. Instead, anhydrous ethanol or other organic solvents should be employed as the binder’s solvent.

(4) Sensitive to heat and prone to decomposition; avoid using water as the solvent for the binder whenever possible, and instead select an ethanol solution of appropriate concentration to reduce particle drying time and lower the drying temperature.

(5) It exhibits stability under humid and high-temperature conditions; a low-cost water-based solvent is selected as the binder’s solvent.

2. Wetting agents and binders

Moistening agents: Liquids that wet the material to generate sufficient adhesive strength, facilitating granulation. These agents are either non‑adhesive or only weakly adhesive themselves, but they can wet the material and elicit its intrinsic adhesiveness, enabling it to agglomerate into a soft mass and be processed into granules. Examples include distilled water and ethanol. Adhesives: Viscous solid powders or thick liquids that impart adhesive properties, allowing materials with little or no inherent adhesion to aggregate, bind together, and form granules or be compressed into tablets. Examples include polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (CMC‑Na), and syrups.

What factors influence the selection of adhesives?

① It is related to the intrinsic properties of the raw and auxiliary materials: for example, if the raw material powder is fine, has a loose texture, exhibits low water solubility, and possesses poor inherent adhesiveness, a larger amount of binder will be required; conversely, a smaller amount should be used.

② For drugs that are unstable under humid and hot conditions, consider the choice of binder and its solvent. Select binders and solvents that are anhydrous and can be applied at low temperatures.

③ Related to mixing time: During the preparation of soft mass, a longer mixing time results in greater viscosity and harder granules.

④ Related to adhesive concentration: Under otherwise constant processing conditions, a higher adhesive concentration results in harder granules.

⑤ When excipients account for more than 80% of the formulation, and provided that the properties of the active pharmaceutical ingredient are not adversely affected, the choice of binder should prioritize the characteristics of the excipients. For example, when sucrose is used as an excipient at levels exceeding 80%, its tendency to exhibit increased viscosity upon contact with water must be taken into consideration; accordingly, a non‑aqueous solvent should be selected to dissolve the binder (binders that are soluble only in water but insoluble in organic solvents are unsuitable). This approach helps reduce interparticulate adhesion while enhancing cohesion within the particles. As an illustration: for azithromycin granules, when the formulation contains more than 80% sucrose, using 95% ethanol to prepare a 5% PVPK30 solution as the binder yields superior granulation compared to using 20% ethanol for the same concentration. Specifically, the former achieves a single‑pass granulation yield of up to 90%, whereas the latter attains only about 50%.

⑥ For the same binder, its viscosity and granulation performance vary depending on the solvent used.

⑦ For materials with excessively high viscosity, a two-step approach—first wetting and dispersing with ethanol, followed by the addition of a binder—can be employed to achieve better granulation. For example, this method has been successfully applied in Zailin granules and azithromycin granules, yielding favorable results.

⑧ Depending on the properties of the raw and excipient materials, two types of binders may be used for granulation. For example, in the Zailin granules, the process involves first wetting and dispersing with ethanol, then adding CMC‑Na as a binder, and finally incorporating syrup.

3. Granulation stirring and cutting time

When preparing the soft mass, the mixing and cutting time should be carefully controlled—typically judged by experience. The mass should form a cohesive lump when firmly pinched between the fingers without sticking, yet crumble easily under light pressure. If the mixing and cutting time is too long, the material becomes excessively sticky, making granulation difficult; if it is too short, the stickiness is insufficient, resulting in poor granule formation.

4. Screen mesh

(1) Nylon mesh sieve: It does not affect the stability of the drug and is elastic, making it suitable for granulating soft materials that are moist but not overly sticky and form good pellets. When the soft material is highly adhesive, sieving proceeds slowly; repeated kneading and mixing result in pellets with greater hardness, which can easily cause the nylon sieve to break.

(2) Galvanized wire mesh: It can be used for granulating relatively sticky, soft materials; however, metal shavings (broken wire fragments) may easily contaminate the granules and potentially compromise the stability of certain drugs. Installing magnets at critical points in the equipment to capture broken wire fragments can also yield good results.

(3) Stainless steel mesh: High-quality, pure stainless steel mesh yields better granulation results; however, broken stainless steel wires may contaminate the granules, and it cannot be attracted by a magnet.

5. Desiccant Drying Equipment

Drying is a process that removes moisture from wet materials by vaporization.

(1) The drying process of wet granules

This refers to the process by which moisture within a wet material diffuses to its surface, where it is heated and vaporized. After the surface moisture evaporates, internal moisture continues to diffuse toward the surface driven by the moisture gradient within the particles, and further evaporates at the surface, thereby achieving the desired drying effect.

(2) Matters to be noted during the drying process of wet granules

A. Wet granules should be dried as soon as possible; otherwise, they are prone to deformation, caking, or deterioration.

B. For drugs that are granulated using dilute alcohol and are prone to hydrolysis, drying should be carried out as promptly as possible. Prolonged standing allows the alcohol to volatilize, leading to a corresponding increase in moisture content and accelerating drug hydrolysis.

C. Strictly control the drying rate of the particles. The drying rate depends on external conditions and the ease with which liquid within the particles diffuses to the surface. External factors include air humidity, temperature, airflow, and the degree of particle dispersion.

D. During the drying process, the temperature should be increased gradually; otherwise, the surface of the particles will dry and form a hard crust, thereby hindering the evaporation of internal moisture.

E. If the granules contain sugar powder and starch, a sudden rise in temperature may cause the sugar to melt and the starch to gelatinize, thereby affecting tablet disintegration.

(3) Drying Equipment

A. Tray-type dryer: The dryer is equipped with multiple shelves, on which material trays are placed. Air, after being heated by a preheater, enters the drying chamber and flows horizontally across the material surfaces to effect drying. Characteristics: The equipment is simple and highly adaptable, but it involves high labor intensity, slow drying rates, and substantial heat consumption.

B. Spray dryer: Its design and operation are similar to those of a spray granulator. It features a large evaporation surface area and very short drying times, making it particularly well suited for heat‑sensitive materials. The dried product is typically a loose, brittle hollow particle with excellent solubility.

C. Fluidized‑bed dryer: A device in which hot air is passed upward through a loose bed of granular or powdered material, inducing a fluidized state to achieve drying; it is also known as a boiling dryer. Characteristics: simple construction, convenient operation, vigorous relative motion between particles and the hot gas stream, large contact area, and rapid drying, making it well suited for heat‑sensitive materials. Vertical fluidized‑bed dryers are suitable for drying tablet granules—typically finer powders—and deliver excellent tableting performance. Horizontal fluidized‑bed dryers are ideal for drying granule‑based formulations and provide good drying results.