Comprehensive Review of Modern Techniques of Granulation in Pharmaceutical Solid Dosage Forms

This comprehensive review explores modern granulation techniques in pharmaceutical dosage forms along with conventional methods, focusing on dry granulation and wet granulation. Dry granulation techniques, including slugging, roller compaction, and pneumatic dry granulation, are dissected with thorough analyses of their processing methods, advantages, disadvantages, and diverse applications. The article delves into eleven wet granulation techniques, offering insights into high-shear granulation, low-shear granulation, fluidized bed granulation, reverse wet granulation, steam granulation, moisture-activated dry granulation, melt granulation, freeze-dry granulation, foam granulation, thermal adhesion, and twin screw wet granulation. Each method is scrutinized, providing a comprehensive understanding of its processing steps, merits, drawbacks, and practical applications in pharmaceutical manufacturing. The article serves as a valuable resource for researchers, pharmaceutical professionals, and students, offering a nuanced exploration of diverse granulation techniques vital in drug formulation. This synthesis of information aims to enhance the understanding of granulation processes, facilitating informed decision-making in pharmaceutical development and manufacturing.

INTRODUCTION

The term “Granulated” is derived from the “Granulatum”, a Latin word denoting a grained mixture. In the pharmaceutical industry in the granulation process, the term “granules” denotes finely powdered particles that aggregate to create a larger, intricate structure.[1] These formations usually range from 0.2 to 0.4 mm. Generally, particles are produced in the range of 0.2 to 0.5 mm., making them well-suited for compression or mixing before compaction.[2] Pharmaceutical granulation plays a crucial role in enhancing drug quality by effectively dispersing agglomerates. Industries employ agglomeration processes not only to minimize dust, to improve handling, but also to optimize the material’s overall functionality. The key components of granulation include wetting and nucleation, coalescence or growth, consolidation, and attrition or breakage.3), 4)

Granulation involves the assembly of particles by creating bonds between them through compression or the use of binding agents. For instance, granulated sugar is easier to compress into tablets compared to powdered sugar due to its better flow and compression characteristics.[5] It is crucial to have sufficient fines to fill the void spaces between granules, promoting better compaction, along with optimal moisture and hardness to prevent breakage and dust formation during processing.[6]

Granulation serves the purpose of preventing segregation. The granules encompass a rounded shape to improve flow properties, and enhance compaction.[7]

The key components of granulation are influenced by factors such as spray rate or fluid distribution, as well as the properties of the feed powder and existing granules. The choice of a granulation process hinges on factors like drug physiochemical properties, excipients, desired flow, and release properties.[8]

The pharmaceutical industry witnesses continual evolution in granulation techniques, including roller compaction, spay drying, supercritical fluid, low/high shear blending, fluid bed granulation, extrusion or spheronization. The ongoing advancements and innovations further shape the landscape of granulation processes. Granulation serves various crucial processes.[9] The types of Granulations are showed in the figure1.

 

1. DRY GRANULATION

Dry granulation in pharmaceutical manufacturing is a moisture-free process which compresses powdered particles into granules, offering advantages such as preventing moisture-induced degradation in active pharmaceutical ingredients and formulations. This method is an alternative to wet granulation that avoids the use of liquid binders, contributing to product quality and

stability.[10] In the dry granulation process, slugging is employed for tablet formation, especially when ingredients are sensitive to moisture or cannot withstand high temperatures. Referred to as dry granulation, pre-compression, or double compression, this method involves the manufacturing of large tablets known as slugs, which are then compressed through a mesh screen or pressure rolls. The granulated slugs are blended with lubricants and subsequently compressed into tablets. Another approach involves pre-compression.[11]

CONVENTIONAL DRY GRANULATION TECHNIQUE

1.1. SLUGGING

Slugging granulation, is a dry manufacturing technique in pharmaceuticals which is employed to create granules from powdered particles or excipients. This process involves compressing dry powder into uniform slugs, subsequently reducing them to achieve the appropriate granule size for final compression. The primary objectives include enhancing powder flowability, minimizing dust, and attaining the desired particle size distribution.[11]The pros and cons of slugging are illustrated in the figure 3.

1.1.1. Characterization of Slugs:

For each batch of the 10 slugs, measurements of individual slug weight and thickness were conducted using a digital micrometer. Subsequently, compaction characteristics were derived. To assess the strength of five of the slugs, a motorized tablet hardness tester was employed.[12]

1.1.2. Procedure

Slugging, is a pre-compression method that is utilized to generate extra-large tablets known as slugs. These slugs often have variable weights due to the poor flow of medication powder. Interestingly, The state of the slug is not a crucial determinant in this approach. The process involves applying the necessary pressure to compact the powder into even slugs. Subsequently, these slugs are reduced in size through screening and milling to achieve the appropriate granule size for final compression. This technique finds application in the dry granulation of hydrolyzable medications like aspirin and metformin, particularly when wet granulation is unsuitable. These medications are recompressed during the process to produce the final tablet.[13]The detailed process of slugging is shown in the figure 2.

1. Aspirin and Maize Starch Mixture:A Manesty solitary impact tablet press was utilized to compress a mixture of aspirin powder (50 g) and cornstarch (6% w/w) into slug forms at an arbitrary load of 45 units. Subsequently, these slugs were diminished to granules and filtered through a sieve with an opening of 710 micrometers.[14]2. Lactose Powder Compression:A large punch and die set were employed to compress lactose powder at pressures of 50, 150, and 270 MNm-2, resulting in cylindrical slugs with a diameter of 38.1 mm. After being removed from the die, the slugs were crushed on a reciprocating granulator before undergoing sieving. This process demonstrated a reduction in lactose slug porosity as the slugging pressure increased.[15]3. Alginic Acid, Microcrystalline Cellulose, and OTC Particles:A typical formulation comprising 1% alginic acid, 78% microcrystalline cellulose, and 21% OTC (oxytetracycline) particles was created using particle residues from the slugging process.[16]

4. Potassium Phenethicillin:

For the creation of a slug, potassium phenethicillin batch 4277, microcrystalline cellulose (MCC), and magnesium stearate were combined using a planetary mixer. Subsequently, these ingredients were compressed on a single tablet punch instrumented machine.[17]

5. Disulfiram Immediate Release Tablets with Polymers:

Disulfiram immediate-release tablets were developed using the slugging granulation method, incorporating a variety of hydrophilic and hydrophobic polymers. Perceived medication and intragranular materials were prepared in precise amounts, including microcrystalline lactose, silicon dioxide, stearic acid, sodium starch glycolate, and cellulose. The slugs were blended, passed through a multi-mill display (1.5″), and underwent filtering through #20 sieves. Extragranular material was used to combine the final granules. The tablet press involved the use of concave round flat punches on a 12-station rotary machine.[18]

1.2. ROLL COMPACTION IN DRY GRANULATION

Roll compaction dry granulation (RCDG) is an agglomeration method utilized across various industries, with a particular emphasis on the pharmaceutical industry. The process involves compressing granules by passing or slugging them between two rolls rotating in opposite directions. Notable advancements in this technique include increased production capacity, enhanced control over operational conditions, and a reduced need for powder lubricants. The intense pressure applied in the roll gap transforms the powder into a condensed structure. When the rolls exhibit smooth, fluted, or knurled surfaces, the substance undergoes compression, forming compact ribbons (flakes, sheets, or strips). In the case of pocket-shaped rolls, the result is briquettes.

The area between the rolls is segmented into 3 zones:

• feeding zone
• compaction zone
• extrusion zone.[19]

Roll compaction stands as a well-established continuous granulation technique, particularly suitable for components that are vulnerable to heat and water exposure or those with inadequate blending mobility. The characteristics of the granules produced are significantly influenced by compaction force, roll gap width, and roll speed. Understanding this relationship early in the roller compaction process is crucial for designing robust medicinal formulations. Recent years have witnessed a growing interest in drug development process and have shown the importance of refining and optimizing roll compaction techniques.[20]

1.2.1. Roller Compaction Process for Microcrystalline Cellulose:

The roller compaction process for creating microcrystalline cellulose involves utilizing Dicalcium phosphate dihydrate, Emcompress Premium, and Ligamed MF-2-V magnesium stearate.

Here’s a detailed breakdown of the process:

1. Equipment Used:

A Gerteis Nano-Polygran roller compactor was applied to produce strips using a celestial granulator. Ribbons were generated utilizing a compaction emulator and an oscillating grinder.

The resulting striplets were then treated through a Frewitt Oscillo Witt-Lab.

2. Granule Collection:

Granules from each manufacturing process were gathered using a Medel-Pharm Styl’One Evolution and a Micromeritics Geopyc 1365. Each sample of mass was calculated using a Mettler Toledo high precision balance.

3. Granule Size Determination:

Laser diffraction was utilized to determine the granule size distribution. Three duplicates of the experiment were carried out to ensure accuracy. The sample size distribution was determined using a Malvern Panalytical Mastersizer for laser diffraction, with a predicted dry powder dispersion rate of 50%.

4. Additional Analysis:

To further analyze the granules, they were subjected to a laser scanning electron microscope. This step helped determine the apparent density of the granules and their size distribution.[21] This comprehensive approach ensures a thorough understanding of the characteristics of the microcrystalline cellulose produced through the roller compaction process.

The Complete Procedure is shown in the Figure 4.

1.2.2. APPLICATIONS OF ROLLER COMPACTION

1. Binder Effects on Properties (1966):

Jaminet and Hess conducted a study on the influence of various binding agents on briquettes, granules, and tablets. The introduction of ethylcellulose enhanced strength, while carbowax 4000 had a reducing effect. The particle size distribution of the granules was impacted by the process parameters employed during dry granulation.[22]

2. RCDG Application to Pharmaceutical Powders (2007):

Parrott employed RCDG on eight distinct pharmaceutical powders utilizing a concavo-convex roll compactor at a pressure of 140 kg/cm2. The roll compacting system utilized in this instance demonstrated superior compression uniformity compared to traditional roll compressors. Funakoshi et al. investigated the variables influencing the distribution of compacting pressure throughout the procedure.23), 24)

3. Employment of Acoustic Emission for Detecting Overcompaction (Preparation of Excipients):

Hakanen and Laine utilized acoustic emission in roll compaction to identify overcompaction in microcrystalline cellulose. They observed a ‘capping’ phenomenon at a compaction force of 30 kN.[25]

4. Influence of Roll Compaction on Granule Friability(Compaction of Lactose):

Inghelbrecht and Remon investigated the effects of roll compaction on the granule friability of four lactose variations, employing a second-order polynomial model. Optimal quality resulted from high pressure and low horizontal screw speed, but the compaction of spray-dried lactose posed challenges.[26]

5. Compaction of Pharmaceuticals and Formulations:

Inghelbrecht and Remon compared seven microcrystalline cellulose (MCC) types with ibuprofen as a model drug for fragmentation. The addition of 25% ibuprofen enhanced granule quality, and higher concentrations further improved it. The study revealed that a minimal amount disrupted MCC binding properties, but higher concentrations compensated for it.[27]

6. Granulation of Herbal Dry Extracts:

In their research, Rocks Loh and team delved into improving the crushing strength and disintegration time of tablets containing high-dose plant extracts. They explored the use of different fillers, disintegrants, lubricants, and glidants for optimization. The study included a comparison of tablets made from distinct plant extracts and granulated plant extracts. Interestingly, the findings highlighted that artificial neural networks (ANN) proved more effective in characterizing the factors influencing crushing strength and disintegration time compared to the conventional multivariate method (PLS), which showed limited predictive ability. This underscores the significance of innovative approaches in pharmaceutical research.[28] The Figure 5 Highlights the Advantages and Disadvantages of the Roller Compaction.

ADVANCED DRY GRANULATION TECHNIQUE

1.3. THE PNEUMATIC. DRY GRANULATION (PDG)

The pneumatic dry granulation (PDG) process stands as an creative and patented technology utilizing Roller compaction and a distinctive technique of air classification. This approach yields granules with remarkable Flow characteristics and compressibility. PDG Technology offers adaptability in adjusting drug loading, disintegration time, and tablet hardness, catering to the requirements of heat-labile and moisture-sensitive drugs. The technology generates porous granules with outstanding compressibility and flowability, applicable to a wide range of pharmaceutical solid dosage ingredients [31].

While wet granulation remains the most prevalent method, its limitations become apparent with moisture and heat-sensitive drugs, coupled with cost-intensive, laborious, and time-consuming processes. PDG Technology emerges as a solution to these challenges, showcasing superior properties compared to wet granulation and dry granulation. The resulting granules exhibit notable compressibility and flowability without the need for exotic and costly excipients.

PDG Technology stands as a pivotal solution for pharmaceutical companies grappling with challenges in developing solid oral dosage forms. It presents advantages of accelerated development and enhanced quality. Rooted in classical rotary granulation (RC),PDG (Pre-Drying Granulation) substantially expands the possibilities of dry granulation by attaining improved flowability at a low ribbon density, consequently enhancing the compatibility of the resulting dry granulation. This paper provides a glimpse into PDG technology, highlighting its potential advantages through an experimental illustration [32].

1.3.1. Pneumatic Dry Granulation (PDG) Process:

In PDG, a roller compactor delicately compresses powder particles, forming a cohesive mass comprising fine particles and granules. A pneumatic system is then employed to segregate grains within the desired size range in a fractioning chamber. Remarkably, PDG allows for substantial drug loading, ranging between 70% and 100%.The Process of PDG illustrated in Figure 6.

The sequential unit operations integral to the dry granulation process encompass:

1. Milling APIs and Excipients: Creating powdery substances.
2. Combining Powder Mixture: Blending the powder components.
3. Consolidation: Forming thick, rigid Solid dosage forms.
4. Ribbons: Achieving the correct size of the particle.
5. Blending with Lubricants and Diluents: Enhancing flowability.
6. Compression of Tablets: Finalizing the tablet formation [33].

The PDG is very useful and its advantages and disadvantages are discussed in Figure 7.

 

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Excipients mentioned in the article: PVP K12, PVP K90, lactose, microcrystalline cellulose, starch, dibasic calcium phosphate

Anil Kumar Vadaga, Sai Shashank Gudla, Gnanendra Sai Kumar Nareboina, Hymavathi Gubbala, Bhuvaneswari Golla, Comprehensive Review of Modern Techniques of Granulation in Pharmaceutical Solid Dosage Forms, Intelligent Pharmacy, 2024, ISSN 2949-866X, https://doi.org/10.1016/j.ipha.2024.05.006.

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This research used MEDELPHARM STYL’One Evo:

STYL’One Evo R&D – Scale-Up and Production Support