FORMULATION - Excipients | Dry Granulation Simplifies Tableting Process

Fast and cost effective compared to wet granulation

Recent advances in formulation technologies have led to a shift from traditional wet granulation to dry granulation manufacturing processes in the development of solid oral dosage forms. This change has come about largely because of process expedition, easy handling, and time and cost savings; the wet granulation process requires multiple steps that involve agglomeration (granulation), drying, sieving, particle size reduction, and blending.¹ Dry granulation is suitable for medium- and high-dose drugs and is particularly applicable for active pharmaceutical ingredients (APIs) that are heat and moisture sensitive.²

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Figure 1. Plasticity of Dry Binders at Different Compression Forces (Plasticity = Plastic Energy/Total Energy)

Direct compression and roller compaction are common processing methods used in dry granulation. These processes enhance solid dosage stability by increasing the final tablet hardness and reducing tablet friability. Excipients play a major role in the development of robust formulations because they can influence the degree of granule compression and binding.³ Excipients can also absorb mechanical stress derived from the granulation and tableting processes without affecting tablet hardness and tensile strength.

This article will review the types of dry binders, both pure and co-processed, that are applicable for dry granulation and will focus on those that are ideally suited for manufacturing tablets by direct compression and roller compaction.⁴

Requirements for Dry Binders

One important requirement for a dry binder is good powder flowability. The dry binding characteristics are influenced by the powder’s morphology; shape and size; porosity; plasticity; hygroscopicity; compressibility; stability to air, moisture, and heat; and compatibility with APIs. The stronger binding characteristics are governed by intermolecular forces and mechanical interlocking, depending upon the excipients’ type. For instance, intermolecular interactions are more prevalent in excipients with a tendency to fracture and/or deform on compression, whereas mechanical locking is prevalent in those with needle-like fibers that interlock by hooking or twisting.⁵

There are two categories of dry binders, depending on their usage level. The first category requires only a small quantity of dry binder to produce tablets with the desired hardness. For example, copovidone (Kollidon VA64/Fine from BASF) can be used at levels as low as 2% to produce hard tablets by direct compression. The second category requires larger quantities of dry binders. For example, microcrystalline cellulose, lactose, calcium phosphate, and maltodextrin need to be used at levels as high as 40% before appreciable tablet hardness is achieved.

Several manufacturers market dry binders. Some of them require only low to modest compression forces to yield harder tablets with good tensile strengths, while others require high compression forces to yield harder tablets with modest tensile strengths. The application of higher compression forces on certain dry binders can have a negative effect on tablet hardness and may result in a significant loss of tensile strength due to double mechanical stress.

Excipient Selection

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Although the dry granulation process is cost effective and improves dosage stability, the excipients’ chemistry, physicochemical properties, and, most impor- tantly, compatibility with APIs can present formulation challenges. For example, cellulosic binders have poor flowability and are incompatible with some APIs, while hydroxypropyl cellulose (HPC) can interact with phenols and anionic polymers. Microcrystalline cellulose (MCC) and hydroxypropyl methylcellulose (HPMC) are incompatible with oxidizing agents, and lactose interacts with APIs containing amino groups. Finally, pre-gelatinized starch has low elasticity and slow plastic deformation, while HPC and HPMC have poor disintegration and dissolution properties.

Kollidon VA64/Fine, on the other hand, has strong binding and compressibility characteristics; has good flowability, porosity, and plasticity; has low glass-transition temperature and low moisture absorption; and is compatible with many APIs. The average particle sizes of Kollidon VA64 and Kollidon VA64/Fine are 55 and 17 microns, respectively. The smaller spherical, hollow particles of Kollidon VA64/Fine provide excellent flowability, compressibility at low compression forces, and plasticity.⁶ Figure 1 illustrates the plasticity of different dry binders in comparison with Kollidon VA64. The data suggest that Kollidon VA64 outperforms other dry binders like polyvinylpyrrolidone (PVP), MCC, and HPMC.

Performance of Dry Binders

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Figure 2. Hardness of Acetylsalicylic Acid Tablets (500 mg) Obtained by Direct Compression With Different Dry Binders

The performance of dry binders has been evaluated with many APIs, including acetylsalicylic acid (aspirin). The formulation composition of aspirin with different dry binders is shown in Table 1. The powder blends were compressed into tablets on a high-speed tablet press (Korsch PH 100/6) with a punch diameter of 12 mm, beveled edge-shaped, at a rotary speed of 30 rpm. The performance on hardness with individual dry binders at different compression forces is shown in Figure 2.

Crospovidone grades were also evaluated as the dry binders.⁷ Crospovidone grades ranging in mean particle sizes from five microns (Kollidon CL-M) to 25 microns (Kollidon CL-SF) to 35 microns (Kollidon CL-F) to 110 microns (Kollidon CL) were selected for direct compression on a single punch Carver press. The compression data of crospovidone grades are shown in Figure 3.

It is interesting to note that crospovidone grades with finer particles, with the exception of Kollidon CL-M, were able to compress significantly harder at low or high compression forces. The compressibility of crospovidone grades decreased in the following order: Kollidon CL-SF > Kollidon CL-F > Kollidon CL > Kollidon CL-M. Such differences in compressibility profiles might be related to greater porosity in the matrix, which could lead to increased hardness of the tablets upon compression. The poor compressibility of Kollidon CL-M was presumably due to micronized pores with fewer void spaces within the polymer matrix.

Although dry binders have good powder characteristics and flowability, dust generation can be potentially hazardous during solid dosage manufacturing. Roller compaction helps avoids this concern in situations when compression yields granules in the dry state in a solvent-free process.

Roller compaction has many process advantages and a few disadvantages. On the negative side are costs associated with purchase, installation, and maintenance of the equipment; generation of dust that may lead to cross-contamination; quality issues due to raw material fines; and the requirement for excipients with good binding/cohesive properties capable of enduring double mechanical stress. All of these factors need to be carefully considered.

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In a typical process, the blend of excipients and API is fed between the two counter-rotating drums of the roller compactor. As the powder blends proceed through the drums, the resulting ribbons are further granulated and passed through sieves before a lubricant is added and the tablets are produced.

Table 2 shows the formulation composition of allopurinol granules prepared by roller compaction using Kollidon VA64/Fine as a dry binder with the appropriate processing conditions. The resulting granules were compressed on a Korsch PH 100/6 at 16 kN to yield 100 mg allopurinol tablets with the following desired characteristics: diameter, 8 mm; hardness, 246 N; friability, <>

Wanted: Appropriate Binding

This article reviews several excipients that can be used as dry binders in direct compression and roller compaction. An excipient with poor binding character poses a challenge in drug development. Thus, identification of a dry binder with appropriate binding characteristics is important to achieve the desired tablet hardness and tensile strength.

Cellulose-based excipients like MCC are the most commonly used binders in direct compression and roller compaction. In roller compaction, MCC generates a large quantity of fines on compression, which, in turn, leads to a significant reduction in tablet tensile strength.⁸ HPC and HPMC also generate fines upon roller compaction, leading to poor tablet friability and decreased tablet tensile strength. Dicalcium phosphate and lactose are highly brittle and fracture upon compression, producing a large quantity of fines, which leads to poor surface contact with APIs and poor binding.

Conversely, PVP and copovidone possess a relatively higher plasticity than lactose, dicalcium phosphate, or cellulose-based excipients. The higher plasticity produces a greater binding effect due to increased polymer/API surface contact as the polymer deforms during compaction. The net result is harder tablets with improved tensile strength.

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Figure 3. Dry Binding Properties of Crospovidone Grades

Kollidon VA64/Fine could play an important role in dry granulation. Recently, Herting and Kleinbudde evaluated insoluble PVP grades (Kollidon CL-M and Kollidon CL-F, SF) and Kollidon VA64/Fine in roller compaction and compared the results with cellulose-based MCC, HPC, and HPMC.⁹ Interestingly, from the compression studies of non-compacted powders, Kollidon CL-M showed tensile strength comparable to Kollidon VA64/Fine but significantly higher than MCC, HPMC, or HPC.

The tensile strength of tablets with Kollidon VA64 and Kollidon CL-F was slightly lower than that of Kollidon CL-M or Kollidon CL-SF. The significant loss in tensile strength of MCC, HPMC, and HPC is predominantly due to generation of a large amount of fines in the granules as compared to PVP-based excipients (~40% vs. ~15%).⁹

The tensile strength of the excipients decreased in the following order: Kollidon VA64/Fine> Kollidon CL-M> Kollidon VA64> Kollidon CL-SF> MCC> HPMC> HPC.

When all is said and done, there is much to recommend dry granulation. It offers a significant advantage over wet granulation because it simplifies the entire tableting process. Direct compression and roller compaction offer process solutions for many drugs sensitive to moisture and temperature. Dry granulation is a fast and cost-effective process. A number of excipients have been evaluated in dry granulation, with some performing better than others on compression.

The data suggest that Kollidon VA64 and Kollidon VA64/Fine are good dry binders for direct compression and roller compaction. A recent study showed that insoluble PVP grades (Kollidon CL-M and Kollidon CL-SF) performed better than cellulosic dry binders in roller compaction. Interestingly, Kollidon CL-M and Kollidon CL-SF outperformed all of the dry binders investigated.

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Dr. Ali is manager of technical sales and Dr. Langley is head of technical sales in Pharma Ingredients and Services at BASF Corporation. Reach them at shaukat.ali@basf.com, nigel.langley@basf.com, or by calling (973) 245-6000.

REFERENCES

1. Nyström C, Glazer M. Studies on direct compression of tablets. XIII. The effect of some dry binders on the tablet strength of compounds with different fragmentation propensity. Int J Pharm. 1985;23:255-263.
2. Maschke A, Meyer-Böhm K, Kolter K. Dry binders used in direct compression. ExAct. 2008;20:2-5. Available at: www.pharma-solutions.basf.com/PDF/Documents/EMP/ExAct/ExAct_20_May2008.pdf. Accessed March 31, 2010.
3. Van Gessel S, van Duinen H, Bogaerts I. Roller compaction of anhydrous lactose and blends of anhydrous lactose with MCC. Pharm Technol Web site. April 1, 2009. Available at: http://pharmtech.findpharma.com/pharmtech/Ingredients/Roller-Compaction-of-Anhydrous-Lactose-and-Blends-/ArticleStandard/Article/detail/590451. Accessed March 31, 2010.
4. Gohel MC, Jogani PD. A review of co-processed directly compressible excipients. J Pharm Pharm Sci. 2005;8(1):76-93.
5. Kolter K, Flick D. Structure and dry binding activity of different polymers, including Kollidon VA64. Drug Dev Ind Pharm. 2000;26(11):1159-1165.
6. Bühler V. Kollidon VA 64 grades (copovidone). In Kollidon: Polyvinylpyrrolidone Excipients for the Pharmaceutical Industry. 9th ed. Ludwigshafen, Germany: BASF SE; 2008:207-252.
7. Ali S, Santos C. Crospovidone in development of directly compressible tablets. Poster presented at: 2009 AAPS Annual Meeting and Exposition; November 2009; Los Angeles, Calif. Available at: www.aapsj.org/abstracts/AM_2009/AAPS2009-001798.PDF. Accessed March 31, 2010.
8. Herting MG, Klose K, Kleinebudde P. Benchmark of different dry binders for roll compaction/dry granulation. ExAct. 2008;20:6-7. Available at: www.pharma-solutions.basf.com/PDF/Documents/EMP/ExAct/ExAct_20_May2008.pdf. Accessed March 31, 2010.
9. Herting MG, Klose K, Kleinebudde P. Comparison of different dry binders for roll compaction/ dry granulation. Pharm Dev Technol. 2007;12(5): 525-532.