Diluents in direct compression

Diluents are a crucial group of excipients in the direct compression process. They must possess suitable properties to ensure that the powder mixture before tablet compression has good compressibility and flowability.

Factors influencing the properties of diluents include particle size, shape, density, solubility, and moisture content. Additionally, since diluents make up a significant portion of the tablet, they greatly affect the uniformity of the final product between batches. The polymorphic form also influences the properties of the diluent; the amorphous form typically exhibits better compressibility and flowability than the crystalline form.

Currently, many improved processes have been applied to enhance the compressibility and flowability of diluents, such as spray drying.

DILUENTS IN DIRECT COMPRESSION

1. MCC (Microcrystalline cellulose)

MCC is produced through the hydrolysis of cellulose by acid under high temperature and pressure. There are various types of MCC with different particle sizes and densities, among which MCC 102, with a particle size of approximately 130 µm, is the most commonly used for direct compression processes due to its excellent flowability. MCC is considered the best diluent in terms of compressibility. It undergoes plastic deformation when compressed, which also allows it to function as a binder, helping to bond the components within the powder mixture. The plastic deformation also helps reduce the wear of the tablet. Additionally, MCC provides good disintegration properties due to its inherent water-absorbing and swelling characteristics of cellulose. Moreover, with a low density, MCC can be used in high amounts in the tablet, improving the properties of the powder mixture. Currently, MCC is one of the most preferred excipients for direct compression.

Different grades of MCC and their properties are described in the table below.

2. Lactose

Lactose is a disaccharide composed of galactose and glucose, and it is a byproduct of the dairy industry, isolated from cow's milk. Regular lactose monohydrate typically has a small particle size, providing good compressibility but poor flowability, making it unsuitable for direct compression processes. This led to the development of spray-dried lactose. The spray-drying process increases the particle size of this excipient, thereby improving its flowability for direct compression. Lactose is a diluent that undergoes brittle deformation, which makes it different from MCC, as lactose can increase the wear of the tablets. However, due to its brittle deformation, lactose helps reduce the sensitivity of the powder mixture to lubricants compared to MCC, thereby minimizing the effects of over-mixing when using lubricants.

With the presence of an aldehyde group in its structure, lactose can undergo Maillard reactions with active ingredients containing amine groups, resulting in a yellow discoloration of the tablets during storage.

3. Calcium salts

The most commonly used calcium salt as a diluent in the direct compression process is Dicalcium phosphate (DCP). Compared to MCC and lactose, DCP is less hygroscopic and more stable at room temperature. While DCP has lower compressibility than MCC, it is better than lactose. Like lactose, DCP undergoes brittle deformation, which can increase the wear of the tablets; however, it also helps reduce the sensitivity of the powder mixture to lubricants. This brittle deformation makes DCP and lactose suitable for use in bilayer tablet formulations, as it creates additional surface area that enhances the cohesion of the powder mixture during the second compression.

DCP has poor solubility, so it is generally not recommended for use at high concentrations in formulations containing poorly soluble active ingredients. Additionally, with the presence of calcium, DCP can also be used to supplement calcium in the formulation.

Other calcium salts used as diluents in the direct compression process include calcium sulfate and calcium carbonate.

4. Starch

Natural starch does not possess sufficient properties for compressibility and flowability to be used in the direct compression process. Therefore, the starch commonly used for direct compression is modified starch (Starch 1500). Modified starch consists of intact starch granules and partially hydrolyzed, agglomerated starch granules. Modified starch meets the requirements for compressibility and flowability for direct compression while retaining the excellent disintegration properties of natural starch.

Modified starch exhibits elastic deformation, making it less stable during the tablet compression process compared to other direct compression diluents. Additionally, starch is more sensitive to lubricants during tablet compression compared to lactose or DCP.

5. Polyols

Sugar and polyol excipients are commonly used as diluents in direct compression, including sucrose, dextrose, sorbitol, and mannitol. These excipients are often produced through a spray-drying process to ensure good flowability and compressibility for direct compression. They typically have good compressibility, allowing for the creation of tablets with high hardness. However, due to their hygroscopic nature, the resulting tablets may become soft during storage.

Among the sugar and polyol excipients, mannitol has the lowest moisture content and does not participate in Maillard reactions with active ingredients containing amino groups.

Similar to lactose and DCP, sugar and polyol excipients undergo brittle deformation, resulting in tablets with high wear but also helping to make the powder mixture less sensitive to lubricants during blending.

Below is a table comparing the compressibility and flowability of various direct compression diluents:

CO-PROCESSED EXCIPIENTS

Currently, with the advancement of formulation and production technology, co-processed excipients have been developed to balance and optimize the necessary properties of diluents for direct compression, such as compressibility, flowability, and deformation characteristics.

For MCC, it is the diluent with the best ability to create cohesion between components in the powder mixture due to its plastic deformation. However, because of this property, no new surfaces are generated, making the powder mixture sensitive to the mixing time of lubricants. Therefore, MCC is often co-processed with other excipients to optimize its properties. For example:

• MCC and Silicon dioxide (SMCC): increasing specific surface area to enhance compressibility and flowability through the addition of silicon dioxide, which reduces sensitivity to lubricants.
• MCC and Lactose: enhancing tablet disintegration by combining two different disintegration mechanisms, balancing the compressibility and good binding properties of MCC with the ability to reduce sensitivity to lubricants provided by lactose.
• MCC and DCP: increasing density compared to standalone MCC, generating new surfaces for bilayer tablet formulations, and reducing the sensitivity of MCC to lubricants.