Direct compression diluents (hoặc Direct compression fillers

Microcrystalline Cellulose (MCC)

MCC is produced through the acid hydrolysis of cellulose under high temperature and pressure. There are various grades of MCC differing in particle size and density, among which MCC 102 (with a particle size of approximately 130 µm) is the most suitable and commonly used for direct compression, providing excellent flowability. MCC is the diluent with the best compressibility. It undergoes plastic deformation when compacted; therefore, it is also considered a binder, helping to bond the components within the powder blend. Plastic deformation also helps MCC reduce tablet friability. Furthermore, MCC offers good disintegration properties due to the inherent water-absorbing and swelling characteristics of cellulose. With its low density, MCC can be used in high concentrations within the tablet, improving the overall properties of the powder blend. Currently, MCC is one of the most popular and preferred direct compression excipients.

(The different grades of MCC and their properties are described in the table below).

Lactose

Lactose is a disaccharide of galactose and glucose, a byproduct of the dairy industry, isolated from cow's milk. Conventional lactose monohydrate has a small particle size, offering good compressibility but poor flowability, making it unsuitable for direct compression. Consequently, spray-dried lactose was developed. The spray-drying process increases the particle size of this excipient, resulting in better flowability for direct compression. Lactose is a diluent that undergoes brittle fracture (fragmentation); therefore, unlike MCC, lactose increases tablet friability. However, also due to this brittle fracture, lactose reduces the powder blend's sensitivity to lubricants compared to MCC, thereby mitigating the impact of over-mixing when using lubricants.

Due to the presence of an aldehyde group in its structure, lactose can undergo the Maillard reaction with active ingredients containing amine functional groups, causing the tablet to turn yellow during storage.

Calcium Salts

The most commonly used calcium salt as a diluent for direct compression is Dicalcium Phosphate (DCP). Compared to MCC and lactose, DCP is less hygroscopic and more stable at room temperature. DCP has lower compressibility than MCC but better than lactose. Similar to lactose, DCP undergoes brittle fracture, which increases tablet friability but helps reduce the powder blend's sensitivity to lubricants. This brittle fracture also makes DCP and lactose suitable for bi-layer tablet formulations, as it creates new surfaces that enhance the cohesive properties of the powder blend during the second compression. Since DCP is poorly soluble, it is generally not recommended for use in high concentrations in tablets containing poorly soluble active ingredients. Additionally, due to the presence of calcium, DCP can also be used as a calcium supplement in the formulation. Other calcium salts used as diluents for direct compression include calcium sulfate and calcium carbonate.

Starches

Native starch lacks sufficient compressibility and flowability properties for use in direct compression. Therefore, the starch commonly used for direct compression is pregelatinized starch (e.g., Starch 1500). Pregelatinized starch consists of intact starch granules and ruptured starch granules that have been partially hydrolyzed and subsequently agglomerated. It meets the compressibility and flowability requirements for direct compression while retaining the excellent disintegration properties of native starch. Starch undergoes elastic deformation, making it less stable during tableting compared to other direct compression diluents. Furthermore, starch is more sensitive to lubricants during the tableting process than lactose or DCP.

Sugars and Polyols

Sugars and polyols commonly used as diluents in direct compression include sucrose, dextrose, sorbitol, and mannitol. These excipients are typically produced via spray drying to ensure appropriate flowability and compressibility for the direct compression process. Excipients in this group generally possess good compressibility, capable of producing highly hard tablets. However, due to their hygroscopic nature, the resulting tablets are prone to softening during storage. Among sugars and polyols, mannitol has the lowest moisture content. Mannitol also does not undergo the Maillard reaction with active ingredients containing amine groups. Similar to lactose and DCP, sugars and polyols undergo brittle fracture, leading to high tablet friability but making the powder blend less sensitive to lubricants during mixing.

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

CO-PROCESSED EXCIPIENTS

Currently, with advancements in formulation and manufacturing technologies, co-processed excipients have been developed to balance and optimize the required properties of direct compression diluents, such as compressibility, flowability, and deformation characteristics. Regarding MCC, it is the excipient with the best binding capacity among powder blend components due to its plastic deformation. However, because of this property, no new surfaces are created, making the powder blend 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): Increases the specific surface area, improving compressibility; enhances flowability due to Silicon dioxide; and reduces sensitivity to lubricants.
• MCC and Lactose: Enhances tablet disintegration by combining two different disintegration mechanisms; balances the good compressibility and binding capacity of MCC with lactose's ability to reduce sensitivity to lubricants.
• MCC and DCP: Increases density compared to standalone MCC; creates new surfaces suitable for bi-layer tablet formulations; and reduces MCC's sensitivity to lubricants.