Microcrystalline Cellulose in Pharmaceutical Formulations: A Comprehensive Review on Applications, Concentrations, And Functional Attributes

1. Overview of Excipients in Pharmaceuticals

Pharmaceutical excipients are inactive substances formulated alongside the active pharmaceutical ingredient (API) of a medication. They serve various roles, including aiding in the manufacturing process, enhancing stability, improving bioavailability, and ensuring patient acceptability. ?

Functions of Excipients

• Enhancing Stability: Excipients protect medications from degradation caused by exposure to air, light, or moisture. For instance, antioxidants prevent oxidation, ensuring longer shelf lives. ?
• Improving Bioavailability: Excipients like solubilizers enhance the absorption of poorly water-soluble drugs, making them more effective. ?
• Providing Aesthetic Appeal: Colorants and flavouring agents improve the appearance and taste of medications, ensuring better patient compliance. ?
• Modulating Release Profiles: Certain excipients can control the release rate of the API, allowing for sustained or delayed release formulations.? [1, 2]

Classification of Excipients

Excipients can be classified based on their function: ?

• Binders: Provide mechanical strength to tablets. ?
• Diluents: Increase the bulk of formulations for accurate dosing. ?
• Disintegrants: Facilitate tablet breakup upon ingestion. ?
• Lubricants and Glidants: Enhance powder flow and prevent sticking during manufacturing. ?
• Preservatives: Prevent microbial growth in liquid formulations. ?
• Sweeteners and Flavouring Agents: Improve taste and palatability. ?
• Colorants: Provide distinctive appearance for identification. ?

The selection of appropriate excipients is critical and depends on factors like the route of administration, desired release profile, and compatibility with the API. [2, 3]

2. Introduction to Microcrystalline Cellulose (MCC):

Structure and Source

Microcrystalline cellulose (MCC) is a purified, partially depolymerized cellulose prepared by treating α-cellulose, obtained from plant sources like wood pulp, with mineral acids. The process removes the amorphous regions of cellulose, leaving behind crystalline segments that are then mechanically processed into fine powders.

STRUCTURE

MCC consists of linear chains of β-1,4-linked D-glucose units. These chains form microfibrils with both crystalline and amorphous regions. The acid hydrolysis process selectively hydrolyses the amorphous regions, resulting in microcrystals of cellulose. This structure imparts MCC with its characteristic properties like high compressibility and insolubility in water. ?

Source

The primary source of MCC is α-cellulose derived from plant materials, predominantly wood pulp. The choice of source material and processing conditions can influence the physical properties of the final MCC product, such as particle size and moisture content, which are critical for its functionality in pharmaceutical formulations. [1, 4]

3. Historical Background and Regulatory Status of MCC

?Microcrystalline cellulose (MCC) has become a pivotal excipient in pharmaceutical formulations due to its exceptional physicochemical properties and regulatory acceptance. Its historical development and regulatory status underscore its significance in the industry. ?

Historical Background

MCC was first introduced as a pharmaceutical excipient in the early 1960s. Its development stemmed from the need for a reliable binder and filler in tablet formulations, particularly suited for direct compression processes. The material's excellent compressibility, binding capacity, and chemical inertness quickly made it a preferred choice among formulators. Over the decades, MCC's application expanded beyond tablets to include capsules, suspensions, and various other dosage forms, solidifying its role as a versatile and essential component in pharmaceutical manufacturing. ?

Regulatory Status

MCC's widespread use is supported by its inclusion in major pharmacopoeias and adherence to regulatory standards: ?

• United States Pharmacopeia (USP): MCC is listed with specific monographs detailing its quality standards, including identification, purity, and performance criteria. ?
• European Pharmacopoeia (Ph. Eur.): MCC is included with defined specifications for its use in pharmaceutical products, ensuring consistency and safety across formulations.
• British Pharmacopoeia (BP): Recognizes MCC as a standard excipient, providing guidelines for its quality and application in medicinal products.

Beyond pharmacopeial standards, regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require that excipients like MCC comply with Good Manufacturing Practices (GMP). These practices ensure that MCC is consistently produced and controlled according to quality standards appropriate for its intended use. Furthermore, excipients must undergo safety evaluations to confirm their suitability in pharmaceutical applications.  MCC's classification as Generally Recognized as Safe (GRAS) by the FDA further attests to its safety profile. This designation indicates that qualified experts consider MCC safe under the conditions of its intended use, based on a long history of common use in food and pharmaceuticals.?[5, 6]

Physicochemical Properties of Mcc:

1. Structure and Chemistry

Microcrystalline cellulose (MCC) is a purified, partially depolymerized cellulose prepared by acid hydrolysis of α-cellulose obtained from plant sources, primarily wood pulp or cotton linters. The hydrolysis process targets the amorphous regions of cellulose, resulting in a fibrous, crystalline product with well-defined physical characteristics.

Structurally, MCC is composed of linear chains of β-D-glucose units linked by β-1,4-glycosidic bonds. The crystalline domains formed during hydrolysis are responsible for MCC's rigidity and mechanical strength. These regions are stabilized by extensive intra- and inter-molecular hydrogen bonding, contributing to the excipient’s high mechanical strength, moisture retention capacity, and low solubility profile.

Figure 1 Structure of Mcc

The crystallinity index of MCC typically ranges between 60% and 80%, depending on the source material and hydrolysis conditions. The high crystallinity is directly associated with enhanced compressibility, which makes MCC suitable for direct compression tablet manufacturing.[6]

2. Particle Size, Bulk Density, and Flow Properties

Particle size plays a pivotal role in MCC’s performance in solid dosage forms. Smaller particle sizes such as those in MCC 101 result in higher binding strength and more uniform compacts, whereas larger sizes like MCC 102 or 200 enhance powder flow, which is advantageous during automated high-speed compression. Bulk density of MCC typically ranges from 0.2 to 0.5 g/cm³. It influences dosage uniformity and packaging, and impacts blend uniformity and tablet weight variation. MCC naturally exhibits moderate flow properties. However, the flow may be insufficient for certain operations, particularly when used with cohesive APIs or in large-scale equipment. Flow can be enhanced by blending MCC with glidants such as colloidal silicon dioxide or by using co-processed MCC grades like SMCC. Compressibility and plastic deformation are other important characteristics. MCC undergoes plastic deformation under compression, forming strong compacts even without added binders—a key advantage in direct compression processes.[7]

3. Solubility and Compatibility

MCC is practically insoluble in water, alcohol, and most organic solvents due to its crystalline structure and extensive hydrogen bonding. However, it can swell in water, which contributes to its mild disintegrant properties. It is chemically inert, does not react with most APIs, and is stable under a broad pH range. This makes MCC a suitable excipient for both acidic and basic drug formulations. It also shows good compatibility with wet granulation binders and film-coating agents. Despite its inert nature, MCC may present incompatibilities with highly hygroscopic drugs or those sensitive to moisture, due to its moisture retention capacity (~3–5%). Similarly, strongly acidic drugs may hydrolyse the glycosidic bonds in MCC under extreme conditions, potentially affecting tablet stability.[8, 9]

Functional Roles of Mcc

1. Diluent/Filler in Tablets

MCC is one of the most commonly used diluents in solid dosage forms. It provides bulk to the formulation, which is essential for low-dose active pharmaceutical ingredients (APIs) that require volume to form tablets of appropriate size and mechanical strength. MCC improves the physical characteristics of the formulation, such as uniform weight distribution, consistent drug content, and tablet integrity.

• Key Benefits:
  • Uniform tablet weight and dosage
  • Low moisture sensitivity
  • Non-reactive with most APIs [9]

2. Binder in Direct Compression

MCC exhibits excellent plastic deformation properties under pressure, allowing it to form strong interparticulate bonds without requiring additional granulation steps. This makes MCC ideal for direct compression techniques, reducing time, cost, and process complexity.

• Mechanism: MCC particles plastically deform under compression, creating solid interlocking networks that result in robust tablets.
• Advantages:
  • High tensile strength of tablets
  • Lower lubricant sensitivity compared to brittle excipients [10]

3. Disintegrant in Combination with Other Agents

While MCC alone has moderate disintegrating properties due to capillary action and wicking, it becomes particularly effective when combined with super disintegrants like:

• Croscarmellose sodium
• Sodium starch glycolate
• Crospovidone

This synergy enhances rapid water uptake and tablet breakup, improving drug release in the gastrointestinal tract.

Mechanism:

• MCC swells upon hydration, initiating tablet rupture.
• Enhances fluid penetration and expansion.[11]

4. Stabilizer in Suspensions

In oral suspensions, MCC is used in colloidal form (often combined with sodium carboxymethyl cellulose, NaCMC) to form a thixotropic gel structure. This structure helps keep the suspended particles uniformly distributed throughout the product’s shelf life.

Figure 2 Structure of Sodium-Cmc

• Benefits:
  • Prevents sedimentation
  • Improves mouthfeel
  • Enhances re-dispersibility

MCC-based suspending systems are widely used in paediatric and geriatric formulations due to their safety and efficacy.[11]

5. Matrix Former in Controlled-Release Tablets

In sustained or controlled-release formulations, MCC serves as a matrix-forming agent. When combined with polymers such as hydroxypropyl methylcellulose (HPMC) or ethyl cellulose (EC), it helps control the rate of drug diffusion and erosion.

• Mechanism:
  • Creates a porous matrix structure
  • Regulates drug release via diffusion and erosion
• Applications:
  • Sustained-release NSAIDs
  • Extended-release cardiovascular drugs [7]

Common Mcc Grades

Microcrystalline Cellulose (MCC) is classified into various grades based on factors like particle size, bulk density, flowability, and specific processing needs. Each grade is tailored for particular applications in pharmaceutical formulations, especially tablet manufacturing via direct compression or granulation. [12, 13]

Table 1: Common Mcc Grades

Table 2: Types of Grades

Other Specialized Grades

MCC PH Grades (e.g., PH 101, PH 102, PH 105)

These are produced by FMC Biopolymer (now DuPont) and are among the most widely used pharmaceutical MCC grades.

Co-processed MCC

These are combinations of MCC with other excipients (like mannitol, sodium starch glycolate, etc.) for multifunctional performance (e.g., improved disintegration + flow). [13]

Table 3: Selection Criteria for Mcc Grades

1. Tablets (Immediate Release)

In immediate-release (IR) tablet formulations, MCC is predominantly employed as a diluent and binder due to its excellent compressibility and flow properties. The concentration of MCC in IR tablets typically ranges from 20% to 90%, depending on factors such as the dose of the active pharmaceutical ingredient (API), desired tablet hardness, and the presence of other excipients. Higher concentrations are often utilized in formulations requiring enhanced mechanical strength and rapid disintegration.

Example: Paracetamol IR Tablets

• API: Paracetamol (acetaminophen)
• MCC concentration: 40–60%
• Formulation role: MCC is used as a diluent and binder to support direct compression and rapid tablet disintegration.
• Observation: MCC improved compressibility and mechanical strength; tablets disintegrated in <15 minutes. [9, 14]

2. Controlled-Release Tablets

In controlled-release (CR) tablet formulations, MCC serves as a matrix-forming agent, often in combination with hydrophilic polymers like hydroxypropyl methylcellulose (HPMC). The typical concentration of MCC in CR tablets ranges from 10% to 40%. This combination facilitates the modulation of drug release profiles by influencing the matrix's porosity and gel strength.

Example: Isoniazid Matrix Tablet

• API: Isoniazid
• MCC concentration: 20–30%
• Formulation role: MCC functions as a matrix former, controlling the release rate of the drug when used with HPMC.
• Observation: The combination of MCC and HPMC provided a sustained release profile up to 12 hours.[15]

3. Capsules

In hard Gelatin capsule formulations, MCC is commonly used as a filler or bulking agent. The concentration of MCC in capsules typically ranges from 30% to 60%. Its inclusion ensures uniform drug distribution, enhances flow properties during capsule filling, and contributes to the structural integrity of the capsule contents.

Example: Ibuprofen Hard Gelatin Capsules

• API: Ibuprofen
• MCC concentration: 30–50%
• Formulation role: MCC is used as a filler to achieve uniform distribution of the API, ensure flowability during capsule filling, and maintain the capsule plug’s integrity.
• Observation: MCC improved uniformity of fill weight and capsule robustness.[16, 17]

4. Oral Suspensions

In oral suspension formulations, MCC is utilized as a suspending agent, often in combination with other stabilizers like sodium carboxymethyl cellulose (NaCMC) or xanthan gum. The concentration of MCC in suspensions generally ranges from 1% to 2%. This combination enhances the viscosity of the suspension, prevents sedimentation of insoluble particles, and improves the overall stability and mouthfeel of the product.

Example: Amoxicillin-Clavulanic Acid Paediatric Suspension

• API: Amoxicillin trihydrate + potassium clavulanate
• MCC concentration: 1.2%
• Formulation role: MCC (with NaCMC) is used to prevent sedimentation, maintain uniform dispersion, and provide a smooth texture.
• Observation: The MCC–NaCMC system-maintained suspension homogeneity and acceptable viscosity over shelf-life.[9, 16]

Table 4: Concentration Ranges of Mcc In Various Formulations

Mcc In Novel Drug Delivery Systems

1. Oro dispersible Tablets (ODTs)

Role of MCC:

In ODTs, MCC serves multiple functions:

• Disintegration Aid: MCC enhances liquid transport into the tablet matrix, accelerating both diffusion and capillary action, leading to rapid disintegration upon contact with saliva. ?
• Binder and Filler: MCC provides the necessary mechanical strength to ODTs, ensuring they can withstand handling and packaging stresses. ?

Formulation Considerations:

• MCC is often combined with other excipients like mannitol to improve mouthfeel and taste masking. ?
• The concentration of MCC in ODTs varies depending on the desired disintegration time and mechanical strength, typically ranging from 10% to 50%. ?

Example:

A study developed a co-processed excipient comprising lactose, low-substituted hydroxypropyl cellulose (L-HPC), and MCC for ODTs. This combination provided rapid disintegration and acceptable mechanical strength. [16]

2. Sustained-Release Matrices

Role of MCC:

In sustained-release formulations, MCC acts as a supportive matrix former:

• Matrix Formation: When combined with hydrophilic polymers like hydroxypropyl methylcellulose (HPMC) or hydrophobic polymers like ethyl cellulose (EC), MCC contributes to the formation of a robust matrix that controls drug release. ?
• Modulation of Release Profiles: The inclusion of MCC can influence the porosity and swelling behaviour of the matrix, thereby modulating the drug release rate. ?

Formulation Considerations:

• The concentration of MCC in sustained-release tablets typically ranges from 10% to 40%, depending on the desired release profile and the properties of the API. ?

Example:

A study formulated sustained-release matrix tablets of timolol maleate using various polymers, including HPMC and EC, with MCC as a diluent. The inclusion of MCC contributed to the desired drug release profile over an extended period. [19]

3. Proliposomes/Lipid-Based Formulations

Role of MCC:

In lipid-based systems, MCC serves as a carrier or stabilizer:

• Carrier for Lipids: MCC can be used to adsorb phospholipids dispersed in organic solvents, facilitating the preparation of proliposomes by drying under reduced pressure. ?
• Stabilization: MCC contributes to the stabilization of lipid vesicles post-hydration, improving the flow properties of the powder and aiding in the formation of uniform liposomal dispersions upon reconstitution. ?

Formulation Considerations:

• The choice of carrier material, including MCC, affects the physicochemical properties of the proliposome formulation, such as particle size, entrapment efficiency, and drug release profile. ?

Example:

A study developed paclitaxel-loaded proliposome tablet formulations for pulmonary drug delivery, utilizing MCC as a carrier. The MCC-based proliposomes demonstrated improved stability and bioavailability of the drug. [20]

ADVANTAGES AND LIMITATIONS

1. Advantages of MCC

Excellent Compressibility

MCC is renowned for its exceptional compressibility, making it ideal for direct compression tablet formulations. The partially crystalline and fibrous nature of MCC enables it to deform plastically under compression. This property promotes strong interparticulate bonding, resulting in tablets with high mechanical strength without the need for external binders or wet granulation.

High Binding Capacity

Beyond compressibility, MCC offers excellent internal cohesiveness, acting as an efficient dry binder. This quality simplifies the tableting process and minimizes the need for additional excipients, thus supporting the development of high-drug-load formulations.

Chemically Inert and Non-reactive

MCC is chemically stable and inert across a wide range of pH levels, making it compatible with a large variety of active pharmaceutical ingredients (APIs). It does not undergo chemical degradation or react adversely with most drugs or excipients, ensuring the integrity of formulations over time.

Biocompatible and Non-toxic

MCC is derived from natural cellulose and has been shown to be non-toxic, non-carcinogenic, and non-irritant in animal and human studies. It is classified as Generally Recognized as Safe (GRAS) by the U.S. FDA, and extensive toxicological evaluations have confirmed its safety for long-term use.

Regulatory Acceptance

MCC is listed in all major pharmacopoeias, including the United States Pharmacopeia (USP), European Pharmacopoeia (Ph. Eur.), and British Pharmacopoeia (BP). Its established monographs detail specifications for identity, purity, and functionality, enabling its widespread use across regulated markets globally.

Multifunctionality

In addition to serving as a binder or diluent, MCC can also function as a disintegrant, a suspending agent in liquid formulations, or a matrix former in sustained-release formulations—enhancing its utility in diverse dosage forms such as tablets, capsules, suspensions, and proliposomes. [13, 21]

2. Limitations of MCC

Poor Flow in Fine Grades

MCC grades with finer particle sizes (e.g., MCC 101) often suffer from poor flow properties, which can lead to issues in die filling during tableting and inconsistent tablet weights. To counteract this, MCC is frequently co-processed with glidants such as colloidal silicon dioxide or blended with coarser excipients like MCC 102 or lactose.

Limited Compatibility with Hygroscopic or Acidic Drugs

Although chemically inert, MCC may interact physically with certain drugs. Its porous nature and water retention can negatively affect the stability of highly hygroscopic drugs, and it may demonstrate reduced compatibility with acidic APIs, potentially altering drug release behaviour.

Moisture Sensitivity

MCC is hygroscopic to a mild extent and can retain ambient moisture, especially under humid storage conditions. This can lead to changes in flow properties, affect compressibility, and impact moisture-sensitive APIs, potentially resulting in degradation or loss of efficacy.

Not Soluble in Water

While its insolubility is advantageous for stability, it limits MCC’s application in formulations where solubility or dissolution in aqueous media is required, such as clear oral solutions or injectables.[22]

Regulatory and Safety Considerations

?Microcrystalline Cellulose (MCC) is a widely utilized excipient in pharmaceutical formulations, recognized for its safety and compliance with international regulatory standards. Its inclusion in major pharmacopoeias and affirmation by regulatory bodies underscore its suitability for use in various drug delivery systems. ?

Pharmacopeial Standards

MCC is officially listed in the United States Pharmacopeia (USP), European Pharmacopoeia (Ph. Eur.), and British Pharmacopoeia (BP), each providing specific monographs detailing its quality attributes. These monographs outline parameters such as identification tests, purity criteria, and performance characteristics. For instance, the USP monograph specifies tests for microbial limits, pH range, loss on drying, and residue on ignition, ensuring the excipient's consistency and safety in pharmaceutical applications. [23]

GRAS Status and FDA Recognition

In the United States, the Food and Drug Administration (FDA) has affirmed MCC as Generally Recognized as Safe (GRAS) for use in food products, reflecting its non-toxic nature and historical safe consumption. This status is based on evaluations by expert panels and comprehensive reviews of scientific data. Although MCC does not appear in the Code of Federal Regulations (CFR), it is considered "prior sanctioned" due to its use in food prior to the 1958 Food Additives Amendment, further supporting its safety profile.[24]

Compliance with Good Manufacturing Practices (GMP)

Manufacturers of MCC adhere to Good Manufacturing Practices (GMP) to ensure the excipient's quality and safety. GMP compliance involves stringent controls over production processes, quality assurance protocols, and documentation, aligning with international standards set by organizations such as the International Council for Harmonisation (ICH). This adherence guarantees that MCC meets the necessary criteria for pharmaceutical use, including purity, consistency, and absence of contaminants. ?

Safety Profile and Toxicological Assessments

Extensive toxicological evaluations have demonstrated MCC's safety for human consumption. Studies have shown that MCC is non-toxic, non-carcinogenic, and well-tolerated upon oral administration. Its inert nature means it does not undergo significant metabolism in the human body, reducing the risk of adverse effects. Moreover, MCC does not interfere with the absorption or efficacy of active pharmaceutical ingredients (APIs), making it a reliable excipient in various formulations. ?

International Harmonization and Regulatory Acceptance

The Pharmacopoeia Discussion Group (PDG), comprising representatives from the USP, Ph. Eur., and the Japanese Pharmacopoeia (JP), has worked towards harmonizing monographs for excipients like MCC. This harmonization facilitates consistent quality standards across different regions, simplifying regulatory processes for pharmaceutical companies operating globally.

Future Prospects and Innovations

1. Nanocellulose Derivatives: A Next-Generation Drug Delivery Platform

Nanocellulose, derived from MCC, encompasses cellulose nanocrystals (CNCs) and cellulose nanofibers (CNFs). These nanostructures exhibit high surface area, mechanical strength, and biodegradability, making them ideal for advanced drug delivery systems.

Table 5: Key Properties of Nanocellulose For Drug Delivery

These attributes enable nanocellulose to serve as carriers for various therapeutic agents, including small molecules, proteins, and nucleic acids, facilitating controlled and sustained release profiles.  [22]

2. Modified MCC for Targeted Drug Delivery

Functionalization of MCC involves attaching specific ligands or molecules to its surface, enhancing its ability to deliver drugs to targeted sites within the body. This approach is particularly valuable in oncology, where precision targeting can improve therapeutic outcomes and reduce systemic toxicity. ?

Table 6: Examples of Functionalized Mcc In Targeted Therapies

These modifications enable MCC-based carriers to respond to specific biological cues, releasing their payloads at the desired site of action. ?[23]

3. Green and Sustainable Production of MCC

Traditional MCC production methods often involve harsh chemicals and generate significant waste. Recent advancements focus on environmentally friendly processes that reduce chemical usage and energy consumption. ?

Table 7: Sustainable Mcc Production Techniques