MicroCrystalline Cellulose (MCC)
What is MCC?
Microcrystalline cellulose is a more purified form of Cellulose. It is a white, odorless, tasteless carbohydrate polymer powder that typically consists of up to 350 glucose units. Humans are unable to digest microcrystalline cellulose, making it Generally Recognized As Safe (GRAS) for human consumption. This, and its lack of odor and taste give it a great use as a thickener, stabilizer or excipient for any food product or pharmaceutical tablet.
Figure 1 Cellobiose, the polymeric structure of cellulose
Processed cellulose already contains partly crystalline segments but also weaker amorphous regions. In microcrystalline cellulose, the crystalline regions of cellulose have been isolated, forming a more crystalline product. It can be made of any material that contains high volumes of cellulose; which is found in cell walls in plants. This abundance in nature makes it cheap to produce. The level of crystallinity is higher when the polymer is extracted from cotton compared to other sources. However, wood is used mainly in pharmaceutical applications due to its abundance and lower price. Beside these two advantages, the possibility that cotton is genetically modified (GM) deters many companies.
Read more below about the composition, production, variability and purity of microcrystalline cellulose, MCC properties and microcrystalline cellulose characterization.
Look here for information about hypromellose.
Microcrystalline Cellulose Characterization Services
Excipia offers fast and flexible hands-on services to reveal and compare hidden microcrystalline cellulose properties like :
the presence of potential reactive impurities or functional groups, degradation products and related substances, just like molecular weight distributions and many other featured characteristics.
In addition, we can help users of MCC to pick the most appropriate microcrystalline cellulose manufacturer, select the most suitable microcrystalline cellulose grade for their finished dosage form, or define customized microcrystalline cellulose specifications to control product performance, quality and safety.
Microcrystalline cellulose has strong intra- and intermolecular binding patterns caused by hydroxyl groups, which cause the polymer to be partly crystalline, mechanically stable, stiff and hard to dissolve. Special solvents are therefore utilized to dissolve cellulose. Low molecular mass cellulose chains are dissolved instantly while higher molecular mass polymers are more difficult to dissolve and require an activation step. The exact mechanisms for the dissolution process of microcrystalline cellulose are not clearly known.
Different suppliers of MCC exist, each with their own product and brand that differs from one another. Although there is no general system for assigning different grades, most manufactures indicate the particle size and moisture content by using numbers. The most common numbers are 101, 102, 200, 301 and 302. The first digit usually indicates a certain density, while the last two digits describe a certain particle size and moisture content combination. However, not all suppliers use this system and may deviate of such. Other letters are sometimes added to indicate an extra step added to the production process. These can consist of properties such as a different drying technique or granulation.
Microcrystalline cellulose composition and production
The production process of microcrystalline cellulose from wood material has been known for more than 70 years. Wood consists of lignin (18-35%), cellulose and hemicellulose (65-75%). Lignin is a phenolic substance consisting of an irregular distribution of differently bonded hydroxyl- and methoxy-substituted phenylpropane units. Together with cellulose, it provides a structural function in plants. It also allows transport of water in the vascular tissues of plant cells better than hemicelluloses and celluloses because of their less hydrophilic properties. Hemicelluloses are supporting polymers and are present in cell walls in the range of 25% to 35%, depending on the plant type. It consists almost entirely of monosaccharides such as glucose, mannose, galactose, xylose, arabinose, as well as 4-O-methylglucuronic acid and galacturonic acid residues. In contrast to (microcrystalline) cellulose, the hemicelluloses are branched, making them largely amorphous. The chemical composition of hemicellulose can differ depending on the type of wood chosen for production. The woody material of some softwoods, such as Norway spruce, may contain up to 20% galactoglucomannans. These are hemicelluloses mainly made of galactose, glucose and mannose. Hardwoods such as conifers mainly contain glucuronoxylans, which consist of glucuronic acid and xylose as the main components. Reports show that the country of origin can have a significant influence on properties such as crystal structure and particle size. These differences can further influence the rheological behaviour, which can cause problems in certain pharmaceutical processes, such as tableting.
Read our Case Study: VARIABILITY OF EXCIPIENTS: Xylose in microcrystalline cellulose
Figure 2 Xylose, Glucose, Galactose, Arabinose and Mannose in their pyranose form.
Microcrystalline cellulose is difficult to purify without increasing degradation products during processing. The general MCC manufacturing process is partially like that of the production of cellulose and starts with chopping up wood into small particles. The woodchips undergo first a pulping process: they are hydrolyzed under heat and pressure by mineral acid or bases. Ordinary pulping processes (Kraft process) can be performed using a mixture of sodium hydroxide and sodium sulfide (NaOH and Na2S) that break the bonds of lignin to cellulose. Another pulp method is sulphite pulping, where the lignin is extracted from the wood pulp and removed with various salts or sulfurous acid (usually sodium bisulfate NaHSO3 or sodium sulphate Na2SO3). Hydrolysis converts insoluble hydroxides, oxides and sulfonates into soluble compounds. Thereafter, an alkaline treatment can be carried out with a solution of NaOH at high temperatures (about 100°C) to remove hemicelluloses.
In the processes, amorphous regions of the cellulose are broken up simultaneously, while leaving the crystalline segments intact. The hydrolysation is carried out until a certain level of polymerization is achieved. After hydrolysis, the material is washed with water, which removes the soluble impurities but leaves the insoluble crystalline cellulose. After filtration, the resulting cake is resuspended in water and spray dried with hot gas. This spraying process can be described as breaking down the cellulosic fiber material into a microcrystalline form and then agglomerating these crystallites into particles. Although all the lignin is likely to be removed during the dissolution and filtering process, some hemicellulose might still be present in the purified powder. In some purification processing the pulp is additionally treated with an aqueous chlorine solution and bleached with NaClO8.
The above MCC production process is a general production method; manufacturers can use different chemicals or production steps to add specific functionality to their product.
Microcrystalline cellulose purity and degradation products
After processing of the wood pulp, microcrystalline cellulose is essentially free of fibrous cellulose. Potential impurities in MCC consist of substances commonly found in the raw materials, including trace amounts of lignin, hemicelluloses, oxycelluloses, furans and water. Atmospheric oxygen, and if present, peroxides and chlorous acids, can readily oxidize to form oxidized cellulose. Oxidized cellulose consists of glucose units with the primary alcohol groups converted to e.g. carboxyl or carbonyl groups. The formation of oxycellulose can cause degeneration of the cellulose backbone. Both hot alkaline and acid solutions can be used during the purification process. These extreme conditions are optimal for the formation of additional undesirable reactive degradation products like organic acids, e.g. formic acid, acetic acid and butyric acid, and furans such as Hydroxy Methyl Furfural (HMF) and Furfural. Furans, oxycellulose, cellulose reducing end groups and linear shaped monosaccharides can form new products through Maillard reactions.
Microcrystalline cellulose variability
Because microcrystalline cellulose is purified and produced by different manufactures, process technology, process parameters and even operator actions can contribute to batch-to-batch inconsistency. Production facilities are located all over the world and can use local tree species that differ in chemical composition. Variability is introduced by deficiencies and fluctuations in specifications of starting materials; crop species, seasonality and different regional origin can have a remarkable impact. The amount hemicelluloses and lignin may differ in the same tree population; trees in the middle of the forest, forest edge, sunny side, wind side, ect. This can result in batch to batch variation within the same manufacturer and grade and affect the reactivity of microcrystalline cellulose with active pharmaceutical ingredients in pharmaceutical formulations.
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Microcrystalline Cellulose Characterization Services
- the presence of potential reactive microcrystalline cellulose impurities or functional groups,
- reducing power of microcrystalline cellulose,
- microcrystalline cellulose degradation products and related substances,
- microcrystalline cellulose molecular weight distributions,
- and many other microcrystalline cellulose characteristics.