Development of Next Generation Excipient by Coprocessing:

The International Pharmaceutical Excipient Council (IPEC) classified pharmaceutical excipients based on safety data into two classes namely ‘new chemical excipients’ and ‘established excipients. The excipient class ‘new chemical excipients’ can be sub-divided into ‘modified excipients’ (i.e., existing excipients that are modified with respect to purity and/or physical properties such as particle size), ‘co-processed excipients’ (i.e., two or more existing excipients which are formulated into a new excipient with physical properties that cannot be obtained by a simple physical mixture and is produced through processes such as spray drying) and ‘novel excipients’ (i.e., new chemical entities used for the first time in a drug product which may include known excipients that are chemically modified). Development of new excipient entities and their evaluation is a costly procedure; modification of existing excipients is very easy, more economical and less time consuming. The development of excipients that are capable of fulfilling multifunctional roles such as enhancing drug bioavailability and drug stability as well as controlling the release of the drug according to the therapeutic needs is one of the most important prerequisites for further progress in the design of novel drug delivery systems.  

Co-processed excipients:

A co-processed excipients are combination of two or more compendia or non-compendia excipients designed to physically modify their properties in a manner not achievable by simple physical mixing and without significant chemical change. Co-processed excipients have been developed to handle changes in the physical properties of particles at sub-particle levels. By co-processing two excipients, formulators can produce an excipient with superior properties as compared to the individual ingredients. Co-processed excipients been developed primarily to address the issues of flowability, compressibility, and disintegration potential etc.

Example of absence of chemical change:  Silicified microcrystalline cellulose (SMCC) which is a co-processed of Microcrystalline cellulose (MCC) and colloidal silicon dioxide (CSD). Detailed studies of this product with X-ray diffraction analysis, solid-state nuclear magnetic resonance (NMR), IR spectroscopy, Raman spectroscopy, and C13 NMR spectroscopy have detected no chemical changes, only indicate physical changes by increase in its surface area, resulting in enhanced powder flow and for this reason it gives superior tablet ability and improved formulation robustness. This is the responsibility of co-processed excipient manufacturer to provide full details just like above then only market acceptance will increase. For this reason, market acceptance of SMCC is very high.

Co-processed excipients and its current overview: 

Once considered mainly an afterthought in a company's lifecycle-management strategy, controlled-release dosage forms are now positioned at the forefront of many formulation strategies. Most of the co-processed excipients available in the market are developed for immediate release drug delivery system. However, whenever it comes to modified release drug delivery, generally physical admixtures of the polymers are being used. Few excipient manufacturers have taken efforts towards development of co-processed excipients for modified release, and this will be an area of interest in future. Few of the major pharmaceuticals or excipients manufacturing companies have worked and commercialized the products.

Steps for Co-Processing of Excipients:

The process of developing a co-processed excipient involves the following steps:

• Identifying the group of excipients to be co-processed by carefully studying the material characteristics and functionality requirements.
• Selecting the proportions of various excipients.
• Assessing the particle size required for coprocessing. This is especially important when one of the components is processed in a dispersed phase. Post processing of the particle size of the latter depends on its initial particle size.
• Selecting a suitable method for coprocessing.
• Selecting a suitable process of drying such as spray- or flash drying or any other suitable method.
• Optimizing the process (because even this can contribute to functionality variations).

How to Register:

Throughout a drug approval process, a team of drug regulatory experts needs to compile mandatory documentation which should comply with the common technical documentation format.

The CTD (common technical documentation) format covers the mandatory description of the excipients used. Such as:

• Excipient´s specification and its justification.
• Excipient´s analytical procedures and corresponding validation.
• Excipient´s origin (human or animal origin)

The workload for filling in this excipient section will depend on the excipient being used (compendial / traditional or novel).

Compendial/ Established excipients:

Compendial/ Established excipients comply with monographs published in multiple compendia such as Ph. Eur., BP, USP-NF, JP, CP, etc. These excipients are well accepted by the regulatory bodies. Thus, the risk of a delayed drug approval process is small or negligible for the prospective marketing authorization holder.

Novel Excipients:

In this context the use of novel excipients (including also co-processed excipients) requires additional documentation (pertaining to co-processed excipients as well). In 2017, the International Pharmaceutical Excipients Council (IPEC) has published its Co-Processed Excipients Guide for Pharmaceutical Excipients acknowledging co-processed excipients as novel excipients.

Novel excipients are defined by the International Council for Harmonisation (ICH) as: “Novel Excipients…excipient(s) used for the first time in a drug product or by a new route of administration”.

Why need of Co-Processed Excipients:

• Pharmaceutical manufacturers have the option of using a single excipient with multiple functional properties, thereby reducing the number of excipients in inventory.
• Allow the development of tailor-made designer excipients with retention of   functional and removal of undesirable properties, which can help in faster product development.
• Improved organoleptic properties such as co-processed excipient of microcrystalline cellulose, and guar gum were shown to have distinctive advantages in chewable tablets in terms of reduced grittiness, reduced tooth packing, minimal chalkiness, better mouthfeel, and improved overall palatability.
• Reduce product cost due to improved functionality and fewer test requirements compared with individual excipients.
• Provide intellectual benefits and opportunity for product life cycle extension.

Advantages of Co-Processed Excipients:

Improving flow properties:

Controlled optimal particle size and particle-size distribution ensures superior flow properties of co-processed excipients without the need to add glidants.

Improve compressibility:

Co-processed excipients have been used mainly in direct-compression tableting because in this process there is a net increase in the flow properties and compressibility profiles and the excipient formed is a filler–binder. The compressibility performance of co-processed excipients has been reported to be superior to the simple physical mixtures of their constituent excipients.

Better dilution potential:

Dilution potential is the ability of the excipient to retain its compressibility even when diluted with another material. Most active drug substances are poorly compressible, and as a result, excipients must have better compressibility properties to retain good compaction even when diluted with a poorly compressible agent.

Fill weight variation:

Materials for direct compression tend to show high fill-weight variations as a result of poor flow properties, but co-processed excipients, when compared with simple mixtures or parent materials, have been shown to have fewer fill-weight variation problems. The primary reason for this phenomenon is the impregnation of one particle into the matrix of another, which reduces the rough particle surfaces and creates a near-optimal size distribution, causing better flow properties.

Reduced lubricant sensitivity:

Most co-processed products consist of a relatively large amount of brittle material such as -lactose monohydrate and a smaller amount of plastic material such as cellulose that is fixed between or on the particles of the brittle material. The plastic material provides good bonding properties because it creates a continuous matrix with a large surface for bonding. The large amount of brittle material provides low lubricant sensitivity because it prevents the formation of a coherent lubricant network by forming newly exposed surfaces upon compression, thus breaking up the lubricant network.

Modulating Drug Release: 

Co-processing can alter and improvise the mechanism of drug release and provide formulator opportunity to tailor the product and overcome limitation of single polymer. Co-processed extended-release polymers can provide better delay or control of release rate of a medicament or nutritional supplement creating a wide range of release profiles for a wide range of medicaments. Through coprocessing of polymers, it is possible to produce equivalent or enhanced tabletting performance for direct compression. These polymers not only improve sustained release characteristics when compared to the individual polymers, but in most cases, in tablet form have shown improved tablet hardness, improved tablet friability and a more manageable and predictable granulation endpoint.

 Drying technique of Co-Processed Excipients:

• Spray drying
• Solvent evaporation
• Crystallization
• Melt extrusion
• Agglomeration

Spray drying is expected to hold the largest market share of the Co-Processed Excipients market over the forecast period followed by the Solvent Evaporation. Spray drying is a technique of continuous transformation of feed from a liquid state into dried particulate form by spraying the feed into a hot drying medium. Solvent Evaporation has the second-largest market share. Solvent evaporation involves the use of liquid as a vehicle to dissolve excipient in an organic solvent in which it is immiscible. A core excipient material is also microencapsulated in the dissolved or dispersed liquid phase to obtain appropriate size microparticles. This mixture is then heated (if necessary) to evaporate the solvent.

Main application of Co-processed excipients:

• Pharmaceutical
• Nutraceutical 

Pharmaceutical is expected to hold the largest market share of the co-processed excipients market over the forecast period followed by the Nutraceutical. Pharmaceutical excipients refer to substances which are comprised in a pharmaceutical dosage form to assist the production process, to support and protect, and improve stability, and for bioavailability. Pharmaceutical excipients are utilized as diluents and fillers, binders, coatings, suspension and viscosity agents, flavouring agents, colorants, lubricants, and many other uses. Factors such as the expanding pharmaceutical sector along with the advancements in excipients, rising uptake of biopharmaceuticals, and increasing adoption of orphan drugs are among the factors propelling the application of co-processed excipients in the pharmaceutical sector.

Conclusion:

Need of industry for ease of processing and improved functionality has forced the excipient industry to search for new excipients. The excipient industry has used co-processing of excipients to deliver new excipients having better performance. Improved functionality is the key to success and acceptance of co-processed excipients. Commercially number of co-processed excipients are available for immediate release formulation; however, there is a need to have more of them for Modified release products. There is a need for us to set up independent approval process to approve new excipient by regulatory bodies. Introduction of new excipients through coprocessing is gaining momentum due to need of improved functionality requirement for formulation of new synthetic and biopharmaceutical drugs. Number of new co-processed excipients have arrived in market which are expected to deliver new performance characteristics which will distinguish them from existing, well-accepted agents. In the end, success stories can be told in many aspects of the drug products from the robust formulation and manufacturing process to smooth scale up and process validation, to strong regulatory acceptance and market-share domination in their therapeutic areas. Paying attention to pharmaceutical excipients and their regulatory issues is an indispensable initial step to the success of drug products. 

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Funding:

This research article did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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About the Author:

Dr. Ajay Kumar Singh, M.Sc. (Gold Medalist), Ph.D. is the author and founder of “Pharma Solutions by Dr. Ajay”.

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Examples used in this article are not meant to be endorsements of any product or technology from the author.