The Functional Attributes of Co-Processed Excipients in Direct Compression

Abstract

The pharmaceutical industry is increasingly adopting co-processed excipients as alternatives to conventional excipients in tablet manufacturing despite certain regulatory challenges. Co-processing of excipients was designed to optimize physical powder properties such as flowability, compressibility, and compactibility, which are critical attributes for efficient tablet production, especially by means of direct compression. This review summarizes the various preparation methods of co-processed excipients and comprehensively discusses the role of co-processed excipients over conventional pharmaceutical excipients in enhancing tablet formulation as well as tablet manufacturing efficiency and consistency due to their improved functionality. Furthermore, the functionality and enhancement of performance of co-processed excipients are discussed on the three levels of solid substances, namely the molecular, particle and bulk levels. It further evaluates the effectiveness of co-processed excipients in addressing common formulation challenges such as moisture, lubricant sensitivity and strain rate sensitivity.

1. Introduction

Tablets remain one of the most important, widely used and preferred pharmaceutical dosage forms for oral drug administration due to their numerous advantages. These benefits include relatively low production cost, high production speed, dose uniformity and precision, ease of handling and packaging, and ease of self-administration by patients, which also enhances patient compliance (Allen and Ansel 2014; Ambore et al. 2014; Osei-Yeboah et al. 2016). Among the various methods employed in tablet manufacturing, direct compression is the most cost-effective, easily scalable and preferred method of tablet manufacturing (Bolhuis and Armstrong 2006).

The increased use of the direct compression method for tablet manufacturing has heightened the requirements of pharmaceutical excipient functionality. Excipient functionality refers to the activity it provides in the tablet formulation such as flowability and compressibility, which can be described as the excipient’s equivalent of the active pharmaceutical ingredient’s (API) efficacy. Thus, the inherent properties of an excipient determine its functionality (Chaudhari et al. 2012). Additionally, many new APIs have poor compressibility, increasing the demand for excipient functionality to overcome the limitations of the API. This has led to the development of co-processed excipients with enhanced functionality (Garg et al. 2013; Ijaz et al. 2017).

Co-processed excipients are defined as “a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing, and without significant chemical change. However, in some instances, formation of necessary components may occur, such as in situ salt formation” (IPEC 2023). Co-processing of two or more excipients to form a novel co-processed excipient not only enhances the functionality but also eliminates unwanted characteristics of the individual components (Nachaegari and Bansal 2004; Kolter 2011). In general, co-processed excipients possess superior flowability and compressibility, reduced moisture and lubricant sensitivity and improved machine processing ability during high-speed tablet manufacturing (Rojas et al. 2012).

The development of new grades of existing excipients resulted in only marginal enhancements of excipient functionality, whereas co-processing could produce novel excipients with substantial improvement of functionality. Substances in the solid-state are characterized on three levels, namely the molecular level (which relates to the molecular arrangement in a crystal lattice and includes polymorphism, pseudo-polymorphism and the amorphous state), the particle level (which includes the physical properties of particles such as particle shape, size, surface area and porosity) and lastly, the bulk level (which includes the properties of a bulk of powder particles such as flowability, compressibility and dilution potential). These levels are interdependently linked and change on one level may affect the other levels. Co-processing alters one or more levels of the solid-state, which in turn enhances a powder’s overall functionality Chaudhari et al. 2012). Regulatory and intellectual property concerns have resulted in the commercialization of only a limited number of novel excipients (e.g., co-processed excipients). From a regulatory point of view, co-processed excipients produced from individual excipients that were already approved, retain a generally regarded as safe, i.e. “GRAS” status due to the absence of significant chemical changes resulting in there being no requirement to perform toxicological assessments. However, new guidelines from the International Pharmaceutical Excipient Council require of risk assessment studies that must be carried out on co-processed excipients (IPEC 2017).

Although excipient manufacturers have put quality control measures in place to ensure reproducible manufacturing of high quality co-processed excipients, there are a number of risk factors that make drug formulators reluctant to use co-processed excipients. As with any ‘new’ material to be used as an excipient, the risk to patient safety should be assessed. The user of any co-processed excipient in pharmaceutical products for human or veterinary use is responsible for assuring its fitness for purpose. One obstacle for pharmaceutical companies is the fact that many co-processed excipients don’t have official monographs. For this reason, the regulatory agency may request additional safety and efficacy data for co-processed excipients (IPEC 2017; Challener 2022).

The potential risk to the patient by co-processed excipients depends on the type of ‘newness’ of the co-processed excipient created. If no new covalent chemistry can be shown in the co-processed excipient through appropriate testing, then a scientific justification can be documented for linking the safety assessment of the co-processed excipient to that of the individual components. Co-processing of individual components by physical means rather than covalent chemical bonding creates a “novel regulatory entity” rather than a “novel chemical entity”. Therefore, if the co-processed excipient has not been chemically altered in comparison to the corresponding physical mixture of the individual components, the safety of the co-processed excipient can be linked to that of the individual components and assessed using analytical rather than toxicological methods (IPEC 2017).

When changes in excipient composition of pharmaceutical formulations occur post-approval of a product beyond certain specified limits (typically ± 10% for filler), then a full bioequivalence study is required. A bioequivalence study would therefore be required when switching from conventional excipients to co-processed excipients in a pharmaceutical product. However, the bioequivalence study may be waived if an acceptable in vivo–in vitro correlation has been verified for the specific active pharmaceutical ingredient (FDA, 1995).

2. Preparation methods of co-processed excipients

Different methods have been employed in the preparation of co-processed excipients, which are briefly described in the sub-sections below.

2.1. Spray drying

The spray drying method is currently the most widely utilized technique for the preparation of co-processed excipients owing to the advantages associated with it, which include rapid operational speed, scalability, enhanced control over the drying process and enhanced control over the final co-processed excipient’s characteristics (Kaushik et al. 2021 and Rao et al. 2021). In this method, the materials, known as the ‘feed’ are transformed from a fluid state (e.g., solution, suspension, dispersion, or emulsion) into a dried particulate state by spraying the feed as droplets into a heated drying gas medium. Spray drying involves five main process steps, namely concentration of the feed, atomization, droplet-air contact, droplet drying and particle separation (Patel et al. 2009). During the atomization phase, the exposed surface area of the liquid feed is increased by scattering the feed into fine droplets. This enhances subsequent heat transfer during drying and allows rapid solvent evaporation within seconds. Importantly, the droplets never reach the high inlet temperature of the drying gas, thereby rendering thermolabile materials suitable for spray drying (Cal and Sollohub 2010). The dried product obtained can be a powder, granules or agglomerates depending on the feed’s physical and chemical properties, the dryer’s design and the desired properties of the final particulate state. In general, this process renders powder particles with a more spherical shape, which are more suitable for direct compression due to the resultant enhanced flowability (Bin et al. 2019).

Table 1 contains a comprehensive list of all the commercially available co-processed excipients manufactured by means of the spray drying method, alongside their components and the enhanced functionality offered.

Table 1: Commercially available co-processed excipients manufactured by spray drying

MCC-Microcrystalline cellulose;

Na-CMC-Sodium carboxymethylcellulose

2.2. Granulation

The granulation method for co-processing can be divided into three sub-methods, namely wet granulation, melt granulation and dry granulation.

2.2.1. Wet granulation

Wet granulation can be performed on a large scale by either fluid bed granulators or high-shear mixers. In fluid bed granulators, an upwards stream of air is injected through the powder mixture to form a fluidized bed that hovers in mid-air inside the granulator. The binder solution is sprayed into the fluidized bed in the opposite direction of the airstream. The collision between the liquid binder droplets that hit the solid powder particles then cause granules to form due to particles sticking to each other. The granules formed are then dried by the upwards stream of hot air and finally sieved to obtain the granule mass. This method is also referred to as fluid bed spray granulation (Faure et al. 2001; Hapgood et al.2009; Daraghmeh et al. 2010).

In high shear mixers, the powder mixture is kept agitated in a closed vessel by an impeller while the binder solution is injected from above. The high shear force prevents the formation of large agglomerates. The granules are then dried in the same vessel using innovative single-vessel technology, also known as one-pot processing. Vacuum drying is typically employed, offering low temperatures and easy recovery of the granulation liquid through condensation. This is particularly beneficial for organic solvent-based granulations, as vacuum drying minimizes solvent emissions, aiding compliance with strict environmental regulations. However, vacuum drying is time-consuming due to limited heat transfer. To address this, microwave drying can be used, significantly speeding up the process and allowing better control, especially for water-based formulations. Generally, the granules obtained by this method have a higher density compared to those prepared by fluid bed granulators (Faure et al. 2001; Van Vaerenbergh and Stahl 2021).

2.2.2. Melt granulation

The melt granulation method begins with the mixing of powders with a suitable meltable binder. The mixture is then subjected to heat above the binder’s melting point while being continuously stirred, causing agglomerates to form. The agglomerated powder is then cooled and sieved, resulting in the co-processed powder. The major drawback of this method of co-processing is the relatively high temperatures required for melting of the binder, making it unsuitable for any thermolabile materials (Gohel and Jogani 2003; Garg et al. 2015).

2.2.3. Dry granulation

Roller compaction is used for dry granulation, where powder particles are first bonded through physical compaction between rollers and then broken up to produce granules. The process commences with the powder mixture that is uniformly mixed and thereafter continuously passed in between counter-rotating compression rolls forming solid ribbons or sheets of compacted powder. These sheets are subsequently milled and sieved to obtain the desired particle size of the co-processed powder. An advantage of this method is its suitability for thermolabile and moisture-sensitive materials (Chang et al. 2008; Teng et al. 2009; Shanmugam 2015).

Table 2 contains a list of the commercially available co-processed excipients manufactured through granulation, alongside their components and enhanced functionality.

2.3. Hot melt extrusion

During the hot melt extrusion method, the melted mass of excipients is pressurized through a die, forming extrudates of various sizes that solidify. The solid extrudates are then sieved to obtain the desired particle size of the co-processed excipient. This method does not require a solvent, as the melted mass moves through the extruder’s orifices to form solid extrudates through thermal binding. However, the use of high temperatures in this method makes it unsuitable for thermolabile materials (Liu et al. 2001; Patil et al. 2024).

Table 3 contains a list of the commercially available co-processed excipients manufactured through hot melt extrusion, alongside their components and the enhanced functionality offered.

2.4. Miscellaneous

Less commonly used preparation methods such as solvent evaporation, milling, co-crystallization, co-precipitation, gelatinization and freeze-thawing for the manufacturing of co-processed excipients are discussed in this section for reasons of completeness.

2.4.1 Solvent evaporation

The solvent evaporation method is conducted in a liquid medium, where the selected excipients, combined in specified ratios, are dispersed in an appropriate volume of an organic solvent, such as isopropyl alcohol. The resulting mixture is subjected to continuous stirring using a magnetic stirrer, with the temperature maintained between 65 °C and 70 °C to promote solvent evaporation. Once the formation of a cohesive wet mass is reached, the material is granulated through a sieve and subsequently dried in a hot air oven. The dried granules are then re-sieved using a suitably sized mesh to obtain a co-processed excipient with the desired particle size (Gohel et al. 2007; Ladola and Gangurde 2014).

2.4.2 Milling

Milling is a co-processing method in which a mixture of excipients is exposed to mechanical forces using high-speed milling equipment. This causes inter-particle collisions that promote bond formation between particles, leading to the formation of co-processed granules/particles (Bin et al. 2019). This technique was applied to co-process cross-linked polyvinylpyrrolidone (crospovidone) with calcium silicate, resulting in a co-processed excipient that demonstrated a significantly improved dissolution profile compared to a simple physical mixture of the individual excipients (Rao et al. 2012).

2.4.3 Co-crystallization

During the co-crystallization method, a supersaturated solution of the excipients is prepared in a suitable solvent. Crystals can then be obtained from the solution by various methods such as cooling the solution while agitating it, adding a second solvent that reduces the solute’s solubility (i.e. antisolvent), a chemical reaction or changing the solution’s pH. The crystals are separated from the solution by means of filtration whereafter they are dried to render co-processed excipient particles (Chaudhari et al. 2012; Mishra et al. 2022).

The only commercially available co-processed excipient manufactured through co-crystallization is Di-Pac® (Domino, USA) consisting of 97% sucrose and 3% dextrin. The co-crystallization process forms a uniform, porous crystalline lattice by integrating a small amount of dextrin into sucrose. This unique structure enhances compressibility and facilitates rapid water penetration leading to accelerated tablet disintegration and improved moisture resistance (Gohel and Johani 2005).

2.4.4 Co-precipitation

The co-precipitation method entails the rapid precipitation of an excipient mixture from a solvent or solvent mixture. The excipient mixture is dissolved in the solvent system, and an anti-solvent is then added to induce solid particle formation. The precipitated particles are subsequently isolated, dried and milled (if necessary) resulting in the formation of a co-processed excipient with enhanced functional attributes. This enhancement is attributed to the method’s ability to provide precise control over particle morphology (Amornrojvaravut and Peerapattana 2023; Dhondale et al. 2023; Sachdeva et al. 2024).

2.4.5 Gelatinization

The gelatinization method can only be utilized to produce co-processed excipients when at least one of the components to be co-processed is starch. This is attributed to starch’s unique thermal properties that renders it ideal to undergo gelatinization (Bhatia et al. 2022). One method entails adding an admixture of starch and povidone to a fluid bed granulator and thereafter spraying an aqueous povidone solution onto the admixture. The mixture is then dried with hot air (Menon et al. 1996). An alternative method entails mixing starch and polymer(s) with water to create a slurry and thereafter adding the slurry to boiling water while continually stirring. The slurry is then dried, grinded and sieved to the desired particle size (Ramja and Chowdary 2013). Both methods render a free-flowing co-processed excipient with enhanced compressibility.

2.4.6 Freeze thawing

During the freeze thawing method – also referred to as spherical crystallization – both crystallization and agglomeration occur simultaneously. The excipient mixture is dissolved in an aqueous vehicle and subjected to a series of freezing and thawing cycles. The agglomerates formed are then dried and sieved to achieve the desired co-processed particle size. Although not commonly employed, this method has been shown to enhance the flowability and compactibility of excipients (Patel and Patel 2009).

Table 4 contains additional commercially available co-processed excipients produced by miscellaneous methods or methods not specified by the manufacturer. Their components and the enhanced functionality offered by co-processing are also provided.

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Excpients mentioned in the article: Cellactose, StarLac, Ludipress, Kollidon^® CL, Prosolv, Compressol, Advantose^™ FS95, Avicel^® HFE-102, CombiLac, MicroceLac^® 100, Sepistab™ ST 200, Methocel, F-Melt^® Type M, Pearlitol^® SD

Coetzee, R., Hamman, J., Steenekamp, J., & Hamman, H. (2025). The Functional Attributes of Co-Processed Excipients in Direct Compression. Pharmaceutical Development and Technology, 1–32. https://doi.org/10.1080/10837450.2025.2584127