INTRODUCTION:

The pharmaceutical industry began using co-processed excipients in the late 1980s, with early examples including co-processed microcrystalline cellulose and calcium carbonate, introduced in 1988, MEGGLE's co-processed cellulose and lactose (1990), and co-processed glucomannan and galactomannan (1996). According to the International Pharmaceutical Excipients Council (IPEC), excipients is defined as the substances other than the API which have been appropriately evaluated for safety and are intentionally included in a drug delivery system. An excipient that has undergone co-processing is a combination of two or more compendial or non-compendial excipients with the purpose of physically changing their properties without affecting chemical qualities.¹Pharmaceutical excipients played a significant part in this transition. Pharmaceutical excipients are described as compounds other than the API that have been adequately studied for safety and are purposely included in a drug delivery system². Excipients are divided into four categories: single entity excipients, physical blends of numerous excipients, new chemical entity excipients and co-processed excipients^3,1. It is predicted that fewer than 20% of medicinal ingredients can be crushed directly into tablets. The remaining materials lack the flow, cohesion, and lubricating qualities required for tablet formation via direct compression. The use of immediately compressible excipients may result in suitable tablets for these materials.

Despite being simple in terms of unit operations, the direct compression process is heavily influenced by powder properties such as flowability, compressibility, and dilution potential. Tablets are made up of active pharmaceuticals and excipients. However, not all drug substances or excipients have the necessary physicomechanical properties for a reliable direct compression manufacturing technique that can be ramped up from laboratory to production scale. Most formulations (70-80%) contain excipients in higher concentrations than the active medicine. As a result, excipients play an important role in determining the functioning and processability of a formulation. Excipient qualities have a direct impact on the direct compression process. Excipients must have strong flowability, compressibility, low moisture and lubricant sensitivity, and machineability for high-speed tabletting with shorter dwell times to guarantee a successful process. The bulk of currently available excipients fail to meet these capability requirements.⁴

Ideal Requirements of Directly Compressible Excipients⁴:

· Directly compressible excipients should be free-flowing. High-speed rotary tablet machines require flowability to provide uniform powder flow and die filling.

· During the short dwell period (milliseconds), transfer the desired amount of powder blend into the die cavities with a repeatability of ±5%. Many frequent production issues are attributable to inappropriate powder flow, such as nonuniform blending, under or over dosing, and inaccurate filling.

· Effective tabletting requires compressibility, which means the mass remains compact even after the compression force is released.

· There are few excipients that can be compressed directly without elastic recovery. As a result, immediately compressible excipients should have a good compressibility, which refers to the relationship between compaction pressure and volume.

ADVANTAGES:

Improved Compressibility:

Compressibility is a key aspect during tablet development. When the compression force is released, the ideal result is a compacted tablet.⁵ However, all typical tablet excipients lack this plasticity. The majority of co-processed adjuvants overcome this constraint, with Ludipress, a co-processed adjuvant, demonstrating greater compressibility to the physical mixes of their constituent excipients.^6,7

Better Dilution Potential:

Dilution potential is defined as the excipient's capacity to maintain compressibility even when diluted with another low compressibility substance. API and many inactive excipients have a low compressibility^8,9.

Stability:

The excipient used in co-processing should be physically and chemically stable. Ingredients should be inert and do not interact with the API.¹⁰

Reduced Lubricant Sensitivity

In general, hydrophobic lubricants have a negative impact on the compression behaviour of powder blends. Plasticity imparts brittleness to an excipient.⁵

Ease of Production:

The use of co-processed excipients facilitates tablet formulation and development. Tablet formulation typically involves weighing the active component and several excipients, followed by mixing, granulation, drying, sieving, and compression. Weighing each component may take time and lead to errors⁴.

Improved Flow Properties:

Controlling the particle size distribution improves the flow characteristics of co-processed excipients compared to individual constituents or physical mixtures. High-speed rotary tablet machines require optimal flowability. Co-processing excipients enhance the flow properties of powders before compression.^11,12

Fast Disintegration:

Fast disintegration is a compendial and formulation criterion for instant release and orally disintegrating pharmaceutical forms. Co-processed adjuvants, due to their high solubility, swelling, and wicking properties, cause the produced formulation to disintegrate rapidly.¹³

Cost Saving:

The manufacturer employs a single excipient with numerous functional qualities, decreasing the number of excipients utilised and labour costs associated with their processing other than the direct compression approach.¹³

Need of Co-Processed Excipients:

Co-processing plays a role by interacting two or more excipients at the sub-particle level in order to provide a synergy of functionality enhancements while hiding the negative features of the separate excipients^2,14. Various particle properties influencing excipient functionality as shown in Table 1.¹⁴

Dis-Advantages¹⁵:

· Pre-clinical species may have poor tolerance for certain lipidic excipients.

· High material losses during processing and moisture-sensitive and thermolabile medicines are poor candidates.

· The formulator's direct connection with manufacturing personnel will be reduced.

Table 1: Various particle properties influencing excipient functionality¹⁴

Particle property	Excipient functionality
Enlargement of particle size	Flowability, compressbility
estricting particle size distribution	Segregation potency
Enlargement of particle porosity	Compressibility, solubility
Surface roughness	Flowability, Segregation potency

General Steps in Developing Co-Processed Excipients:

To create a new co-processed excipient that fits the functionality requirements of a specific application, a few steps must be taken.

1. Identification of the group of excipients to be co-processed:

A good co-processed excipient should consider how a material balances its brittleness and flexibility¹⁵. Unwanted elastic energy storage during compression is eliminated by the combination of plastic and brittle material. As a result, the product will have less stress relaxation and a decreased propensity for capping and lamination, resulting in optimal tableting performance ¹⁶. To obtain the desired results, the excipient combination should work in concert with one another and complement one another⁵.

2. Evaluating the size of the particles:

The final product's flowability and compressibility will be impacted by particle size. The goal should be to create the final co-processed adjuvant with a homogeneous particle size if the initial particle sizes of the participating excipients vary.^17,18

3. Selecting a suitable technique to co-process various excipient

Co-processing can be done in a variety of ways, including hot melt extrusion, freeze drying, spray drying, melt granulation, and wet granulation^18,19

4. Optimizing the process and the proportion of each excipient

Variations in the final product's functioning may result from this. To produce a finished product with the specified features, a variety of optimisation strategies and experimental designs along with reliable statistical analysis can be used.^19,20,21

Sources of New Excipients:

New excipients can emerge from novel chemical entities, modified grades of existing materials, or innovative combinations. However, the high cost, regulatory hurdles, and limited market exclusivity make independent development challenging^22,23,24.

Methods of Co-Processing:

Spray Drying:

Feed can be transformed from a fluid state into dried particles using this spray drying technology. A solution, suspension, dispersion, or emulsion can all be used as the feed. The final powder attributes required by the dryer design and the physical and chemical characteristics of the feed will determine whether the dried product forms as agglomerates, granules, or powders. It is an ongoing drying and particle processing process^25,26. By spraying it into a heated drying medium, the method turns a feed—which could be a solution, suspension, or dispersion—into dried particle form. Throughout the process, excipients form particle-particle bonds. High temperatures and higher droplet surface area result in the creation of spherical particles with better flowability and appropriate direct compression applications, like Starlac²⁶.

Advantages of Spray Drying:

· It is feasible to link non-miscible items that are in constant use.

· It enables the simultaneous blending and drying of both soluble and insoluble compounds.

· Repair and safeguard the delicate active ingredient on the natural carrier.

· Reduces disintegration time and increases machine tableting speed.

· Increases compressibility and hardness.^25,27

Wet Granulation:

High-shear mixers and fluid bed granulators are two frequently used pieces of equipment for the same purpose. A flow of air is pumped upward through the granulator's bottom screen to fluidised the powder mixture in fluid bed granulation. On the powder bed, the binding solution is sprayed in the opposite direction of the air flow. When the solid particles and liquid droplets collide on the bed, adhesion occurs, leading to the eventual creation of granules. Throughout the granulation process, the fluidizing air continuously partially dries the material ^28-31. A common and easy technique for producing co-processed adjuvants is wet granulation. High shear mixers and fluid bed granulators are two frequently used pieces of equipment for the same purpose. A flow of air is pumped upward through the granulator's bottom screen to fluidised the powder mixture in fluid bed granulation. On the powder bed, the binding solution is sprayed in the opposite direction of the air flow. When the solid particles and liquid droplets collide on the bed, adhesion occurs, leading to the eventual creation of granules. Throughout the granulation process, the fluidizing air continuously partially dries the material. An impeller maintains the powder moving in a confined vessel during high-shear granulation. The top is sprayed with the binding solution. High shear force prevents the formation of big agglomerates. The new single-pot method uses the same system for drying. It makes sense that the granules produced are denser than those produced by fluid bed granulation^32,33,25.

Hot Melt Extrusion:

Heat at a temperature higher than 80 °C is used in hot melt extrusion. Materials that are thermolabile cannot be handled with this technique. After being melted and forced through the die, the excipients harden into a range of shapes. The molten polymer can act as a thermal binder, negating the need for the solvent³⁴.

Solvent Evaporation:

The liquid manufacturing vehicle is used to carry out this process. A volatile solvent that is immiscible with the liquid production vehicle phase dissolves the coating excipient. The coating polymer solution dissolves or disperses the core excipient substance to be microencapsulated. To create the right size microcapsule, the core coating material combination is agitated and distributed throughout the liquid manufacturing vehicle phase. The solvent is then evaporated by heating the mixture, if required. With continuous agitation, the liquid vehicle temperature is lowered to room temperature (if necessary) once the solvent has completely evaporated. At this point, the microcapsules can be separated as powders, coated onto substrates, or employed in suspension form. Either water-soluble or water-insoluble materials could make up the fundamental components1. Evaporation of solvents occurs in a liquid production apparatus. The core excipient is then dissolved or dispersed in the coating solution after the coating excipient has been dissolved in a volatile solvent that is immiscible with the liquid production vehicle. To get the appropriate encapsulation size, agitation force is used. The solvent is evaporated using heat.^1,6-9

Crystallization

The production of solid crystals that precipitate from a solution, melt, or, less frequently, are deposited straight from a gas is known as crystallization. Another chemical method of solid-liquid separation is crystallization, which involves the mass transfer of a solute from a liquid solution to a pure solid crystalline phase¹.

Roller Drying:

The homogenous solution or dispersion comprising the pre-blended excipients is dried using a roller dryer. This method was used to co-process lactose with lactitol and sorbitol. The temperature was high enough to produce a product primarily composed of crystalline β-lactose^33,35.

Co-processing of Excipients^36-39:

The following procedures are involved in the actual development of a co-processed excipient:

· Studying the material characteristics and functionality requirements by identifying the group of excipients to be co-processed.

· Choosing the different excipients' concentrations or quantities.

· Determining the necessary particle size for co-processing. When one of the components is handled in a dispersed phase, this is particularly crucial

· The latter's post-processing particle size is determined by its starting particle size.

· Selecting a suitable process.

Table 5. Recent Research on Co-processed Excipients for Direct Compression

Sr No	Co-processed excipients investigated	Technology / Method used for Co-processing	Drugs studied (category)	Result/Purpose	Reference
1	Crospovidone-Croscamellose sodium {1:1, 1:2,1:3}	Solvent evaporation	Metoclopramide (antiemetic)	Superior in flow and compression characteristics	54
4	Chitosan and Aerosil (1:1)	Co-precipitation method	Metoclopramide (antiemetic)	Superior in flow and compression characteristics	53
6	Lactose and Mannitol (1:1, 1:2, 2:1, 1:3, 3:1, 90, 80 and 70%)	Melt granulation	Acetaminophen (NSAID) Paracetamol (antipyretic)	The tablets manufactured showed relatively better disintegration time and in-vitro drug release	55
7	Microcrystalline Cellulose	Gelatinizing potato starch in presence of MCC	Sulphamethoxazole (Anti bacterial) Paracetamol (Antipyretic) Aceclofenac (NSAID)	PGS-MCC co-processed excipient developed in this study was found to be a promising directly compressible vehicle	56
8	Mannitol: Cellulose (50:50, 60:40, 70:30)	Freeze thawing technique	Aceclofenac (NSAID) Nimesulide (NSAID) Metformin (antidiabetic)	Flowability, compactability, and dissolution rate were improved profoundly	57
14	Starch –PEG 1500	Gelatinizing potato starch in the presence of PEG 1500	Pioglitazone (antidiabetic) Gliclazide (antidiabetic)	The co-processed excipient was found to be a promising directly compressible vehicle.	58,59
18	Microcrystalline cellulose with SSL Hydroxypropyl cellulose (1:1, 1:2, 1:3)	Spray drying	Tizanidine Hydrochloride (Centrally acting muscle relaxant)	Formulation showed minimum disintegration time and higher amount of drug release in 1:3	60

FUTURE TRENDS:

The growing limitations of traditional excipients and advancements in co-processing technologies are driving the development of multifunctional excipients with enhanced performance. Rising demand for direct compression and cost-effective formulation is encouraging the creation of high-functionality co-processed excipients. Future trends will focus on excipients that meet safety, regulatory, and performance standards, enabling the use of single multifunctional excipients in place of multiple ones, gaining increased attention from both industry and academia.

CONCLUSION:

This review highlights the recent advancements in co-processed excipients, which address the limitations of single-component excipients by enhancing functionality without altering chemical structure. These multifunctional excipients, classified as GRAS, improve tablet formulation through better flowability, compressibility, disintegration, and mechanical strength. Co-processing holds significant promise for the future of pharmaceutical formulation, especially in direct compression technologies, warranting further research and development.

ABBREVIATIONS:

IPEC - International Pharmaceutical Excipients Council

NSAID- Nonsteroidal anti-inflammatory drug

MCC- Microcrystalline Cellulose

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Received on 05.05.2025 Revised on 19.06.2025

Accepted on 26.07.2025 Published on 08.10.2025

Available online from October 17, 2025

Asian J. Pharm. Tech. 2025; 15(4):405-411.

DOI: 10.52711/2231-5713.2025.00058

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Physical Mixtures⁴⁰	Co-Processed excipients ⁴¹
Physical mixtures, as the name suggests, are simple admixtures of two or more excipients typically produced by short duration low-shear processing.	Combinations of two or more excipients that offer performance benefits not possible with a physical mixing of the same combination of excipients are known as co-processed excipients.
They may be either liquids or solids and are generally used for convenience rather than for facilitating the manufacturing process or improving the resultant pharmaceutical product.	Typically, they are produced using some form of specialized manufacturing process. The performance benefits relate to the manufacture or performance of the finished pharmaceutical product.

Method	Advantages and limitations	Examples
Chemical modification	Relatively expensive, Requires toxicological data, Time consuming	Ethyl cellulose, Methyl cellulose and HPMC.
Physical modification Grinding and/or sieving	Relatively simple and economical, compressibility may alter	Dextrose or Compressible sugar, Sorbitol.
Crystallization	Impart flowability to excipients, Requires stringent control on possible polymorphic conversions.	β-Lactose, Dipac
Spray drying	Spherical shape and uniform size, good flowability.	Spray-dried lactose, Emedex, Fast Flo Lactose, Avicel pH.
Granulation / Agglomeration	Transformation of small, cohesive, poorly flowable powders into a flowable.	Granulated lactitol, Tablettose
Dehydration	Increased binding properties	Anhydrous α- Lactose

Brand name (Manufacturer)	Excipients	Application	Advantages
Advantose FS- 95 (SPI polyols, France)	Fructose, starch	Nutraceuticals and chewable vitamin applications	-
Avicel CE-15 (FMC USA)	MCC, Guar gum	-	Improved palatability, less grittiness, reduced tooth packing
Cellactose (Meggle, Germany)	MCC, lactose	High-dosage tablet, herbal formulations	Highly compressible, good mouth feel, low cost
DI-PAC (American sugar, USA)	Sucrose, dextrin	-	Directly Compressible
Ludipress (BASF, Germany)	Lactose, PVP, Crospovidone	For use in chewable tablets and Lozenges and as bulking agent for modified release formulations.	Good flowability, Low hygroscopicity, Hardness independent of machine speed
Pearlitol SD (Roquette, France)	Granulated Mannitol	For chewable and effervescent tablets	-
Pharmatose DCL 40 (DMV Netherlands)	Anhydrous lactose, lactitol	-	High compressibility, low lubricant sensitivity
Plasdone S-630 (ISP, USA)	Vinyl acetate, Vinyl pyrollidone	-	-
Prosolv (Pen west USA)	MCC, Colloidal Silica	-	Better flow, hardness, Reduced friability