Recent Advancements in Co-Processed Excipients

Over the last decade, there has been a notable shift in emphasis within both academic circles and the pharmaceutical industry, moving away from the development of new active pharmaceutical ingredients (APIs) towards advancements in technique for formulation ^[1] Excipients used in pharmaceuticals have been a significant factor in this change. Following a thorough safety investigation, these excipients—which are different from the active pharmaceutical ingredient (API)— are purposefully incorporated  to a medication method of delivery. ^[2] According to the 2009 The International Council of Pharmaceutical Excipients, Components of a finished pharmaceutical dosage form are called excipients that do not contain the active ingredient..  ^[3] The basic categories into which excipients can be separated are single entity excipients, physical combinations of several excipients, novel chemical compound excipients, and combined processing excipients.^[4] Formulation specialists usually concur that no excipient made with just one component has all the properties required to effectively formulate an active pharmacological substance into a particular dose form.^[5] Nevertheless, creating an innovative chemical excipient necessitates a large financial commitment.^[6]Co-processing is a novel strategy that formulation scientists have put forth to overcome this issue. With this technique, two or more excipients that provide unique advantages not possible with a straightforward physical combination of the same excipients are combined.^[7]A coprocessed excipients refers to the integration of two or more excipients, whether Whether it's compendial or not, aimed at altering their physical characteristics in a way that cannot be accomplished through mere physical blending, while maintaining minimal chemical alteration.^[2] Using a specific manufacturing procedure to combine many excipients into a single composite material enhances the functionality of the finished product. ^[8] Recently, this has been a popular practice in formulation development.^[9] There has been a lot of interest in using co-processed excipients in the formulation of various dosage forms, such as tablets, capsules, powders, creams, ointments, and more.^[10] A physical mixture is very different from co-processed excipients. A physical mixture just requires a simple shear processing step to combine many excipients. As opposed to a physical mixing of the same excipients, co-processed excipients provide performance advantages.^[11] When the proper proportions of additional functional elements are mixed with an inexpensive excipient, the end product performs better than if the components were just combined.^[12] Chemical changes are usually not the outcome of coprocessing. Changes inside the excipient particles' physical characteristics are commonly cited as the cause of the functional alterations..^[13] The most popular approach to medicine delivery is still oral administration. ^[14] When it comes to easy drug administration, the oral drug delivery method has a lot to offer. Because of their simple production method, small size, and convenience of self-administration, tablets and hard gelatin capsules comprise a significant portion of the drug delivery systems on the market today.^[15,16] Additionally, the drug exhibits better stability in solid dosage forms as opposed to liquid ones.^[17] The three primary techniques utilized in tablet manufacturing consist of direct compression, dry granulation, and moist granulation. ^[18] The primary constituents in the formulation may possess adequate compressibility and fluidity already, negating the need for granulation. One of the most widely used processes is direct compression because of its advantages, which include time savings, ease of manufacturing because only a few steps are required, and the absence of moisture and warmth throughout the procedure.^[19] Shangraw and Damarest's study found stated the technique most frequently employed was direct compression. for producing tablets, surpassing both moist granulation and compaction using rollers. Despite the fact that 41.1% of the companies surveyed said they used both direct compression and wet granulation, over 41% said they favored direct compression. Only 1.7% of those surveyed claimed to have never used direct compression, while 15.5% indicated it wasn't advised..^[19] The fact that tablets disintegrate into their component particles without going through the granular aggregation phase is another advantage of direct compression. This consequently results in a greater effective surface area, which speeds up the drug's disintegration.^.[20The approach is limited, nonetheless, by the absence of appropriate excipients for direct compression. Compressibility and flowability are two crucial particle characteristics that significantly affect the process of direct compression. ^{[ 21,22]} The excipients now on the market are insufficiently capable of performing the necessary functions. Excipients with improved functions must be developed immediately in light of this circumstance. The technological gap related to indirect compression can be filled by the coprocessed excipient. ^[23]

ADVANTAGES:

1. Enhanced Compressibility: When formulating tablets, compressibility is a critical component. When the compression force is released, a tablet should ideally maintain its compact structure ^[6]. However, the required flexibility is frequently absent from conventional tableting excipients. This restriction is successfully circumvented by numerous co-processed excipients. According to Flores et al. (2000), the co-processed excipient Ludipress® has a compressibility that is higher more than the actual mixes of its component ingredients.^[24-25]

2.Elevated Potential For Slution:Potential of dilution refers to an excipient's ability to retain its compressibility when combined with less compressible components. Many active pharmaceutical ingredients (APIs) and inactive excipients generally have low compressibility. However, a high dilution potential co-processed excipient is beneficial since it maintains the compressibility of the powder blend even when mixed with other excipients..^[26]

3. Decreased Lubricant Sensitivity: Powder blend compression properties are frequently adversely affected by hydrophobic lubricants. A brittle character may result from an excipient's plasticity. Reduced lubricant sensitivity occurs when there is a noticeable level of brittleness in a co-processed excipient. This phenomenon happens because brittleness disrupts the lubricant structure by creating freshly exposed surfaces during compression, which inhibits the creation of a cohesive lubricant network.^[6]

4. Simplified Production Process: The formulation and development of tablets is made easier by the use of co-processed excipients. Weighing the active ingredient and other excipients is usually the first step in tablet formulation. Other steps include mixing, granulation, drying, sieving, and compression. Weighing every component can be time-consuming and prone to mistakes.^[25]

5. Better Flow Characteristics: Because of the regulated particle size distribution, the co-processed excipient exhibits better flow characteristics when compared to its constituent parts or physical mixes.^[29] Especially for high-speed rotary tablet machines, effective flowability is essential ^[6]. With co-processed excipients, Significant improvements have been made to the powder mass's flow properties for compression. Studies show that compared to cellulose and lactose, co-processed Cellactose® has better flow properties. This is due to the fact that particles created using the spray drying approach have spherical shapes and homogeneous surfaces.^[30]

6. Compendial standards specify that rapid disintegration is necessary for oral disintegrating and immediate-release dose forms.^[31]

2.1 Typical Procedures For Creating Co-processed Excipients  
A few important considerations must be made while creating a novel co-processed excipient that meets the functional needs of a certain application.

a. Identification of the Excipient Group for Co-Processing 

A material's balance between brittleness and flexibility should be taken into account while creating an efficient co-processed excipient. Combining plastic and brittle materials prevents undesired elastic energy from building up during compression. By lowering the propensity for capping and laminating and creating a product with minimal stress relaxation, this will lead to the best tableting performance possible. The excipient combinations must cooperate and enhance one another in order to provide the intended results. ^[6]
 

b. Evaluating Size of Particles

Particle size will affect the final product's flowability and compressibility. Creating a final coprocessed adjuvant with uniform particle sizes should be the aim if the starting particle sizes of the participating excipients vary. ^[36,39]
 

c. Choosing a Good Technique To Co-process Different Excipients

 Hot melt extrusion, freeze drying, spray drying, melt granulation, and wet granulation are examples of co-processing methods. In this review, a thorough explanation is given later on^[.36,39]

d. Improving The Procedure and Each Excipient's Ratio

Differences in the final product's functionality could result from this.A final product with the desired qualities can be produced using a variety of optimization approaches, experimental designs, and trustworthy statistical analysis. ^[2]
 

4. The Technologies Used to Produce Co-Processed

1. Excipients By Compaction of Rollers: Dry granulation, which creates particle bonding, is the concept underlying roller compaction. This technique works effectively for materials that are prone to heat and moisture. A ribbon of compacted material is produced by evenly mixing and compressing the powder blend between counterrotating rollers. The ribbon is then pulverized into granules of the proper particle size^[32]

2. Moist Granulation: Coprocessed adjuvants are made using this simple, conventional method. High-shear mixers and fluid bed granulators are two frequently used pieces of equipment for this purpose. In the fluid bed granulation process, the powder mixture is fluidized by pumping air upward through the granulator's bottom screen. The binding solution is then sprayed onto the powder bed in the opposite direction of the airflow. Granules are created when the solid particles and liquid droplets stick together after colliding with the bed. Because of the fluidizing air, some drying occurs simultaneously with the granulation process^.[45,47]

3. Extrusion With Hot Melt: Heat is applied at temperatures higher than 80 °C during the hot melt extrusion process. Heat-sensitive materials shouldn't be handled using this method. The excipients are pushed through a die and solidify into a variety of shapes after being heated to the melting point. In this technique, the molten polymer serves as a thermal binder, negating the need for a solvent^.[34]

4. Drying With a Spray: Usually, spray drying consists of five stages: atomization, interaction of droplets with air, drying of droplets, concentration of feedstock, and separation and collection. I apologize, but it looks like there’s no specific text provided for me to paraphrase. Could you please share the text you'd like me to work on? A feed material is converted from a solution, suspension, or dispersion into a dry particle form by atomizing it in a heated liquid for drying. During the process, excipients form connections with each other at the particle scale. Spherical particles exhibiting improved flowability are produced due to the elevated temperature and increased surface area of the droplets, rendering them ideal for direct compression uses like Starlac.^[35]

5. Using a Roller For Drying : A roller drier is utilized to eliminate moisture from a uniform solution or dispersion that includes pre-blended excipients. Meggelaars et al. (1996) utilized this technique to co-process lactose alongside sorbitol and lactitol. Due to the elevated temperature, most of the final product consisted of crystalline ?-lactose^.[52]

6. Combined Transformation : Using heat or a solvent effect, one excipient's particle is "opened up" (swelled) in the co-transformation procedure. The aforementioned excipient's "opened-up" structure is mixed with the other excipients. The enhanced excipient improves the functionality of the finished product. ^[36–37].
 

7. Grinding : : For milling or dry grinding, one can use a roller mill, ball mill, bead mill, millstone mill, jet mill, or hammer mill. After their blending, the excipients are processed in a high-speed milling machine. As the particles are pushed through the mill or screen, they interact with each other and form bonds during the milling process. Rao et al. (2012) employed this technique to coprocess calcium silicate alongside cross-linked polyvinylpyrrolidone.  ^[38]

8. Melting Granulation : A meltable binder, which is typically in a solid state below 80?C, is combined with the combination of excipients. To separate the material into agglomerates, the mixture is heated over the binder's melting point while being continuously stirred. In order to produce granules of the appropriate size, the cooled agglomerates are ultimately filtered. ^[39]

9. Evaporation of Solvents :  In a machine for liquid production, solvents vaporize. The primary excipient is dissolved or dispersed in the coating solution following the dissolution of the coating excipient in a volatile solvent that does not mix with the liquid production vehicle. The agitation force is applied to achieve the correct encapsulation size. The solvent is removed by applying heat ^[40]

4.1 Co-processed Excipients Reported in the Literature

1. Microcrystalline Cellulose Combined With Calcium Carbonate

A patent was awarded to Mehra et al. for a coprocessed excipient made from calcium carbonate and microcrystalline cellulose. The creation of a directly compressed vitamin tablet utilized these co-processed excipients. Two advantages of the invention were cost-effectiveness and low sensitivity to lubricants. ^[44]

2. Lactose, Crospovidone, and Polyvinylpyrrolidone (PVP)
According to Lang, wet granulation, spray granulation, or spray drying techniques were used to create a blend of lactose, PVP, and crospovidone. The novel direct tableting excipients showed excellent disintegration qualities, efficient compressibility at low pressure, favorable flow characteristics, considerable hardness, and low abrasion^[45]

3.Sorbitol and B-lactose
Meggelaars and colleagues created a uniform blend that included a dried solution rich in ?-lactose and sorbitol at concentrations ranging from 1% to 15% w/w. Thedrying process was performed using a roller drying method. This excipient can be used to produce tablets with a high level of hardness^[45]

4. Starch and Polyvinylpyrrolidone
A coprocessed excipient made using the fluid bed spray granulation technique that blends corn starch and polyvinylpyrrolidone was described by Menon et al. This formulation has outstanding compressibility and is distinguished by its free-flowing quality^.[45]
 

5. MCC and Colloidal Silicon Dioxide
In contrast to conventional commercially available MCC, Sherwood et al. obtained a patent for an inventive excipient that combined MCC with colloidal silicon dioxide and showed improved compressibility, disintegration qualities, and free-flowing characteristics^.[46]
 

6. MCC and Guar gum
Ratanraj and Reilly developed a coprocessed excipient for chewable tablets by meticulously blending an aqueous dispersion of microcrystalline cellulose (MCC) with guar gum through    highshear methods at room temperature. After spray drying, this uniform dispersion resulted in a bulk powder mostly consisting of spherical particles. The final excipient demonstrates enhanced compressibility,and Lang noted a lactose, PVP, and crospovidone blend created through spray granulation, spray

drying, or wet granulation techniques. The new

excipients for direct tablet making exhibited outstanding disintegration properties, good flow

behavior, impressive hardness, minimal abrasion, and efficient compressibility under lowpressure. Enhanced mouthfeel and decreased tooth packing. ^[47]

7. Sucrose That Melts Directly
The formulation contains 95% sucrose and 5% maltodextrin. With its free-flowing properties, compressibility, and pleasant test and mouth feel, this sugar-based excipient effectively masks the bitter taste of the active pharmaceutical ingredient.^.[48]

8. MCC and Alginate of Sodium
In 1999, Augello and Reier created a weight granulation binder excipient that is the subject of the invention. First, sodium alginate and microcrystalline cellulose (MCC) were combined to form a uniform aqueous mixture, which was then dried to yield granular particles^.[49]

9. Alfalfa, Calcium Carbonate, and MCC
Ibrahim and Saraiya co-processed alfalfa root, microcrystalline cellulose (MCC), and calcium carbonate to produce an excipient. The process of development involved the use of spray drying. Vitamin and nutritional supplements were later made with this product^.[50]

10.MMC and Maltodextrin: Following the combination of maltodextrin and microcrystalline cellulose (MCC), Buliga proceeded to spray-dry the blend. Significant regarding this invention was its ability tobe combined with carboxyl methyl cellulose to create adry blend that may be used as a stabilizer in food and cosmetic uses. ^[51]

Co-processed Directly Compressible Excipients [40,41,42,43]