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Review Article

Ajay et al., eISSN 2249-5797

Journal of Advanced Pharmaceutical Sciences Formulation Development Techniques of Co-processed Excipients

Ajay Subhash Chougule,* Amrita Dikpati and Tushar Trimbake AISSMS College of pharmacy, Kennedy Road, Near R.T.O., Pune-01, India. Email: ajaychougule05@gmail.com Mob. No- 9404953361

Abstract: There has been a radical change in tablet manufacturing due to the introduction of processes
such as direct compression method and use of high-speed machines. Due to the above-mentioned technologies, there has been an increased demand for exploiting the diverse functionalities of excipients that makes use of their flow and compression properties. Due to the simplicity in terms of manufacturing and associated cost implied, direct compression method is a highly preferable method of tablet production. This in turn has lead to an increased research and detailed study for developing newer excipients with better tableting properties. Various techniques along with substantial usage of particle engineering and material sciences have been employed for the introduction of a new class of excipients called as co processed excipients. This review article has been written with the aim of giving detailed information about the sources of new excipients, potential advantages of co-processed excipients, material characteristics required for co-processing, various methods of preparing co-processed excipients for direct compression available in the market, description of some available co-processed excipients, evaluation parameters for checking the functionality of co-processed excipient and their future developments. Keywords: Direct compression, co-processing, new sources, and evaluation parameters improving the resultant pharmaceutical product. Introduction: Examples of such physical mixtures include In recent years drug formulation scientists immediate-release film coating powders for have recognized that single-component excipients dispersion that reduce the time required to prepare do not always provide the requisite performance film coating suspensions and to minimize color to allow certain active pharmaceutical ingredients variation of the final product. Such physical to be formulated or manufactured adequately. In mixtures are not appropriate for consideration for response to these deficiencies, drug formulation National Formulary (NF) monographs because the scientists have relied on increasing number of individual components are isolated (distinct and combination excipients introduced by excipient intact) before mixing; i.e., the manufacturing manufacturers into the commercial market. process of each of the individual components has Combination excipients fall into two broad been taken to completion, and consequently these categories: physical mixtures and co-processed components can be adequately controlled before excipients. mixing. Physical mixtures, as the name suggests, Co-processed excipients are combinations are simple admixtures of two or more excipients of two or more excipients that possess typically produced by short duration low-shear performance advantages that cannot be achieved processing. They may be either liquids or solids using a physical admixture of the same and are generally used for convenience rather than combination of excipients. Typically they are for facilitating the manufacturing process or
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Ajay et al., produced using some form of specialized manufacturing process. The performance benefits relate to the manufacture or performance of the finished pharmaceutical product. This improvement in performance has been a primary drive for the introduction of co-processed excipients into the marketplace. Co-processed excipients are appropriate for consideration as new monographs because one or more of the components may be formed in-situ, or the component may not be isolated prior to coprocessing. That is, the manufacturing process for one component may not have been taken to completion before the addition of the other components, and/or the co-processed excipient combination cannot be adequately controlled using the monograph tests for the individual component excipients.(1) There are many dosage forms in which coprocessed excipients are used mainly in solid dosage forms such as tablets, capsules, powders, etc., liquid dosage forms such as emulsions, suspensions, injections, etc., semi-solid dosage forms such as creams, ointments, pastes, etc. As they have been used to enhance different properties of dosage forms so, it finds application in nearly each and every dosage form but mainly in solid dosage form. Tablets are the most preferred dosage form of pharmaceutical professionals because they can be accurately dosed and provide good patient compliance. The ease of manufacturing, convenience in administration, accurate dosing, and stability compared to oral liquids, tamperproofness compared to capsules, safe compared to parental dosage forms makes it a popular and versatile dosage form and can be produced at a relatively low cost. The development in the field of APIs, excipients and tabletting machines during the past decades has made tablet manufacturing a science. This popularity of tablets coupled with an increased understanding of the physics of compression and of manufacturing process variables have matured the manufacture of tablets as a science in its own right. Since the introduction of tableting process in the early 1840s, numerous changes have taken place, apart from changes in tablet manufacturing, including the establishment of stringent regulatory requirements for the materials that should be used, the establishment of stability requirements, and the development of high performance tabletting machines that can produce 100,000200,000 tablets/hour. Interestingly, such developments have affected the manufacturing process negatively because the number of materials that can fulfill such regulatory and performance requirements has decreased substantially.(2) Prior to the late 1950s, the literature contained few references on the direct compression of pharmaceuticals. A great deal of attention has been given to both product and process development in the recent years. The availability of new materials, new forms of old materials and the invention of new machinery has allowed the production of tablets by simplified and reliable methods. In early 1960s, the introduction of spray dried lactose (1960) and Avicel (1964) had changed the tablet manufacturing process and opened avenues of direct compression tableting. Previously, the word direct compression was used to identify the compression of a single crystalline compound (i.e. sodium chloride, potassium chloride, potassium bromide, etc.) into a compact form without the addition of other substances.(3) Shangraw conducted a survey in the United States of America in which 58 products were surveyed to determine the most preferred granulation process in which direct compression method was the most accepted method. The results were in favour of direct compression. Of the five processes listed in the survey, the average score (1.0 being the perfect score) for direct compression was 1.5 compared to wet massing and fluid bed drying (2.0), wet massing and tray drying (2.5), all in one (3.3) and roller compaction (3.6). About 41% of the companies indicated that direct compression was the method of choice, and 41.1% indicated that they used both direct compression and wet granulation. Only 1.7% of

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Ajay et al., the respondents indicated that they never used direct compression and 15.5% indicated that the process was not recommended.(4) The direct compression process is highly influenced by powder characteristics such flowability, compressibility, and dilution potential. No single material is likely to exhibit all the ideal characteristics. The physicomechanical properties of excipients that ensure a robust and successful process are good flowability, good compressibility, low or no moisture sensitivity, low lubricant sensitivity, and good machining ability even in high speed tableting machines with a reduced dwell time. Excipients with improved functionality can be obtained by developing new chemical excipients, new grades of existing materials and new combinations of existing materials. New combinations of existing excipients are an interesting option for improving excipient functionality because all formulations contain multiple excipients. A much broader platform for the manipulation of excipient functionality is provided by co-processing. Coprocessing is one of the most widely studied options in the field of direct compression on order to obtain functionality added excipients. In coprocessing, two or more excipients interact at the sub-particle level, the objective of which is to provide a synergy of functionality improvement as well as masking the undesirable properties of individual components. A larger number of patented co-processed excipients are available worldwide.(5) Usually, a combination of plastic and brittle materials is used for co-processing. This combination prevents storage of too much elastic recovery during compression, which results in a small amount of stress relaxation and a reduced tendency of capping and lamination thereby resulting in optimum tableting performance. Hence, co-processing these two kinds of materials produces a synergistic effect in terms of compressibility by selectively overcoming the disadvantages and helps improve functions, such as the flow properties, compaction performance, strain rate sensitivity, lubricant sensitivity or sensitivity to moisture. One such material commercially available internationally is Ludipress (BASF, USA), which contains lactose (93.4%), povidone (3.2%), and crospovidone (3.4%).(5) Tablets are manufactured primarily by either granulation compression or direct compression. The latter involves the compression of a dry blend of powders that contains drugs and various types of excipients. The simplicity and cost effectiveness of the direct-compression process have positioned direct compression as an attractive alternative to traditional granulation technologies. The demand of excipients with improved functionalities, mainly in terms of flow and compression properties, has increased with the advancement of tablet manufacturing process. Co-processed excipients are a mixture of two or more existing excipients at sub particle level, offer substantial benefits of the incorporated excipients and minimize their drawbacks. These multipurpose excipients have significantly reduced the number of incorporating excipients in the tablet. The present review discusses the development and source of new excipients, potential advantages of co-processed excipients, material characteristics required for coprocessing, methods of preparing directly compressible adjuvants and various co-processed excipients for direct compression available in the market.(2) Because many co-processed excipients contain a macromolecular excipient as one of the constituents, responsibility for reviewing these monographs and recommending them for inclusion in NF falls within the purview of the EM2 Expert Committee, one of three Expert Committees that set excipient standards for NF in USPs Council of Experts. Recently there has been increased interest in NF monographs for coprocessed excipients. The Expert Committee is therefore addressing the more general question of compendial acceptance of these types of excipients. To this end the EM2 Expert Committee believes that guidelines for the

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Ajay et al., acceptance of monograph proposals for covariations as a result of poor flow properties, but processed excipients would be useful.(1) co processed excipients, when compared with simple mixtures or parent materials, have been Advantages of co-processing(2)&(6) shown to have fewer fill weight variation Improved Flow Properties Controlled optimal particle size and problems. The primary reason for this particle- size distribution ensures superior flow phenomenon is the impregnation of one particle properties of co-processed excipients without the into the matrix of another, which reduces the need to add glidants. rough particle surfaces and creates a near optimal size distribution, causing better flow properties. Improved compressibility Co-processed excipients have been used Fill weight variation tends to be more prominent mainly in direct compression tabletting because in with high-speed compression machines.(2) this process there is a net increase in the flow Reduced lubricant sensitivity properties and compressibility profiles and the Most co processed products consist of a excipient formed is a fillerbinder.(2) relatively large amount of brittle material such as lactose monohydrate and a smaller amount of Better dilution potential Dilution potential is the ability of the plastic material such as cellulose that is fixed excipient to retain its compressibility even when between or on the particles of the brittle material. diluted with another material. Most active drug The plastic material provides good bonding substances are poorly compressible, and as a properties because it creates a continuous matrix result, excipients must have better compressibility with a large surface for bonding. The large properties to retain good compaction even when amount of brittle material provides low lubricant diluted with a poorly compressible agent.(6) sensitivity because it prevents the formation of a coherent lubricant network by forming newly Fill weight variation In general, materials for direct exposed surfaces upon compression, thus compression tend to show high fill weight breaking up the lubricant network.(2) Table 1: Co processed directly compressible excipients.(2) Co-processed excipients
Lactose, 3.2% kallidon 30, kallidon CL Lactose, 25% cellulose Sucrose 3% dextrin Microcrystalline cellulose, Silicon dioxide Microcrystalline cellulose, Guar gum Calcium carbonate, Sorbitol Microcrystalline cellulose, Lactose

Trade name

Basfag, ludwigshafen, germany Meggle gmbh & co. Kg, germany Penwest pharm. company Penwest pharmaceuticals company Fmc corporation Merck Meggle

Added advantage
Low degree of hygroscopicity, good flowability, tablet hardness independent of machine speed Highly compressible, good mouth feel, better tableting at low cost Directly compressible Better flow, reduced sensitivity to wet granulation, better hardness of tablet, reduced friability Less grittiness, minimal chalkiness, overall palatability Controlled particle size distribution Capable of formulating high dose, small tablets with poorly flowable active ingredients


Cellactose Dipac Prosolv Avicel ce-15 Formaxx Microlela

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Ajay et al., Need of co-processed excipients The excipients industry to date has been an extension of the food industry. Moreover, excipients are products of the food industry, which has helped maintain a good safety profile. Increasing regulatory pressure on purity, safety, and standardization of the excipients has catalyzed the formation of an international body, the International Pharmaceutical Excipients Council (IPEC). IPEC is a tripartite council with representation from the United States, Europe, and Japan and has made efforts to harmonize requirements for purity and functionality testing. The development of new excipients to date has been market driven (i.e., excipients are developed in response to market demand) rather than marketing driven (i.e., excipients are developed first and market demand is created through marketing strategies) and has not seen much activity as shown by the fact that, for the past many years, not a single new chemical excipient has been introduced into the market. The primary reason for this lack of new chemical excipients is the relatively high cost involved in excipients discovery and development. However, with the increasing number of new drug moieties with varying physicochemical and stability properties, there is growing pressure on formulators to search for new excipients to achieve the desired set of functionalities.(7) Other factors driving the search for new excipients are The growing popularity of the direct- compression process and a demand for an ideal fillerbinder that can substitute two or more excipients Tableting machinerys increasing speed capabilities, which require excipients to maintain good compressibility and low weight variation even at short dwell times. Shortcomings of existing excipients such as loss of compaction of microcrystalline cellulose (MCC) upon wet granulation, high moisture sensitivity, and poor die filling as a result of agglomeration. The lack of excipients that address the needs of a specific patient such as those with diabetes, hypertension, and lactose and sorbitol sensitivity. The ability to modulate the solubility, permeability, or stability of drug molecules. The growing performance expectations of excipients to address issues such as disintegration, dissolution, and bioavailability.(7) Sources of new excipients Excipients with improved functionality can be obtained by developing new chemical excipients, new grades of existing materials, and new combinations of existing materials. Any new chemical excipient being developed as an excipient must undergo various stages of regulatory approval aimed at addressing issues of safety and toxicity, which is a lengthy and costly process. In addition, the excipient must undergo a phase of generic development, which shortens the market exclusivity period. The high risk and significant investment involved are not justified in view of the meager returns from the new excipients. A plausible solution is for excipient and pharmaceutical manufacturers to develop drug products jointly, during which a new excipient becomes part and parcel of the eventual new drug application. This type of arrangement already has been successfully applied in the intravenous delivery field, in which Cy Dex and Pfizer worked collaboratively to obtain the approval of a solubilizer.(2) The combined expertise of pharmaceutical and excipient companies can lead to the development of tailor made innovative excipients. Developing new grades of existing excipients has been the most successful strategy for the development of new excipients in past three decades, a process that has been supported by the introduction of better performance grades of excipients such as pregelatinized starch, croscarmellose, and crospovidone.

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Ajay et al.,

Fig 1: Comparative developmental time lines for a drug product and a new chemical excipient.(8)

However, functionality can be improved only to a certain extent because of the limited range of possible modifications. A new combination of existing excipients is an interesting option for improving excipient functionality because all formulations contain multiple excipients. Many possible combinations of existing excipients can be used to achieve the desired set of performance characteristics. However, the development of such combinations is a complex process because one excipient may interfere with the existing functionality of another excipient. Over the years, the development of single- bodied excipient combinations at a sub particle level, called co processed excipients, has gained importance. New physical grades of existing excipients and co processed excipients are discussed further in the following section of this article that explains particle engineering. Particle engineering is a broad- based concept that involves the manipulation of particle parameters such as shape, size, size distribution, and simultaneous minor changes that occur at the molecular level such as polytypic and polymorphic changes. All these parameters are translated into bulk level changes such as flow

properties, compressibility, moisture sensitivity, and machinability. 3.1 Particle engineering as source of new excipients Solid substances are characterized by three levels of solid state: the molecular, particle, and bulk level. These levels are closely linked to one another, with the changes in one level reflecting in another level. The molecular level comprises the arrangement of individual molecules in the crystal lattice and includes phenomena such as polymorphism, pseudopolymorphism, and the amorphous state. Particle level comprises individual particle properties such as shape, size, surface area, and porosity. The bulk level is composed of an ensemble of particles and properties such as flowability, compressibility, and dilution potential, which are critical factors in the performance of excipients. The fundamental solid state properties of the particles such as morphology, particle size, shape, surface area, porosity, and density influence excipient functionalities such as flowability, compactability, dilution potential, disintegration potential, and lubricating potential.

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Ajay et al.,

Fig 2: Three levels of solid state.(8) Hence, the creation of a new excipient must begin with a particle design that is suited to deliver the desired functionalities. Varying the crystal lattice arrangement by playing with parameters such as the conditions of crystallization and drying can create particles with different parameters. It is also possible to engineer particles without affecting the proceeding molecular level. Avicel 101 and 102 (microcrystalline cellulose) and spray dried lactose are examples in which such an approach has been successfully applied. However, particle engineering of a single excipient can provide only a limited quantum of functionality (2) improvement. A much broader platform for the manipulation of excipient functionality is provided by co-processing or particle engineering two or more existing excipients. Co-processing is based on the novel concept of two or more excipients interacting at the sub particle level, the objective of which is to provide a synergy of functionality improvements as well as masking the undesirable properties of individual excipients. The availability of a large number of excipients for co-processing ensures numerous possibilities to produce tailor made designer excipients to address specific functionality requirements. Co-processed excipients are prepared by incorporating one excipient into the particle structure of another excipient using processes such as co-drying. Thus, they are simple physical mixtures of two or more existing excipients mixed at the particle level. Coprocessing was initially used by the food industry to improve stability, wettability, and solubility and to enhance the gelling properties of food ingredients such as co processed glucomannan and galactomannan.(2) Co-processing of Excipients in the pharmaceutical industry can be dated back to the late 1980s with the introduction of co processed microcrystalline cellulose and calcium carbonate, followed by Cellactose (Meggle Corp.,Wasserburg, Germany) in 1990, which is a co processed combination of cellulose and lactose. A similar principle was applied in developing silicified microcrystalline cellulose (SMCC), which is the most widely used co processed excipient. Co-processing excipients leads to the formation of excipient granulates with

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Ajay et al., superior properties compared with physical mixtures of components or with individual components. They have been developed primarily to address the issues of flowability, compressibility, and disintegration potential, with fillerbinder combinations being the most commonly tried. The combination of excipients chosen should complement each other to mask the undesirable properties of individual excipients and, at the same time, retain or improve the desired properties of excipients. For example, if a substance used as a fillerbinder has a low disintegration property, it can be co-processed with another excipient that has good wetting properties and high porosity because these attributes will increase the water intake, which will aid and increase the disintegration of the tablets.(2) Technologies used in preparation of co processed excipients Roller compaction Dry granulation process is a particle-bonding process. Miller described the theory of granule bond formation as: a. Particle rearrangement b. Particle deformation c. Particle fragmentation d. Particle bonding.

Fig 3: Co-processing methodology.(8)

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Ajay et al., In the roller compaction process, powder blends first pass a feeding zone, where most of the rearrangement occurs. The dense powders then go through a compaction zone, where increasing force is being exerted by two counter-rotating rolls. As the pressure goes up further into the compaction zone, the particles deform, fragment, and bond to form ribbons. Roller compaction is widely applied to dry granulation. It offers many superior characteristics, e.g., good control of process and cost-advantages compared to wet granulation. As no liquid or drying is involved, this process is more suitable for water or heatsensitive drugs.(9) Compared to direct compression, roller compaction can handle high drug loading, improve flow and content uniformity, and prevent segregation. Like any other processes, dry granulation has its own issues, such as loss of compactibility or dissolution problem. A systematic approach of formulation and process development is the key to high quality drug products. Fig. 4 outlines a brief flow chart for formulation and process development using roller compaction. At high drug loading, the compactibility and flowability of drug substance will be critical for roller compaction and tableting processes.(10) Different excipients need to be evaluated in formulation development to achieve desirable chemical stability, tablet properties, and process control. After selecting a suitable roller compactor, potential critical process parameters and material attributes can be identified using a risk management strategy. The fishbone diagram and Failure Mode and Effects Analysis (FMEA) are useful tools for risk management. Design of experiment (DOE) can be used to identify the critical quality attributes and design space for the overall process.(11)&( 12) Wet granulation Wet granulation is a process still widely used in the pharmaceutical industry. It has not been replaced by direct compression technology, partly because of development cost considerations and habits, and partly because it remains in some cases an attractive technique.

Fig 4: A brief flow chart for formulation and process development using roller compaction.(11) It provides better control of drug content uniformity at low drug concentrations, as well as control of product bulk density and ultimately compactibility (brittle fracture), even for high drug contents. Processing takes place in one of two types of closed granulating systems: fluid bed granulators or high-shear mixers. The two techniques differ technically on the mode of solid agitation, and fundamentally on the mode of granule growth. In fluid bed granulation, the powder mix is maintained as a fluidized bed by a flow of air injected upwards through the bottom screen of the granulator. The binding solution is sprayed above the powder bed, in a direction opposite to the air flow. Other spraying directions can be used on the same equipment for solids coating. The granules result from the adhesion of solid particles to the liquid droplets that hit the bed. Partial drying by the fluidizing air occurs continuously during granulation. The process continues until all the powder has been

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Ajay et al., agglomerated, and it needs to be stabilized as far as moisture balance is concerned. The equilibrium may not be constant, however, as the moisture content of the granules could be increasing slightly throughout the process, and the trajectories of the particles may change with changes in the density of the agglomerated powder bed. Complete drying is quickly achieved in the hot air stream when binder spraying is stopped.(13) In high-shear granulation, an impeller maintains the powder in agitation in a closed vessel, and here also a binder solution is sprayed from the top. As the liquid droplets disperse in the powder, they form the first nuclei of future granules. The agitation forces prevent the development of large agglomerates, because they would be too fragile to sustain the shear. However, as mixing and spraying proceed, the existing agglomerates undergo densification, whereby the internalized binder is squeezed out to the surface of the wet agglomerates. This has two consequences. It makes the agglomerates harder, and their surface more adhesive, and hence granule growth enters a new, more efficient phase. The process is stopped somewhere in this phase before an excess of liquid or excessive densification provokes a phase inversion, i.e. a slurry or uncontrollable growth (balling phenomenon). The drying step traditionally takes place after transferring the damp mass into another piece of equipment (fluid bed dryer), but the use of single-pot technology (drying in place) is now spreading. The granules formed are understandably denser than those obtained in fluid bed granulation.(14) By definition, process scale-up is the transfer of a controlled process from one scale to another. It implies that the process on the small scale is understood and controlled, and ideally that some basic rules can be followed to quickly obtain optimization and control of the process at the bigger scale.(15) The above figure is the flow chart of how a general process of wet granulation occurs at industrial level.

Fig 5: Flow chart of wet granulation (16) Hot melt extrusion (HME) Hot melt extrusion is another thermal processing technique that has attached interest as a novel approach for the development of polymeric immediate, sustained release or transdermal/transmucosal delivery system. This process is widely used in transferring and melting of polymer inside a barrel by a rotating screw. The polymer melt is then pressurized through the die and solidify into variety of shapes. Extrusion can be further processed into tablets or granules. HME is a continuous, simple and efficient process. No water or no solvent is required as the molten polymer can function as a thermal binder. The intense mixing and agitation during HME also deaggregates particles and improves the content uniformity of the extrudates. HME requires high temperature greater than 80C. The excipient and the active ingredient need to be stable under those conditions. Plasticizers, antioxidants and other excipients can be included into the power blend to improve the processing condition and stability of each component during extrusion.(17) Spray dryingThis technique enables the transformation of feed from a fluid state into dried particulate form by spraying the feed into a hot drying medium. It is a continuous particle processing drying operation. The feed can be a solution, suspension, dispersion or emulsion. The dried product can be in the form of powders, granules or agglomerates depending upon the physical and chemical properties of the feed, the dryer design and final powder properties desired.(18)

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Ajay et al., Spray drying process mainly involves five steps: i. Concentration: feedstock is normally concentrated prior to introduction into the spray dryer. ii. Atomization: the atomization stage creates the optimum condition for evaporation to a dried product having the desired characteristics. iii. Droplet-air contact: in the chamber, atomized liquid is brought into contact with hot gas, resulting in the evaporation of 95%+ of the water contained in the droplets in a matter of a few seconds. iv. Droplet drying: moisture evaporation takes place in two stages- 1) during the first stage, there is sufficient moisture in the drop to replace the liquid evaporated at the surface and evaporation takes place at a relatively constant rate. The second stage begins when there is no longer enough moisture to maintain saturated conditions at the droplet surface, causing a dried shell to form at the surface. Evaporation then depends on the diffusion of moisture through the shell, which is increasing in thickness. v. Separation: cyclones, bag filters, and electrostatic precipitators may be used for the final separation stage. Wet Scrubbers are often used to purify and cool the air so that it can be released to atmosphere. Spray drying process (Figure V ) have advantages that can be designed to virtually any capacity required. Feed rates range from a few pounds per hour to over 100 tons per hour. Operation is continuous and adaptable to full automatic control. It can be used with both heatresistant and heat sensitive products. Nearly spherical particles can be produced. There are some limitation that includes limited versatility in producing particles or structures with the complex morphologies, and rapid drug release rates often exhibiting a burst effect.(19)

Figure V : Spray drying.(19) Some examples of coprocessed excipients Ludipress Ludipress, a co-processed product, consists of 93.4% a-lactose monohydrate, 3.2% polyvinyl pyrrolidone (Kollidon 30) and 3.4% crospovidone (Kollidon CL). It consists of lactose powder coated with polyvinyl pyrrolidone and crospovidone. Although, Ludipress contains disintegrant, the disintegration of tablets takes longer than tablets containing a-lactose monohydrate, Tablettose and anhydrous lactose.(20) At low compression force Ludipress gives harder tablets but the addition of glidant and disintegrant is needed. It is reported that binding capacity of Ludipress was higher than that of microcrystalline cellulose. The dilution potential was high (upto 70%) when aspirin was used a model drug.(21) Baykara et al. reported that the dilution potential of LudipressR with paracetamol is lower than that of Avicel PH-101, Elcema G250 and Elcema P050. The binding properties of Ludipress, both unlubricated and lubricated with 1% magnesium stearate was found to be much better than corresponding physical mixture.(22) Plaizier-Vercammen et al. reported that the addition of a lubricant was necessary and its mixing time had little effect on crushing strength of Ludipress tablets. Authors also reported that Ludipress exhibits better tableting characteristics for low dose APIs, and good batch-to-batch

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Ajay et al., uniformity than Cellactose.(23) The compressibility of Ludipress is similar to that of Avicel PH-200. The disintegration time of Ludipress containing tablets remained unchanged at about 100 MPa compaction pressure while significant prolongation was observed with Cellactose.(24) Schmidt and Rubensdorfer reported that the tablets manufactured with Ludipress exhibited optimum disintegration time and compaction pressure independent dissolution of glibenclamide. While, increasing compaction pressure had a negative effect on drug dissolution from compacts containing Cellactose.(25) It has been reported that among various lactose based directly compressible excipients, Ludipress exhibited a better flow rate compared to Avicel PH 101. Ludipress exhibited highest flowability followed by Cellactose, Tablettose, Fast Flo lactose and anhydrous lactose as demonstrated by lower static and dynamic angles of repose than the other excipients.(26) The values of compressibility could be ranked from maximum to minimum in the following order: Tablettose, Cellactose, Ludipress and Fast Flo lactose. Fragmentation propensity was from maximum to minimum in Tablettose, Cellactose, Ludipress and Fast-Flo lactose.(27) Cellactose Cellactose is a co-processed product consisting a-lactose monohydrate (75%) and cellulose (25%). Apart from good flowability, it has good compactibility. The compactibility is attributed to a synergetic effect of consolidation by fragmentation of lactose and plastic deformation of cellulose.(28) Because the lactose covers the cellulose fibers, moisture sorption is much lower than that of microcrystalline cellulose alone. Aufmuth et al reported that the Cellactose exhibited increased crushing strength of the compacts along with reduced friability and lower disintegration time than the dry blend of lactose and cellulose. Armstrong et al. pointed that Cellactose exhibit the dual consolidation behaviour since it contains a fragmenting component (lactose) and a substance that consolidates primarily by plastic deformation (Cellulose).(29) Ruiz et al. and Reimerdes found that the Cellactose exhibited better compressibility compared to Ludipress, Fast Flo lactose, Tablettose, Di-pac and anhydrous lactose.(30) Belda and Mielck found that due to co-processing Cellactose exhibited enhanced crushing strength compared to the powder mixtures each containing 25% w/w Avicel PH-101 or Elcema P-100 and 75% w/w Tablettose or lactose (100#).(31) Casalderrey et al reported that the Cellactose tablets prepared at a compression pressure that largely eliminated macro pores had better mechanical properties but much poorer disintegration than tablets of the other blends having similar composition, particle size, and true density at the same punch pressure. Authors further reported that the tensile strength and disintegration time of Cellactose tablets decreased rapidly as the compression pressure is reduced.(31) Gohel and Jogani(32) prepared and evaluated coprocessed directly compressible adjuvant containing lactose and microcrystalline cellulose using starch as a binder. The percentage fines, Carrs index of the agglomerates as well as friability and tensile strength of the tablets were affected by the ratio of lactose to microcrystalline cellulose and percentage of starch in binder solution. A product containing lactose: microcrystalline cellulose (9:1) and 1% starch paste exhibited satisfactory flow, compressibility and friability. Tablets of diltiazem hydrochloride and acetaminophen prepared using the coprocessed excipients exhibited satisfactory tableting properties.(32) Gohel et al. prepared and evaluated coprocessed diluents containing lactose and microcrystalline cellulose using a 23 factorial design. Ratio of lactose to MCC (75: 25 and 85:15), type of binder (hydroxypropyl methylcellulose or dextrin) and binder concentration (1 or 1.5%) were studied as independent variables.(33) The results revealed that the lactose: microcrystalline cellulose ratio 75:25 and dextrin as a binder are better than the ratio of 85:15 and hydroxypropyl methylcellulose as a

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Ajay et al., binder. The tableting properties of the developed adjuvant were ascertained using diltiazem HCl as a model drug.(33) Gohel and Jogani prepared coprocessed directly compressible adjuvant containing lactose and microcrystalline cellulose using melt granulation technique. Gohel et al. demonstrated use of factorial design in development of directly compressible adjuvant of desired characteristics consisting of lactose, dicalcium phosphate and microcrystalline cellulose.(34) Pharmatose DCL 40 It is a co-processed product consisting of 95% lactose and 5% anhydrous lactitol. Due to spherical shape and favourable particle size, it exhibits good flowability. It has high dilution potential than other lactose based products due to better binding property. It has very low water uptake at high humidity.(35) Prosolv It is co-processed silicified microcrystalline cellulose. It consists of 98% microcrystalline cellulose and 2% colloidal silicone dioxide. The manufacturer claim better flowability and compressibility compared to Emcocel and Avicel PH 101 or physical mixture of MCC with colloidal silicone dioxide. Allen reported that Prosolv containing tablets were significantly robust than those produced from regular cellulose by wet granulation. In the presence of magnesium stearate (0.5 %), tablets prepared with Prosolv maintained tensile strength profiles, whereas the tensile strength of regular cellulose was significantly affected. Author further reported that Prosolv is about 20% more compactable than regular cellulose. Fraser et al reported that silicified microcrystalline cellulose has some improvement in flow but considerably enhanced mechanical properties. Lahdenpaa et al. demonstrated that Silicified microcrystalline cellulose is useful to prepare tablet containing poorly compressible ingredients by direct compression.(36) The silicification affects the moisture sorption and the packing during tapping as well as the particle deformation during tableting. Prosolv showed slight increase in the tensile strength but marked increase in the disintegration time of the tablets compared to Avicel. Bolhuis et al. demonstrated that the coprocessing of microcrystalline cellulose with colloidal silicone dioxide has no significant contribution on the tablet strength of lubricated tablets containing the physical mixture of microcrystalline cellulose and colloidal silicone dioxide.(37) StarLac Starlac is a co-processed excipient consists of lactose monohydrate and maize starch produced by spray drying. The advantage of Starlac are its good flowability depending on the spray-drying process, an acceptable crushing force due to its lactose content, its rapid disintegration depending on starch. Gohel and Jogani demonstrated use of multiple linear regressions in development of co-processed lactose and starch. Authors concluded that as the lactose/starch ratio increased Carrs index of the adjuvant and crushing strength of the tablets increased while friability decreased. Percentage of starch paste has inverse effect on the friability.(32) Microcrystalline cellulose (MCCII) Microcrystalline cellulose (MCCII) was recently introduced as a new filler/binder for solid dosage forms, and has been recommended as a suitable excipient when a rapidly disintegrating compact is desirable. However, the main shortcoming of this excipient is its low compactibility and its fibrous shape, which limit its application to formulate poorly compactable and poorly flowing drugs. Traditionally, excipient functionality has been economically accomplished by engineering particles physically. New grades of existing excipients have been created by modifying the fundamental properties of materials, including their morphology, particle size, shape, surface area, porosity and density. These modifications can result in improved derived properties such as flowability, compressibility, compactibility, dilution, disintegration and lubrication potentials.(1)&(38) However, if one attribute is improved, another could be compromised. For example, Avicel

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Ajay et al., products have been engineered in different size grades such as Avicel PH200, which has excellent flow properties but a poor compactibility. Conversely, Avicel PH101 has poor flow properties, but excellent (39) compactibility. One of the most successful approaches used in recent years for particle engineering is co-processing two or three excipients together. In this technique, excipients interact at the particle level, enhancing functionality as well as masking the undesirable properties of the individual components. The resulting excipient has superior properties compared to the physical blending of the individual components. Excipients that are physically modified in this fashion do not lose their chemical structure and stability, and they maintain their independent chemical properties. Particles of one material can be incorporated onto the companion material by spray-drying, wet granulation, spheronization, co-milling, cocrystallization, and other techniques. Amorphous SiO2 has been widely used as a flow enhancer in powder formulations for food and pharmaceutical applications. Recently, it has been used as a companion excipient for co-processing with starch (10:1), chitin (1:1), or cellulose I (98:2) resulting in products with improved unique characteristics different from the parent materials. For example starch:SiO2 compacts disintegrate rapidly, often within 30s. Chitin:SiO2 powders have increased bulk density and good flow properties. Likewise, cellulose I:SiO2 products have excellent compaction properties, show less sticking to the lower punches and have superior dissolution stability over the physical mixture of MCCI and SiO2. Further, calorimetric and water sorption studies determined a surface heterogeneity for SMCCI. For all the above reasons, coprocessing materials are gaining wider acceptance. After conducting preliminary screening studies using several coprocessing companion materials and different techniques, SiO2 along with spray drying was the only combination that improved the mechanical properties of MCCII without detriment of its self-disintegrating characteristics.(40) Directly compressible sucrose Sucrose is one of the oldest ingredients used by the food and pharmaceutical industries. This natural product has been around for thousands of years and has enjoyed immense popularity because of its pleasant sweet taste. It has been used in a wide range of applications, mostly because of its ability to mask the bitter taste of other ingredients with its sweetness. In the pharmaceutical arena, taste masking is a particularly attractive benefit of using sucrose. Unfortunately sucrose in its natural state does not compress well and various crystallization techniques have been employed to make it compressible. Granulating sucrose with a small percentage of another ingredient has been successful in producing directly compressible sugars. There are many types of compressible sugars available today and most of them are sucrose granulated with a small percentage of modified dextrins in order to make the sucrose compressible. Recently, a new directly compressible sucrose has been introduced onto the market that shows some benefits over existing products. It is made by a unique crystallization process in which 95% sucrose and 5% sorbitol are combined. The result is a highly compressible sugar excipient for tableting applications.(41) Di-PacDi-Pac is a directly compressible, cocrystallized sugar consisting of 97% sucrose and 3% modified dextrin. It is a free flowing, agglomerated product consisting of hundreds of small sucrose crystals glued together by the highly modified dextrin. At high moisture level, Di-pac begins to cake and loose its fluidity. Tablets containing a high proportion of Di-pac tend to harden after compression at higher relative humidity. Its sweet taste makes it suitable for most directly compressible chewable tablets. Rizzuto et al., demonstrated that co-crystallized sucrose and dextrin deformed readily by plastic fracture to provide much harder compacts than those obtained from sucrose crystals alone.(42)

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Ajay et al., Starch 1500It is a directly compressible, free flowing, USP grade of partially hydrolyzed cornstarch. It is prepared by subjecting cornstarch to physical compression or shear stress in high moisture conditions causing an increase in temperature and a partial gelatinization of some of the starch granules. The product is consists of about 5% free amylose, 15% amylopectin and 80% unmodified starch. It provides fair to good binding properties and dilution potential, but requires high pressures to produce hard tablets. It also produces a dense tablet with good disintegration properties. Starch 1500 exhibits self-lubricating property. It has poor flowability compared to other directly compressible adjuvants and shows higher lubricant sensitivity. It is also used as filler in capsule formulation. Monedero Perales et al.(44) demonstrated that Starch 1500 exhibited better flowability and lower binding property and plasticity than the Sepistab 200. Terfenadine tablets prepared using rice starch (Era Tab) exhibited higher crushing strength and lower friability than partially pregelatinized starch, Super-Tab, Emcompress and lower than Avicel PH 101. Uni-Pure is a fully gelatinized maize starch. It gives tablets with strong binding properties and significantly faster disintegration. Clausen reported co-processed polymethacrylic acid-starch as a pH-sensitive directly compressible excipient for controlled delivery of model drugs amoxicillin and rifampicin.(43)&(44) Evaluation parameters for co processed excipients Particle size distributionThe particle size distribution can be calculated by statistical method such as frequency curve method. When the number, or weight, of particles lying within a certain size range is plotted against the size range or mean particle size, a so called frequency curve is obtained.(45) Carrs indexThe bulk density is the quotient of the weight to the volume of sample. The tapped density was determined as the quotient of the weight of the sample to the volume after tapping a measuring cylinder 500 times from a height of 2 inches. Carrs index (percentage compressibility) was calculated as one hundred times the ratio of the difference between the tapped density and bulk density to the tapped density.(46)

Hausner RatioHausner ratio is the ratio of bulk density to the tapped density.(46)

Angle of reposeThe angle of repose is a relatively simple technique for estimating the flow properties of a powder. It can easily be determined by allowing a powder to flow through a funnel and fall freely onto a surface. The height and diameter of the resulting cone are measured and the angle of repose calculated from this equation:

Where, h is the height of the powder cone and r is the radius of the powder cone.(16) Case studies Gohel and Jogani prepared co-processed directly compressible adjuvant containing lactose and microcrystalline cellulose using melt granulation technique. Gohel et al. demonstrated use of factorial design in development of directly compressible adjuvant of desired characteristics consisting of lactose, dicalcium phosphate and microcrystalline cellulose.(34) Stoltenberg et al., Breitkreutz et al., (2011) carried out study of development of orally disintegrating mini tablets (ODMTs) as a suitable dosage form for paediatric patients. The suitability of five commercially available ready-to-use tableting excipients, Ludiflash_, Parteck _ ODT, Pearlitol_ Flash, Pharmaburst_ 500 and Prosolv_ ODT, to be directly compressed into minitablets, with 2 mm in diameter, was examined. All of the excipients are based on co-processed mannitol. The use of coprocessed excipient was found to be improving ODMTs properties such as crush strength and friability.(47)

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Ajay et al., Olowosulu1 et al, Oyi1 et al, Isah1 et al, Ibrahim et al (2011) have developed an efficient direct compression tabletting excipient of coprocessed particles of maize starch (MS) and acacia gum (Ac) by co-drying their well dispersed aqueous mixtures.(48) Gonnissen et al., Remon et al., Vervaet et al.,(2007) have developed a technique of Continuous production of directly compressible powders by coprocessing acetaminophen and carbohydrates via spray drying.(49) Future trends The obvious advantages of solid dosage forms and changing technological requirements will keep alive the search for newer excipients. The newer excipients are required to be compatible not only with the latest technologies and production machineries, but also with the innovative active principles such as those originating from biotechnology. Developments in the field of excipients and manufacturing machinery have helped in establishing traditional inert excipients as functional components. A deeper understanding of their solid-state properties and its impact on excipient functionality is further going to fuel this trend. Functionalities, hitherto unavailable to the formulator, can now be incorporated into the product by judicious choice of high-functionality excipients. Further, a narrow pipeline of new chemical excipients, and an increasing preference for the direct compaction process, creates a significant opportunity for the development of high-functionality excipients. A greater synergy between excipient manufacturers and the pharmaceutical manufacturer in the future is going to help in the development of tailor-made designer excipients complying with safety, performance, and regulatory issues. Conclusions Technological advancements in tablet manufacturing, introduction of high-speed machineries, and a shift in tableting toward direct compaction have catalyzed the search for newer excipients meeting these requirements. Excipients are no more considered as inert ingredients of a formulation, but have a well-defined functional role. Developments in particle engineering have provided wide avenues for designing excipients with predefined functionality requirements. Coprocessed excipients are a result of this arduous innovation only, wherein two excipients are coprocessed to provide products with improved functionality by retaining their favorable and avoiding the unfavorable properties. A better appreciation of this concept can be viewed from the vast number of coprocessed excipients available in the market. The success of these excipients depends on their quality, safety, and functionality. Although the first two parameters have remained constant, significant improvements in functionality provide wide opportunities for the increased use of coprocessed excipients. The advantages of these excipients are numerous, but further scientific exploration is required to understand the mechanisms underlying their performance. The main obstacle in the success of coprocessed excipients is the noninclusion of their monographs in official pharmacopeias, which discourages their use by pharmaceutical manufacturers. With recommendations from IPEC and the continual efforts of excipient manufacturers, these products could find their way into official monographs, either as mixtures or as single-bodied excipients. Once the obstacles are overcome, the use of coprocessed excipients can be expected to increase by many false.(8) References 1. LH Block, RC Moreton, SP Apte, RH Wendt, EJ Munson, JR Creekmore, IV Persaud, C Sheehan, H Wangc (2009). Co-processed excipients. Pharm. Forum. 35. 10261028. 2. Minakshi Marwaha, Deepak Sandhu, Rakesh Kumar Marwaha (2010). coprocessing of excipients: a review on excipient development for improved tabletting performance, International Journal of Applied Pharmaceutics, Vol 2, Issue 3. Pg no. 41-42. 3. MC Gohel (2005). A review of co-processed directly compressible excipients, J Pharm Pharmaceut. Sci. 8(1): 76-93.

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Ajay et al., compression excipient. Drug Dev. Ind. Pharm. 25; 711-716. 44. MC Monedero Perales, A Munoz-Ruiz, MV Velasco Antequera, and MR JimenezCastellanos (1994). Study of the compaction mechanisms of lactose-based direct compression excipients using indentation hardness and heckel plot. J. Pharm. Pharmacol. 46: 177-181. 45. Alfred Martin (2005). Physical pharmacy, Chapter- Micromeritics. 4th edition, Lippincott Williams & Wilkins. 426-428. 46. USP30-NF25, Powder flow, 1174, Pg no618. 47. I Stoltenberg, J Breitkreutz (2011). Orally disintegrating mini-tablets (ODMTs) A novel solid oral dosage form for paediatric use, European J. of Pharmaceutics and Biopharmaceutics. 78, 462469. 48. AK Olowosulu1, O Avosuahi, AB Isah1, MA Ibrahim (2011). Formulation and Evaluation of Novel Coprocessed Excipients of Maize Starch and Acacia Gum (StarAc) For Direct Compression Tabletting, International J. of Pharmaceutical Research and Innovation, Vol. 2: 39-45, 39. 49. Y Gonnissen, JP Remon, C Vervaet (2007). Development of directly compressible powders via co-spray drying. European J. of Pharmaceutics and Biopharmaceutics 67, 220226.

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