About Authors: Biswajit Panda1*, Abhinav Raoot1, Vaishali Kilor1, Nidhi Sapkal2
Dept of Pharmaceutics1 and Dept of Pharmaceutical Chemistry2
Gurunanak College of Pharmacy, Nagpur
Reference ID: PHARMATUTOR-ART-1049
Abstract
Excipients are all substances contained in a dosage form other than the active substance. Tablets are the most commonly used dosage form because of the ease of manufacturing, convenience in administration, accurate dosing and stability compared to oral liquids and direct compression is the preferred method for the preparation of tablets because of several advantages. In order to justify the high rise in new drug development and high industrial output demand, new excipients with purpose satisfying characteristics are the need of the hour.New combinations of existing excipients are an interesting option for improving excipient functionality now-a-days. The current review article is prepared to have a look over the recent development in excipient technology and the approaches involved in development of such excipients. It signifies the synergistic outcome of the combination of excipients taking their material property into consideration. It also emphasises on the particular material properties in terms of physic-mechanical that are useful to overcome the limitation of existing excipients. All the developed co-processed excipients are enlisted highlighting their multi-functional and beneficial characteristics. Regulatory issues concerned with the development of new excipient are also discussed.
Introduction
Excipients are all substances contained in a dosage form other than the active substance. Solvents used for the production of a dosage form but not contained in the final product are considered to be excipients. Another definition of excipients is ‘‘Substances, other than the active drug substance or finished dosage form, which have been appropriately evaluated for safety and are included in a drug delivery system to either aid the processing of the drug delivery system during its manufacture, protect, support, enhance stability, bioavailability, or patient acceptability, assist in product identification, or enhance any other attributes of the overall safety and effectiveness of the drug delivery system during storage or use’’ (The International Pharmaceutical Excipients Council, 1995)1. Many pharmaceutical scientists have focused their attention on the production of multifunctional excipients with enhanced performance to meet the needs of formulation experts in terms of costs of production, enhanced excipient functionality and quality of tablets.
Tablets and capsules are the most preferred dosage forms of pharmaceutical scientists and clinicians because they can be accurately dosed and provide good patient compliance, they are easy for companies to manufacture, and they can be produced at a relatively low cost. Tablets are manufactured primarily by either granulation compression or direct compression. The latter involves the compression of a dry blend of powders that comprises drugs and various excipients. The simplicity and cost effectiveness of the direct-compression process have positioned direct compression as an attractive alternative to traditional granulation technologies2.Despite many research studies being conducted in the field of drug delivery, none of them have been able to match the characteristic features and advantages offered by oral unit dosage forms such as tablets and capsules. With the advent of this form of drug delivery, the subsequent researches of betterment of this delivery system emerged, which included sophisticated machinery and superior tabletting aids.
Although simple in terms of unit processes involved, the direct-compression process is highly influenced by powder characteristics such as flow ability, compressibility, and dilution potential. Tablets consist of active drugs and excipients, and not one drug substance or excipient possesses all the desired physico-mechanical properties required for the development of a robust direct-compression manufacturing process, which can be scaled up from laboratory to production scale smoothly. Most formulations (70–80%) contain excipients at a higher concentration than the active drug. Consequently, the excipients contribute significantly to a formulation’s functionality and processability. In simple terms, the direct-compression process is directly influenced by the properties of the excipients. The physico-mechanical 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 machineability even in high-speed tableting machinery with reduced dwell times3. The majority of the excipients that are currently available fail to live up to these functionality requirements, thus creating the opportunity for the development of new high-functionality excipients.
Search for new excpients:
The continued popularity of solid dosage forms, a narrow pipeline of new chemical excipients, and an increasing preference for the direct-compression process creates a significant opportunity for the development of high-functionality excipients. The advantage of the existing excipient for a particular method found to be misappropriating for the other. 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 for the past many years, very few 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 excipient discovery and development. However, with the increasing number of new drug moieties with varying physicochemical and stability properties, there is growing pressure to search for new excipients to achieve the desired set of functionalities and to obtain compounds having superior properties (hygroscopicity, flow ability, and compact ability) compared to the individual excipients or their physical mixtures. Hence, at this juncture development of new excipient by the modification of pre-established ones seems to be useful and justified one3.
Other factors driving the search for new excipients are;
* The growing popularity of the direct-compression process and a demand for an ideal filler–binder that can substitute two or more excipients
* Tableting machinery’s 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 agglomeration4.
* The lack of excipients that address the needs of a specific patients 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.
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 materials5. 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. The high risk and significant investment involved are not justified in view of the meagre returns from the new excipients. Developing new grades of existing excipients (physicochemical) has been the most successful strategy for the development of new excipients in past three decades6, a process that has been supported by the introduction of better performance grades of excipients such as pregelatinized starch, croscarmellose, and crospovidone7. However, functionality can be improved only to a certain extent because of the limited range of possible modifications. New combinations of existing excipients are 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. Development of single-bodied excipient by bringing change in the sub-particle level has gained importance over the years resulting in co processed excipients. To deal with change of particle’s physical property at sub-particle level and methodology for development of a new synergistic combination leads to the phenomenon of co-processed excipient. Co-processing excipients leads to the formation of excipient granulates with 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 filler–binder combinations being the most commonly tried.
Approaches for development of co-processed excipients:
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 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 galactomanan8. 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 carbonate9, followed by Cellactose in 1990, which is a co-processed combination of cellulose and lactose. It involves a thorough understanding of material properties and processing two or more excipients by methods such as co-spray drying or co-precipitation etc.
Particle engineering: a handy tool:
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 machineability. 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, pseudo-polymorphism, 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. A change at one level affects the other levels. This interdependency among the levels provides the scientific framework for the development of new grades of existing excipients and new combinations of existing excipients10.
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. Hence, the creation of a new excipient must begin with a particle design that is suited to deliver the desired functionalities11.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 preceeding molecular level. However, particle engineering of a single excipient can provide only a limited quantum of functionality improvement. A much broader platform for the manipulation of excipient functionality is provided by co-processing or particle engineering two or more existing excipients. In order to characterize a new excipient, the investigation of powder technological properties, including flowability, crystallinity, and water content, is necessary as is the study of the tableting properties.
Co processing: combinatorial engineering:
Co-processing is the novel phenomenon of developing a new single-bodied excipient, interacting two or more excipients at sub-particle level, the objective of which is to provide a synergy of functionality improvement as well as masking the undesirable properties of individual excipients11. Co-processing 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 galactomanan8. Co-processed excipients are prepared by incorporating one excipient into the particle structure of another excipient using processes such as co-drying or co-precipitation. During this a common dispersion of the under processing excipients is made. Then it is dried and converted into particulate of desirable size range by drying. Thus, they are simple physical mixtures of two or more existing excipients mixed at the particle level, where one particle interacts at the sub-particle level to form a single-bodied excipient. 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 filler–binder 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.
The actual process of developing a co-processed excipient involves the following steps:
* Identifying the group of excipients to be co-processed by carefully studying the material characteristics and functionality requirements
* Selecting the proportions of various excipients
* Assessing the particle size required for co-processing. This is especially important when one of the components is processed in a dispersed phase. Post processing the particle size of the latter depends on its initial particle size.
* Selecting a suitable process of drying such as spray- or flashdrying
* Optimizing the process (because even this can contribute to functionality variations).
Consideration of material properties:
Material science plays a significant role in altering the physicomechanical characteristics of a material, especially with regard to its compression and flow behaviour. Co-processing excipients offers an interesting tool to alter these physicomechanical properties. Materials, by virtue of their response to applied forces, can be classified as elastic, plastic, or brittle materials. In the truest sense, materials cannot be classified in one category absolutely. Pharmaceutical materials exhibit all three types of behaviour, with one type being the predominant response. This makes it difficult to demarcate which property is good for compressibility. Besides these, existed pharmaceutical materials are also of diversified material characteristics starting from hygroscopic to lubricant sensitive. Co-processing is generally conducted with one excipient that is plastic and another that is brittle. Maarschalk reports co-processing performed with a large amount of brittle material and a small amount of plastic material, as exemplified by Cellactose in which 75% lactose (brittle material) is coprocessed with 25% cellulose (plastic material)12. This particular combination prevents the storage of too much elastic energy during compression, which results in a small amount of stress relaxation and a reduced tendency of capping and lamination13. However, examples of the other extreme also exist (e.g., SMCC has a large amount of MCC [plastic material] and a small amount of silicon dioxide [brittle material]). These two situations exemplify the fact that co-processing is generally performed with a combination of materials that have plastic deformation and brittle fragmentation characteristics. A combination of plastic and brittle materials is necessary for optimum tableting performance. Hence, co-processing these two kinds of materials produces a synergistic effect, in terms of compressibility, by selectively overcoming the disadvantages. Such combinations can help improve functionalities such as compaction performance, flow properties, strain-rate sensitivity, lubricant sensitivity or sensitivity to moisture, or reduced hornification14.
Advantages:
Co-processing excipients leads to the formation of excipient granulates with superior properties compared with physical mixtures of components or with individual components. The process is carried out to bring about a synergistic change in the individual undesirable property or improve the same. The following properties are being the criterion;
• ABSENCE OF CHEMICAL CHANGES
Many detailed studies of an excipient’s chemical properties after co-processing have proven that these excipients do not show any chemical change. Detailed studies with X-ray diffraction analysis, solid-state nuclear magnetic resonance (NMR), IR spectroscopy, Raman spectroscopy, and C13 NMR spectroscopy have detected no chemical changes and indicate a similarity to the physicochemical properties. This absence of chemical change helps reduce a company’s regulatory concerns during the development phase.
• IMPROVED FLOW PROPERTIES
Controlled optimal particle size and particle-size distribution ensures superior flow properties of co-processed excipients without the need to add glidants. e.g. the volumetric flow properties of SMCC13 are improved in comparison with MCC. The particle-size range of these excipients is found to be similar to those of the parent excipients, but the flow of co-processed excipients is better than the flow of simple physical mixtures. A comparison of the flow properties of Cellactose is also performed. The angle of repose and the Hausner ratio of Cellactose are found to be better and thus have better flow characteristics than lactose or a mixture of cellulose and lactose12. The spray-dried product had a spherical shape and even surfaces, which also improved the flow properties.
• IMPROVED COMPRESSIBILITY
Co-processed excipients have been used mainly in direct-compression tableting because in this process there is a net increase in the flow properties and compressibility profiles and the excipient formed is a filler–binder. The pressure–hardness relation of co-processed excipients, when plotted and compared with simple physical mixtures, showed a marked improvement in the compressibility profile. The compressibility performance of excipients such Cellactose12, SMCC13, and Ludipress22 have been reported to be superior to the simple physical mixtures of their constituent excipients. In a comparative study of compaction-hardness it was found that SMCC retained its compaction properties even at high compression forces, yielding tablets of good hardness. MCC, however, lost its compaction properties. Excipients such as MCC lose compressibility upon the addition of water, a phenomenon called quasihornification14. This property is improved, however, when it is coprocessed into SMCC.
• BETTER DILUTION POTENTIAL
Dilution potential is the ability of the excipient to retain its compressibility even when diluted with another material. Most active drug substances are poorly compressible, and as a result, excipients must have better compressibility properties to retain good compaction even when diluted with a poorly compressible agent. Cellactose is shown to have a higher dilution potential than a physical mixture of its constituent excipients12.
• FILL WEIGHT VARIATION
In general, materials for direct compression tend to show high fill-weight variations as a result of poor flow properties, but co-processed excipients, when compared with simple mixtures or parent materials, have been shown to have fewer fill-weight variation problems. The primary reason for this phenomenon is the impregnation of one particle into the matrix of another, which reduces the rough particle surfaces and creates a near-optimal size distribution, causing better flow properties. Fill-weight variation tends to be more prominent with high speed compression machines. Fill-weight variation, studied with various machine speeds for SMCC and MCC, and SMCC showed less fill-weight variation than MCC13. Other co-processed excipients such as Microcelac 100 also show very less fill-weight variation.
• REDUCED LUBRICANT SENSITIVITY
Most co-processed products consist of a relatively large amount of brittle material such as lactose monohydrate and a smaller amount of plastic material such as cellulose that is fixed between or on the particles of the brittle material3. The plastic material provides good bonding properties because it creates a continuous matrix with a large surface for bonding. The large amount of brittle material provides low lubricant sensitivity because it prevents the formation of a coherent lubricant network by forming newly exposed surfaces upon compression, thus breaking up the lubricant network.
• MISCELLANEOUS PROPERTIES
Co-processed excipients also offer the following additional advantages:
* Pharmaceutical manufacturers have the option of using a single excipient with multiple functional properties, thereby reducing the number of excipients in inventory.
* Improved organoleptic properties such as those in Avicel CE-1517 which is a co-processed excipient of MCC, and guar gum were shown to have distinctive advantages in chewable tablets in terms of reduced grittiness, reduced tooth packing, minimal chalkiness, better mouth feel, and improved overall palatability.
* Although co-processing adds some cost, the overall product cost decreases because of improved functionality3 and fewer test requirements compared with individual excipients.
* Because they can retain functional advantages while selectively reducing disadvantages, co-processed excipients can be used to develop tailor-made designer excipients. This can be helpful in reducing the time required to develop formulations.
* Co-processed excipients can be used as proprietary combinations, and in-house formularies can be maintained by pharmaceutical companies, which could help in developing a formulation that is difficult to reproduce and provides benefits in terms of intellectual property rights.
Overview of marketed formulations:
* MICRO-CRYSTALLINE CELLULOSE-
Microcrystalline cellulose is purified, partially depolymerised cellulose prepared by treating alpha cellulose which is obtained as a pulp from fibrous plant material with mineral acids. Microcrystalline cellulose (MCC) is widely used as a filler and binder for wet granulation, direct compression tableting and as a filler for hard gelatin capsules. It has low chemical reactivity combined with excellent compactibility at low pressures. However, recent review of the direct compression properties of MCC with respect to its use as a primary excipient nevertheless pointed out a number of limitations to the use of MCC, the most important of which were considered to be its low bulk density, high lubricant sensitivity, poor flow characteristics and the influence of moisture on the compression characteristics. To address some of the functional problems outlined above it has been suggested that co-processing of MCC with other excipients may improve the performance of materials in direct compression (24).
* Microcrystalline cellulose-Silicon dioxide:
Trade name- Prosolv / Silicified Microcrystalline cellulose.
Composition- Simultaneous trituration of 2% Silicon dioxide with MCC to form a dispersion of silicified MCC followed by drying.
Characteristics- When microcrystalline cellulose is silicified in the preparation of SMCC, no bulk chemical change in the MCC is observed at the resolutions tests and no observable polymorphic changes are induced. The process of silicification leads to the deposition of silicon, presumably in the form of silicon dioxide, both on the outer envelope surface of the particle and on exposed surfaces within the particle. In addition, SMCC has been shown to possess a number of pharmaceutical advantages in terms of powder flow, tablet strength, lubricant sensitivity and wet granulation. Preliminary data also suggests that the material performs well in direct compression formulations and roller compaction. Available in three grades: Prosolv SMCC 50, SMCC 90, and SMCC HD 90, which differ in average particle size and bulk density13.
* Microcrystalline cellulose–Starch:
Trade name- Not recognised.
Composition- Formation of dispersion of maize-starch and solution of MCC separately. Addition of starch dispersion into MCC solution adjusting pH of the mixture followed by spray drying to produce micro-particles.
Characteristics- A new polymer type was generated from the pH and temperature controlled hybridization effected by mixing colloidal dispersions of MCC and Maize-starch. A more efficient multifunctional excipient in terms of disintegration efficiency and loading capacity for the formulation of oral tablets for rapid release of APIs by direct compression process along with other enhanced physic-mechanical properties is obtained15.
* Microcrystalline cellulose-Mannitol:
Trade name- Avicel HFE102
Composition- Co-processing of 90% Avicel PH102 and 10% mannitol.
Characteristics- Flow properties of Avicel HFE102 are significantly better than those of Avicel PH 102. The Avicel HFE 102 exhibits a better tabletability at a slower tableting speed, especially when lubricated. Avicel HFE 102 is also less sensitive to lubrication16.
* MCC-Guar gum:
Trade name- Avicel CE-15
Composition- Co processed MCC and Guar gum in a common solution and spray dried.
Characteristics- Provide smoother, creamier mouthfeel, less tooth-packing, and all this without sacrificing flow or compaction17.
* MCC-Sodium carboxymethyl cellulose:
Trade name- Avicel CL-611
Composition- Co processed MCC and sodium carboxymethyl cellulose via co-drying process.
Characteristics- Impart a thixotrophic viscosity profile, and increase formulation stability across a wide range of pH. Used as a stabilizer17.
* Microcrystalline cellulose–Calcium carbonate:
Trade name- Not recognised.
Composition-Co-processed from MCC and Calcium carbonate by spray drying.
Characteristics-a mixture with very good compactibility as compared MCC alone. Also has a little lubricant sensitivity. Along with PVP and Mg-St produces direct compressible powder9.
* LACTOSE:
Lactose is one of the major excipient used in the tableting process. Most of them are used both for direct compression as well as wet granulation. At the beginning, untreated materials were applied for direct compression, such as powder cellulose or α-lactose- monohydrate. Then, the materials were improved by using other manufacturing processes, such as spray drying (spray-dried lactose), or by using a special sieve fraction (lactose 100-mesh).The next technological innovation advancing the positive excipient properties for direct compression is the production of co-processed excipient using two or more excipients targeted towards the particular process.
* Lactose–Cellulose:
Trade name- Cellactose12.
Composition- co processed α-lactose and cellulose.
Characteristics- improved flow property and high dilution potential along with excellent binding properties.
* Lactose- Microcrystalline cellulose:
Trade name- Microcelac 100.
Composition- A co processed spray dried filler/binder for direct compression and composed of 75% w/w a-lactose monohydrate and 25% w/w microcrystalline cellulose.
Characteristics- Superior flow ability and binding properties compared to physical mixtures of microcrystalline cellulose with different lactose grades e.g. a-lactose monohydrate (lactose 100 M), anhydric β-lactose (Pharmatose DCL21), and spray dried lactose (Pharmatose DCL11). It also shows the least lubricant sensitivity18.
* Lactose-maize starch:
Trade name- StarLac
Composition- A co processed spray dried filler/binder for direct compression and composed of α-lactose monohydrate and Maize-starch.
Characteristics- The new product should combine the good flowability and plastic deformation of spray-dried lactose with the elastic deformation and rapid disintegration of native maize starch. StarLac demonstrated good compactibility and release behaviour. It exhibited deformation behaviour with higher parts of plastic and elastic deformation than FlowLac, therefore StarLac is of interest for the manufacture of pressure-sensitive drugs19.
* Lactose-polyvinyl pyrrolidone:
Trade name- Ludipress.
Composition- A co processed filler-binder from α-lactose monohydrate, poly-vinyl pyrrolidone and crospovidone.
Characteristics- An excellent filler binder with very high dilution potential and good binding property18.
* α-lactose monohydrate & β-cyclodextrin.
Trade name- Not recognised.
Composition- Co processed by taking 75:25 and 60:40 ratio of α-lactose monohydrate & β-cyclodextrin via spray drying.
Characteristics- Excipient with good flowability, compressibility and compactibility. The limitations of β-CyD for its flowability and lubricant sensitivity is overcome20.
* Starch:
Starch is the most widely used filler-binder for its availability and lower cost. In tablet formulation, freshly prepared starch paste is used at a concentration of 5-25% w/w in tablet granulation as binder. They have also good disintegrate property. However, unmodified starch does not compress well and tends to increase tablet friability and capping. But the more hygroscopic character and lower dilution potential leads to co-process physico-mechanically developed excipients of starch.
* Pregelatinised starch:
Trade name- Insta starch / Lycatab / Sepistab.
Composition-By heating an aqueous slurry containing up to 42% w/w of starch at 62-720C, having additives such as gelatinisation aid (salt or bases) and surfactants. Then they are spray-dried, roll-dried or drum-dried.
Characteristics- As binder-diluent in oral capsule and tablet. Having enhanced flow and compression characteristics. Tablet-binder in dry compression21.
* Poly-vinyl pyrrolidone:
PVP is the widely used filler-binder. Used primarily in wet granulation as binder. Many derivatives of PVP have been developed to act as better excipient for a particular process. Grades such as Povidone K-12, Povidone K-30, Povidone K-90 has been developed to be used as suspending, stabilising or viscosity imparting agent. But being very hygroscopic it becomes difficult to incorporate in tablet coating and dry granulation. Hence newer congeners are being developed from the combination of PVP which are found to be more useful for tableting procedure.
* Copovidone:
Trade name- Kollidon VA 64/Plasdone S 630.
Composition- Copovidone is a linear random co-polymer based on N-vinyl-2 pyrrolidone and vinyl acetate in the ratio of 6:4 by mass.
Characteristics- Copovidone is a white/yellow-white with fine particle size and excellent flow properties. Dry Binder in Tablets (Direct compression), Binder in Tablets, Pellets & Granules (Wet Granulation), Dry Binder in Granules (Roller Compaction), Film Former for Tablet Film Coating & Sugar Coating, Film Former for Subcoating Tablets and Matrix Former for Melt-Extrusion for tablets22.
* Mannitol:
Mannitol is mostly used as the direct compression as well as wet granulation purpose. They have good mouth-cooling property for which it is incorporated in chewable tablets. But they are highly hygroscopic and posses difficulty in dry-compression process. Many derivative co-processed excipients have been developed from mannitol and other excipients;
* Mannitol-Povidone:
Trade name- Ludiflash.
Composition- Coprocesed blend of 90% Mannitol, 5% Kollidon CL-SF (Crospovidone) 5% Kollicoat SR 30 D (polyvinyl Acetate).
Characteristics- Specially designed for directly compressible, high speed tableting and hard tablet with very low friability. Ludiflash have good flowability, less water absorption, and no segregation of the active ingredients23.
* Orocell:
Trade name- Orocell 200 & Orocell 400.
Composition- Spheronised mannitol with different particle size.
Orocell 200 with 90% mannitol (<315μm)
Orocell 400 with 90% mannitol (<500μm).
Characteristics- A developed filler-binder with high dilution potential and good disintegrating property useful for orally disintegrating tablets23.
* Other developed coprocessed excipients:
Besides these above said excipients lots of other excipients have also been developed to satisfy the particular process or formulations as well as the commercial requirement of high machineability and direct compression. They are as follows;
* Cellulose-Calcium sulphate:
Trade name- Cel–O–Cal.
Composition- Coprocessed from Cellulose andCalcium sulphate by spray drying.
Characteristics- Used widely as a filler11.
* Fructose:
Trade name- Not recognised.
Composition- Fructose coprocessed with polysaccharide24.
Characteristics- Good flowability and ccompressability.
* Other Carbohydrates:
Trade name- F-melt type C & M.
Composition- Coprocessed by forming dispersion at a fixed ratio followed by spray drying and is produced from Mannitol, Xylitol, Calcium sulphate, and Crospovidone.
Characteristics- F-MELT exhibits excellent tabletting properties and facilitates rapid water-penetration for a fast disintegration time. It has advantages of highly flowable with spherically dense particles, less sticking or capping, excellent tablet hardness and low friability, high API Loads23.
* Chitin-sillica:
Trade name- Not recognised.
Composition- Coprocessed by coprecipitation from a mixed dispersion of Mg-sillicate and Chitin followed by oven drying and passing through 200µm sieve.
Characteristics- Minimises the deleterious effect of Mg-silicate. The physical interaction between chitosan and silica create an insoluble, hydrophilic highly absorbent material, resulting in superiority in water uptake, water saturation for gelling formation. It has water wicking and swelling properties. It is super-disintegrant with improved flow and compaction proper-ties. It acts as super-disintegrant and filler both. Super disintegrant property as compared to that of Avicel-silicate25.
* HPMC-Lactose:
Trade name- Not recognised.
Composition- Agglomerates (60-80#) are prepared using different proportions of hydroxypropyl ethylcellulose, lactose and starch. 5% polyvinyl pyrrolidone in isopropyl alcohol is used as agglomerating agent.
Characteristics- A proper combination of HPMC (bio-adhesive and hardness), lactose (flow and compressibility), and starch (synergist in bio-adhesion) yield a co-processed, directly compressible multipurpose excipient that can serve as a diluents and a bio-adhesive material26.
Future Prospective:
The particular phenomenon of co-processed excipient is a field having vast scope for development of excipient with desirable property for direct compression as well as for specific method and formulation. The limitation of the existing excipients for new rapidly developing API’s can be overcome. The process also opens opportunity for development and use of single multifunctional excipient rather than multiple excipients in formulation. Now a day’s many excipients are also being co-processed directly with API’s to develop a composition ready for direct compression, e.g. co-spray drying of acetaminophen, mannitol, erythritol, maltodextrin and a super disintegrant in spray dryer yields powders with improved tablet disintegration in combination with acceptable physicochemical powder properties, tablet hardness and friability, while Kollidon CL minimised tablet disintegration time27. Also some of the excipients can be co-processed to have a better physio-chemical property, e.g. granules of Carbopol and MCC prepared from dried sodium hydroxide solution is pressed into tablet and is used for treatment of gastro-esophageal reflux26. Newer excipients are being developed to aid in targeted drug delivery e.g peptide Dalargin to brain using Polyisobutyl cyano acrylate whose surface is being modified with Tween 8021.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.
Regulatory concern:
As excipients are incorporated in the final formulations that also remain in the final product they should have safety concern. To support marketing authorisation (MA) applications, increased information is required on active ingredients. Genuinely new excipients, those not previously registered with the regulatory authority, are to undergo a full safety evaluation, because of the requirement in Directive 75:318: EEC. Compatibility of excipients with other ingredients may have to be demonstrated in the development pharmaceutics (Euro Direct 155:96) and analytical validation (European Commission, 1998b) sections of the MA application dossier. An excipient can be the subject of a ‘PhEur Certificate of Suitability’ (Council of Europe Resolution, 1998) which can partly and sometimes fully satisfy the data requirements, within a MA application dossier, for that ingredient (European Commission, 1998c)1. With the absence of a chemical change during processing, co-processed excipients can be considered generally regarded as safe (GRAS) if the parent excipients are also GRAS-certified by the regulatory agencies.
Conclusion:
Excipient mixtures or co-processed excipients have yet to find their way into official monographs, which is one of the major obstacles to their success in the marketplace. The success of any pharmaceutical excipient depends on quality, safety, and functionality. Although the first two parameters have remained constant, significant improvements in functionality open the door for the increased use of co-processed excipients. The advantages of these excipients are numerous, but further scientific exploration is required to understand the mechanisms underlying their performance. With development a number of new chemical entity rising day by day, there is a huge scope for further development of and use of these excipients in future. Exploring material property of natural polymers and co-processing them with the existing ones will create a large inventory of new developed excipients. Rather than developing an entirely new excipient which would have to undergo a full safety evaluation, and would be enormously expensive, it is better to develop physico-mechanical property of an established product.
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