1. INTRODUCTION:

There are many ways to coat tablets. Sugar coating was one of the earliest methods, and the process is still widely used in the confectionery industry. Wurster coating is another means. It employs a cylindrical chamber in which tablets are suspended by air and a coating solution is introduced into the air stream. Fluid-bed coating is a similar process. Dry coating is the technique of making a tablet within a tablet. But the principle means of applying a coating to pharmaceutical and nutraceutical. Film coatings are a mixture of solids and liquids. For many years, the liquid component of coatings was a volatile solvent, such as alcohol or other quick drying substances like methylene chloride. While solvent-based coatings performed well in many respects, they presented problems in handling, operator safety, recovery, and odor.

They could even make the finished tablets smell like solvent, which is not a desirable side effect. Solvent-based coatings are still used in some applications, but water based, or aqueous, coatings have largely replaced them. As a result, coating has become much more challenging, because water based coatings are much less forgiving. You must apply the coating and remove the water before it can jeopardize the integrity of the tablet.¹

Typically in the pharmaceutical industry, drug products exist in two dosage forms, solid and liquid dosage forms. Included in solid dosage forms are tablets, pellets, pills, beads, spherules, etc. These solid dosage forms are often coated for various reasons, such as odor or taste masking, prevention from moisture, light and/or air, protection from destruction by gastric acid or gastric enzymes, enhanced mechanical strength, aesthetics or controlled release including controlling release sites and/or release rate. At present, the commercially used technology for coating solid dosage forms is the liquid coating technology. Generally, a mixture of polymers, pigments and excipients is dissolved in an appropriate organic solvent (for water insoluble polymers) or water (for water soluble polymers) to form a solution, or dispersed in water to form a dispersion, and then sprayed onto the dosage forms and dried by continuously providing heat until a dry and smooth coating film is formed. A typical liquid coating process is carried out in a rotary pan coater for larger size solid dosages such as tablets, or in a fluidized bed coater for smaller size dosage forms such as pellets or pills. The liquid coating process and equipment have been well established and widely adopted by the pharmaceutical industry. The liquid coating technology can obtain exceptionally uniform smooth lustrous coating surface. However, the inherent disadvantages caused by using organic solvents or water have become increasingly obvious: firstly, vaporizing organic solvents or water is energy consumptive, which adds a large bill to the coating cost; secondly, long processing time up to hours and even days is essential for liquid coating to get a dry, uniform, and smooth coating surface; in addition, using organic solvents results in environmental pollution, solvent recycling cost and operation dangers of explosion; finally, organic solvent itself imposes another cost to the coating process in addition to the energy-consumption and long processing time.²

2. SOLVENTLESS PHARMACEUTICAL COATING:

Coatings are an essential part in the formulation of pharmaceutical dosage form to achieve superior aesthetic quality (e.g. color, texture, mouth feel, taste masking etc.), physical and chemical protection for the drugs in the dosage forms, and modification of drug release characteristics. Most film coatings are applied as aqueous- or organic-based polymer solutions. Both organic and aqueous film coating bring own disadvantages. Solvent less coating technologies can overcome many of the disadvantages associated with the use of solvents (e.g., solvent exposure, solvent disposal, residual solvent in product) in pharmaceutical coating. Solvent less processing reduces the overall cost by eliminating the tedious and expensive processes of solvent disposal/treatment. In addition, it can significantly reduce the processing time as there is no drying evaporation step. These environment-friendly processes are performed without any heat in most of the cases (except hot-melt coating), and thus can provide an alternative technology to coat temperature-sensitive drugs. This review discusses and compares six Solvent less coating methods -- compression coating, hot-melt coating, supercritical fluid spray coating, electrostatic coating, dry powder coating and photo curable coating -- that can be used to coat the pharmaceutical dosage forms.³There are several solvent free coating techniques being actively investigated. Solvent less coating offers many advantages over solvent based coatings; for e.g. there is no requirement for solvent evaporation and drying in this technique, hence the processing time is much shorter than solvent based systems. It reduces cost by eliminating the expensive process of solvent disposal.

In this review, six approaches to solvent less film coating are discussed. Compression Coating, Hot Melt Coating, Electrostatic Spray Powder Coating, Dry Powder Coating, Supercritical Fluid Spray Coating and Photo Curable Coating differ in their mechanism of film formation and their stage in development to commercialization.^{4, 5}

2.1 Different Types of Solventless Coating:

2.1.1Compression coating

2.1.2Hot melt coating

2.1.3Supercritical fluid spray coating

2.1.4Electrostatic spray powder coating

2.1.5Dry powder coating

2.1.6Photo curable coating

2.1.1 Compression Coating:

Compression coating is also known as dry coating / press coating, was one of the first solvent free coating method. In general, a compression coated tablet consists of an inner drug core and an outer coating shell. The inner core is completely surrounded by the outer layer and, thus, the selection of the material in the outer layer control / contributes greatly to the performances of the tablets including mechanical strength of the coating, release of drug and stability. Conventionally, the compression coating process involves the compressions of the core, followed by the compression of core-coating material around the core. The die is filled with the outer-layer forming materials. The core tablet is placed on the powders for the outer layer. The core is then surrounded with the outer layer forming material and compressed with the powder and core inside it. One problems associated with this method is the location of core tablet in the coating. When the core tablet is not located in the center of the system, there may be variation in coating performance. ^6-11

In summary, compression coating has some unique features. Due to the thickness of the coating, it can provide many functions including delayed release and controlled release. However, its use has largely been restricted to specific application due to the problem of reproducibility of placement of core in the center to obtain uniform coating thickness. The technology described by Hariharan and Gupta may overcome this limitation. In addition, due to the relatively large thickness of the coating, drug loading may be limited. The solvent free nature of the process and reduction of steps (with no truly separate coating step) make compression coating an attractive alternative.

Fig. 1: Process Principle of Hot Melt Coating

2.1.2 Hot-Melt Coating:

In ‘hot-melt coating', the coating material is applied in its molten state over the substrate and then solidified by cooling which is depicted in fig.1. The choice of the coating excipients depends primarily on its function (e.g., retarding the drug-release rate, preventing environmental degradation and masking unpalatable taste) in the dosage form. Lipids and waxes are generally used as coating materials. Typically, any fluidized-bed coating equipment can be modified to suit the needs of hot-melt coating.

Advantages of hot melt coating:

v Particle and pellet coating, micro coating, flavour encapsulation.

v Effective process

v Fast coating

v No evaporation of solvents required

v Protection against moisture

v Delayed release of active ingredients in the case of pharmaceutical drugs.

v Taste masking

v Uniform and dense coatings

v Low to high coating masses in comparison with the particle to be coated

Coatings must be dense and without mechanical damage and cracks. Hot melt coating is a very effective process for the application of waxes and molten materials as protective films for manipulating the particle properties.¹²Glatt offers Fluid Bed Coating (Top Spray Coating, Bottom Spray Coating, and Rotor Coating) as a technical solution for coating different particles and tablets. For particles difficult to fluidize, Glatt Spouted Bed Technology was developed. The coating fluid is sprayed onto solid materials, which are presented to it. The introduction of process air causes the film coating to solidify. Small droplets and a low viscosity ensure that the distribution is uniform. The time and energy evaporation of solvents can be dispensed with by the use of molten materials as coating liquids.¹²

A hot-melt coating material as it name implies, is applied in its molten state over the substrate and then solidified upon cooling. Hot-melt coating has been investigated for its use to improve stability, mask taste and achieve sustained release. Released of drug from hot-melt coating, is dependent on the coating material and can be a function of moisture, pH, heat, shear or contact with digestive enzymes with the release mechanism being diffusion and dialysis, pH-dependent dissolution and enzymatic breakdown.

The most commonly used coating materials and their melting points are:

v Partially hydrogenated cottonseed oil,

v Soybean oil (51-55°C).

v Partially hydrogenated palm oil (58 -63°C),

v Partially hydrogenated cottonseed oil (61-65°C),

v Partially hydrogenated soybean oil (67-7100),

v Beeswax (62-65°C),

v Paraffin wax (55°C).

v Carnauba wax (84°C),

v Partially hydrogenated castor oils (85-88°C).

v Polyethylene glycol 3350 (54-58°C),

v Glycerol behenate (69-74°C)

v Gelucires (different melting points for different grades).

Many of these materials are derived from plants or animals, so purity is an issue in obtaining good batch-to-batch reproducibility of processing and performance. Blends of materials can be used to alter release properties However, when blends result in a broad melting-point range, processing is more difficult.

Hot melt coating consists of four processing stages: equipment warming, preheating of the substrate, melting and spreading of the coating agent, and cooling and congealing of the coating. The coating liquid is maintained at a constant temperature during application, which can be as high as 140-150°C. Steam jackets, heated atomizing air and or heating tapes are often used to prevent the congealing of coating agent within spray line and at the nozzle. The need for elevated temperature during the liquid storage and spraying through the nozzle brings challenges to formulators and operators in terms of safety during processing ¹³. The spraying equipment is key to the successful implementation of hot melt coating. The top spray fluidized bed is the system of choice for hot melt coating due to its ability to maintain the product temperatures closest to the congealing temperature of the melt. Other fluidized bed process can also be used, e.g., conventional top spray, wurster bottom spray / rotary tangential spray. The molten liquid is supplied at low pressure and is atomized into droplets by pressurized air through a binary nozzle. High atomization air pressure is employed to keep the droplet small and discrete. Low viscosity of the melt and relatively low spray rate favor small droplet formation. The spray rate of the molten materials is very critical as lower spray rate of molten material leads to a more uniform distribution of coating material. Low spray rates prevent agglomeration by allowing adequate congealing of wax. A key challenge in using pilot scale equipment is maintaining the coating material molten while delivering it at slow rate (less than 30 gm/min) required achieving good coating uniformity. When compared to solvent-based coating, this rate is extremely low. However, in hot-melt coating the coating liquid is 100% solids. So even at these low rates, coating times can be as low as 20 minutes. In selecting spray nozzles, consideration of the relatively low spray rates and high coating viscosities will ensure appropriate droplet size, spray pattern and avoidance of clogging¹⁴. Theoretically, hot melt coating is straighter forward than solvent based coating. Once a Solvent based coating is applied, one must account for both heat and mass transfer during solvent loss. However, in hot-melt coating, heat transfer is not complicated by mass transfer. In practice, however, the heat transfer is difficult to control within a good operating range that allows adequate spreading of the molten coating without excessive tackiness. The liquids temperature during atomization of the molten coating and the temperature of the fluidizing product are very importance in order to achieve good quality of coating. If the product temperature is too low, it may lead to poor spreading of coating over the core material and that may sacrifice the quality of coating. In practice, inlet air temperatures are 10 to 15°C less than the melting point of the coating to obtain heat transfer rates that maintain the product bed temperature close to the congealing temperature of the coating material. The atomizing air and spray liquid temperatures exceed the melting point by 40 to 60° C. Small pellets, granules and particles with mean particle size ranging from 100 to 2000 μm can be coated with hot-melt coating process using a fluidized bed process. However, substrates with particle size ranging from 100-750 μm and with densities of 0.5 gm/cm or less will fluidize more easily than those near the higher end of the size range. Many pharmaceutical materials have sizes smaller than 100 μm. It is difficult to fluidize the smaller materials fully and they are very prone to adhere to the equipment surfaces due to static electricity. Static charge can be avoided by choosing the corrects spraying condition. For example, Jozwiakowski and Coworkers showed that fine granules (mean particle size 77 μm range 10-150 μm) could be coated with partially hydrogenated cottonseed oils. They used fluidized bed configuration suited for handling small particles. It had an elongated expansion chamber and split filter housing at the top of the expansion chamber, such that alternate filters could be shaken to return fines back into the batch without disruption to air-flow. The operating parameters, such as atomization air and molten wax temperatures of 120°C and atomization air pressure of 5 bars, were nearing the limits of safe equipment use. Thus modification may have to be made to hot-melt coat such fine particles.^15-16

In summary, the hot melt method of coating pharmaceutical dosage form is suitable when the active ingredients are stable at / below the congealing point of the coating material. The in vivo fate of the lipidic coating material is not well known at this time. Also, the batch to batch variability of lipidic excipients and their physiochemical characterization for functionally can be challenging. Sometimes, organic solvent is required to thin the hot melts. In that case, process will not be truly solvent free. In all cases where hot melt coating was used to produce sustained release, there was very fast release phase followed by a slow release phase. The dramatic difference in two rates deserves some attention to formulation / process modification. Nevertheless, this solvent less process holds promises to replace the solvent based coating system when the optimum conditions are fulfilled.

2.1.3 Supercritical Fluid Spray Coating:

The ‘supercritical fluid spray coating' process consists of dissolving the coating material or drug in supercritical carbon dioxide, and gradually reducing the solvent power of carbon dioxide to enable the coating material to precipitate onto drug particles dispersed in the medium which is depicted in fig. 2. Although this process is technically a solvent-based coating process, the use of carbon dioxide as the supercritical fluid avoids some of the challenges associated with traditional solvent-based processes. In the absence of co-solvents, the coating materials used in supercritical fluid coating are limited mainly to lipids.¹⁷Supercritical fluids (SCF) have variable liquid-like densities, gas-like viscosities, and the zero surface tension of gases. These three basic properties provide unique advantages in modifying the surfaces of medical devices to provide better therapies.¹⁷By applying the coating using a non-reactive gas in its supercritical (fluid) state, Micelle can avoid exposing both the coating and the substrate to solvents or extreme temperatures that could alter the structure, chemistry, morphology, or most importantly the therapeutic effectiveness of the drug. And because the fluid is actually a gas, it does not affect materials already coated on the device. This allows for multiple layers containing one or more therapeutic agents to be coated onto the device while maintaining specific control over drug elution profiles. The variable density of supercritical fluid allows careful control over the solvation, diffusion, and flow of the drugs and polymers during the surface modification process. It also facilitates the generation of drug-eluting coatings with precise control over drug morphology and polymer composition, as well as multi-drug and multi-layer coatings. The ability to create multi-drug and multi-layer combination coatings has presented a significant challenge using current solvent-based methods because the solvents tend to dissolve or otherwise debilitate the previously coated layer. The gas-like viscosity and surface tension of supercritical fluids allow the coating to access the most intricate areas of medical devices. The supercritical fluids are also unaffected by or indifferent to the surface characteristics of the pre-treated medical device, and allow application processes that are up to ten times faster than those requiring transport of materials in traditional solvents. These properties actually make it possible to deliver therapeutic chemistry into micro- and nonporous openings in medical devices.¹⁷

Fig. 2: supercritical fluid coating

Advantages of SCF:

Micelle’s supercritical fluid technology (SCF) provides several unique advantages in the modification and coating of biomedical surfaces with advanced polymers and drugs. Compared to current solvent-based coating systems, Micelle’s technology for creating drug eluting coatings:

v Dry - Polymers, drugs and medical devices are not exposed to conventional liquid solvents.

v Cool - Processes utilize moderate temperatures to preserve the structure and morphology of therapeutic agents.

v Flexible - By combining electrostatic attraction with supercritical fluids, Micelle can create surface modifications for a broad range of medical devices using a variety of polymers and drugs.

The supercritical fluid process allows the use of therapeutic agents that may be sensitive to elevated temperatures or traditional solvent processes. Most existing coating processes for medical devices involve an organic solvent that may alter the chemistry of the therapeutic agent or affect human health. Micelle’s SCF-based methods - which are completely solvent free - avoid the challenges associated with the use of common solvents and offer opportunities for significant and rapid process advantages.¹⁷

Supercritical carbon dioxide has wide use as an extraction fluid in the food industry and is being actively explored for particle engineering in the pharmaceutical industry and other industrials. Its use for coating is more limited, particularly in the absence of co-solvents. The supercritical state is defined as a state where both the pressure and temperature of substances are greater than its critical pressure (Pc) and Critical temperature (Tc) .The thermal and physical properties of supercritical fluids fall in between pure liquids and gas. In a near critical isotherm (between Tc and 1.2 Tc), the density, viscosity, diffusivity and other physical properties. Such as solvent strength and dielectric constant , can be varied in a range from gas-like to liquid like with small changes around the critical pressure (0.9-2.0 Pc).Carbon dioxide is an ideal supercritical medium for the pharmaceutical purposes due to its relatively low critical temperature(31⁰C) and critical pressure (72 bar). Thus, it is possible to obtain the advantages of near critical operation near to room temperature. Carbon dioxide in a supercritical state, possess gas-like diffusivities and liquid like densities and solvencies. It is inexpensive, non-toxic, non-flammable, easily available, environment friendly and can be easily recycled. ^18-20 Supercritical Carbon dioxide can be used both as a solvent and as a non-solvent or anti-solvent depending on the pharmaceutical application. In a comprehensive review article, it was reported that supercritical Carbon dioxide can be used in coating active substances. In most cases that were cited in this review, the particles were composite micro particles rather than micro capsules which are coated in the more traditional sense of the word. Here we focus on coating that encapsulates each core. In a preview on supercritical fluids, Sunkara and Kompella pointed out that for a successful coating, the supercritical fluid ideally dissolves only the coating material, leaving the core completely undissolved. Thus, in its current state, supercritical coating may be limited by the properties of the coating and the core.

In summary, supercritical fluid spray coating is useful for coating small particles. This method can be completely eliminated with a quick decompression, leaving the active ingredient and encased in the coating material. However, the used of this coating method is limited due to the poor solubility of most coating materials in supercritical fluid and the requirement of the core to be insoluble. In addition, there is some necessary investment in high pressure processing equipment that limits the broad use of supercritical fluid spray coating as a preferred coating method in the pharmaceutical industry.

2.1.4 Electrostatic Spray Powder Coating:

This is a solvent less coating technique where the powder can be utilized nearly 100% because they can be recovered fully by precipitation from the exhaust / by deposition and collection below the coating zone which is shown in fig. 3. This process has the ability to coat one / both tablet faces with the same of different material. The process is useful to coat water sensitive drugs, but requires heat for film formation. The coating materials and tablet core must possess certain conductive properties or be modified to satisfy the requirements of powders coating. The resistively of the core or pharmaceuticals dosage form must be less than 109 Ωm to allow the core to be properly earthed when in contact with "grounded" material. There are several methods to increase conductivity of the surface of the core. It can be wetted with water, as the layers of moisture decrease resistance. In practice, this can be accomplished by exposing tablets to high humidity for a short period just prior to coating. The surface of the drug substrate can also be modified using polar groups (e. g. quaternary ammonium compounds). These compounds can be dissolved in volatile solvent and then applied to the surface where it deposits as a thin film after solvent evaporation. This film absorbs water from the atmospheres and forms an electrically conductive swollen gel layer. Addition of certain excipients like dicalcium phosphates and ionic salts (1-3%) can produce conductive properties in the core.²¹ Electrostatic spraying is the most widely used method to apply powder coating because it is more versatile and provides better control over the coating thickness. Accordingly, most of the research and development are focused on this technology.²²

Fig. 3: Electrostatic Spray Coating

Process Description:

The electrostatic spray process consists of four main steps:

1. Pneumatically transport the coating powder from a fluidized bed feeder to the spray gun,

2. Charge the particle with the spray gun.

3. Deposit the powder on the grounded pan inside a booth,

4. Collect the over spray and recycle it to the feeder.

After coating, all the parts are conveyed to the oven for final curing. The process involves four types of equipment: the powder delivery system, the electrostatic spray gun, the coating booth and the powder recovery system.

Delivery system:

The delivery system consists of a powder storage container or feed hopper and a pumping device that pneumatically transports a mixture of powder and air into hoses or feed tubes. The feed hoppers are usually fluidized to facilitate the feeding and transportation of coating particles. Good fluidization quality is important for consistent, uniform powder flow.

Electrostatic Spray Gun:

The Electrostatic spray gun charges coating powder, directs the flow of the powder, and controls the pattern size, shape, and density of the powder cloud. Electrostatic powder coating is based on applying electrostatic charge to particles of dry powder. There are two charging methods used in powder coating applications: corona charging and tribe- (frictional) charging. Corona charging is the most widely used charging technology in the industry due to its high efficiency and productivity, as well as low sensitivity to the air humidity.

Coating booth:

The powder spray booth is designed to safely contain the powder so that the overspray cannot escape into other areas. The booth is also configured to enhance the deposition efficiency. The airflow through the booth should be sufficient to lead all overspray to the recovery system but not so high that it would disrupt the powder deposition and residence time in the booth.

Powder recovery system:

Powder must be separated from the contaminants and air stream before it can be recovered to reuse or disposal. Additionally, the air must be cleaned to the regulated level. The primary techniques to recover powder are cartridge filtration, cyclone separation and filter belt filtration. Collected powders are screened to remove large contaminants before being recycled to the feeder.²²A coating powder may be composed of multiple components. Composite particles are often used so that the powder behaves like a single component. Electrostatically to avoid segregation of the components, the coating particles generally have a particle size range of 30-100 μm. Deposited of smaller particles is poor due to the fact that small particles follow the electric field and are carried around on the tablet. The larger particles, on the other hand, do not follow the electric field lines due to their large momentum. Instead, they impact the tablet a narrow particle size distribution assures uniform conveyance of the charged powders to the tablet surface. The resistivity of the powders is required to be: 10 Ωm to permit charge retention until the coating is formed. The coating thickness is usually thicker in the powder coating (50 μm compared to 25 μm for solvent based system). The thickness of electrostatic spray powder coatingscan be controlled by the resistivity of the powder. Low resistance powders (10 Ωm lose their charge to the surface resulting in poor deposition. Highly resistant powders (10 Ωm) can result in back ionization which repels further powder deposition and limit coating thickness. However, back-ionization can reportedly result in coating defects. 10¹² Ωm) ²³ Powders, usually polymers, in the coating powder are molted by IR radiation onto the substrate after electrostatic adhesion. The coating materials ideally melt at relatively low temperature (100⁰C-120⁰C) and have a low melt viscosity to obtain a rapids flow of the coating material on the core surfaces. Surface tension promotes flow and coalescence of coating powder while viscosity retards it. Flow modifiers (e. g. polyvinyl butyral and cellulose acetate butyrate) are used in concentrations of 0.5-1% to reduce the viscosity of the melted polymer to obtain better surface coverage and a uniform coating.²⁴Phoqus pharmaceutical UK^25-26 introduced the dry powder deposition coating technology at the commercial scale. In their process; the active ingredients can be in the tablet core or in the coating or both depending on their nature and use. With the application of electric field, the tribo charged powders are attracted to and deposited on the tablet surface. Porter stated that the powders deposition process can be controlled very precisely. The coating patterns can be easily altered by changing the process settings. Once the coating powder has been deposited, radiant heat is applied for about 1-2 min. to fuse and fix the coating powder on to the tablet core. This process coats each side of the tablet separately. Each side of the tablets exposed to heat for about 80 seconds. The core temperature reaches approximately 80ºC and the coat temperature is about 120ºC. The Phoqus powder coating process reportedly handles the dosage forms individually and gentle compared to conventional coating process, and thus, tablets can be less robust than conventional film coating processes. The size and shape of the core is not critical for this process. This continuous coating process is performed at ambient conditions of temperature 25-30ºC and 40 ± 5% relative humidity. Porter also reported that this powder coating process forms very uniform film across the entire surface of the tablets and provided the possibility of productive uniform designs, logos, spots and stripes on the tablet coating using this technology.²⁷

Electrostatic spray powder coating is a solvent less coating technique where the powders can be utilized nearly 100% because they can be recovered fully by precipitations from the exhaust or by deposition and collection below the coating zone. This process has the ability to coat one or both tablet faces with the same or different materials. The process is useful to coat water sensitive drugs, but require heat for the film formation.

2.1.5 Dry Powder Coating:

Dry coating is a coating technology for solid pharmaceutical dosage forms derived from powder coating of metals. In this technology, powdered coating materials are directly coated onto solid dosage forms without using any solvent, and then heated and cured to form a coat. As a result, this technology can overcome such disadvantages caused by solvents in conventional liquid coating as serious air pollution, high time- and energy-consumption and expensive operation cost encountered by liquid coating. Several dry coating technologies, including plasticizer-dry-coating, electrostatic-dry-coating, heat-dry-coating and plasticizer electrostatic- heat-dry-coating have been developed and extensively reported.²⁸

At present, the commercially used technology for coating solid dosage forms is the liquid coating technology. Generally, a mixture of polymers, pigments and excipients is dissolved in an appropriate organic solvent (for water insoluble polymers) or water (for water soluble polymers) to form a solution, or dispersed in water to form a dispersion, and then sprayed onto the dosage forms and dried by continuously providing heat until a dry and smooth coating film is formed . A typical liquid coating process is carried out in a rotary pan coater for larger size solid dosages such as tablets, or in a fluidized bed coater for smaller size dosage forms such as pellets or pills. The liquid coating process and equipment have been well established and widely adopted by the pharmaceutical industry. The liquid coating technology can obtain exceptionally uniform smooth lustrous coating surface. However, the inherent disadvantages caused by using organic solvents or water have become increasingly obvious: firstly, vaporizing organic solvents or water is energy consumptive, which adds a large bill to the coating cost; secondly, long processing time up to hours and even days is essential for liquid coating to get a dry, uniform, and smooth coating surface; in addition, using organic solvents results in environmental pollution, solvent recycling cost and operation dangers of explosion; finally, organic solvent itself imposes another cost to the coating process in addition to the energy-consumption and long processing time. In order to overcome these limitations of the liquid coating technology, new efforts have been made in recent years to develop solvent less coating technologies. The developed solvent less coating technologies include hot-melt coating, supercritical fluid spray coating, photo curing coating and powder coating. Bose and Bogner (2007) gave an excellent review on these solvent less coating techniques. Among these solvent less coating techniques, Powder coating technique, which is often termed as “dry coating” in the pharmaceutical coating fields, is the most widely studied one and has not been elaborated.^28-29

Dry Particle Coating: ^30-32

Following are different types of devices.

1. Mechanofusion

2. Hybridizer

3. Magnetically Assisted Impaction Coater (MAIC)

4. Rotating Fluidized Bed Outer (RFBC)

5. Theta Composer

A summary is that large number and diversity of dry coating approaches reviewed confirm the increasing interest towards avoiding the use of water within the coating of solid cores. Advantageous applications have been described with respect to process time, overall manufacturing costs and ability to overcome water-induced degradation of active ingredients. In depth knowledge of the mechanisms of coating formation and, in some cases, availability of suitable coat forming agents and industrial-scale equipment should be regarded as the main issues for the consolidation of dry coating technology in the pharmaceutical field. The dry powder coating is another solvent less process where some of the processing conditions may require little solvent to promote film formation. Dry powder coating has all the advantages of solvent less coating and is useful to coat water sensitive drug. On the other hand, this process requires relatively high temperature annealing for approximately 24 hrs.

2.1.6 Photo Curable Coating:

The methods discussed above represent physical approaches to achieve solvent free coating where the coating materials do not undergo chemical reactions. Photo curing, provides a chemical approach to form a coating at room temperature or below at an extremely rapid rate³³. This coating process offers similar advantages over the solvent-based coatings. In addition, it provides some advantages when compared to other solvent-less coating methods. It is an appropriate technology for temperature sensitive drugs as there is no heat required. On the other hand, this method may not be suitable for coating photosensitive drugs Photo curing is a very common solvent free technique used in the paint, adhesive and photo-imaging industries. It has wide application in dental and medical field, Composite dental filling, preventive treatment for cares, assembly of medical devices and wound dressing is examples of medical and dental applications of photo curing.³³

Photo curing involves a free-radical polymerization reaction in which the functional moieties present in the photo curable materials react to form a cross linked network. Photo curing systems generally consists of three major components: an UV/visible light source, photo curable materials which are specially functionalized liquid monomer/pre polymer(s) and photo initiator and/ photo sensitizer. Light generate a polymerization reaction which involves free radical, catatonic or anionic mechanisms depending on the functional groups of the monomer/pre polymer and initiators or catalyst used. Among the photo curable materials that have been studied, acrylate functional pre polymers are the most widely used. Chemical reaction of the functionalized liquid monomer/pre polymer results in transition from liquid to coating film. Oxygen has the ability to slow down and/or reduce the extent of curing in some acrylate- functionalized silicone systems by quenching excited states and scavenging free radicals from the initiators and the growing polymer network. Photo curable systems are usually purged with nitrogen to reduce this complication.

Camphorquinone is the most frequently used photo sensitizer in visible light curing in dental sciences. It is widely used with acrylates in medically relevant applications. Initiator or initiator sensitizer systems such as 1) benzoin methyl ether, 2) Camphorquinone and N, N-dimethyl amino ethyl methacrylate .3) Camphorquinone and 1-phenyl -1, 2-propanedione and 4) Camphorquinone and ethy-4-dimethyl amino benzoate are widely used in medical and dental applications.³⁴Savage and Clevenger used water-soluble photo curable polymer systems for coating pharmaceuticals dosage forms with visible or ultraviolet light However, their process involved depositing the coating of hydroxyethyl methacrylate by an aqueous-based process prior to photo curing .35 Solvent less photo curing was first investigated as a pharmaceutical coating technique by Wang and Bogner who used UV light to cure derivatized silicone polymer films on nonpareil beads in small scale coating equipment. The photo cured silicone films formed a complete and almost perfect barrier to drug diffusion. Such that drug release depended on defects or weak points in the coating. Later, Bose and Bogner extended the work to produce functional photo curable coating by incorporating various powdered pore-forming agent to the liquid pre polymer and then curing it with UV light. In the method developed by Bose and Bogner, the coating time was very short. In laboratory scale coating equipment, nitrogen was flushed to remove oxygen from the system. The liquid photo curable pre polymer was introduced onto a bed of cascading non-pareils. Once this oily material was distributed onto the beads, a powdered pore-forming agent was dusted onto the pre polymer. The liquid coating was exposed to ultraviolet/visible light to produce one cross linked layer. The process was reheated to coat with 3-6 layers. In a small scale coating equipment, 8 minutes was required for formation at each layer for UV curable film coating. The number of layers was varied in order to obtain desire released properties. When exposed to dissolution media, the powder in the coating dissolved and created pores through which core compounds were release in either an immediate or sustained profile. The release properties were altered by changing the type and amount of pore-forming agents and the number of coating layers.³⁵ While the UV photo curable coating of siloxane based system was shown to be feasible, the toxicity profiles of the siloxanes used is unknown at this time. An alternative coating materials is being investigated for pharmaceutical use. Tetraethyleneglycol dimethacrylate (TEGDMA) and bisphenol A-glycidyl methacrylate (Bis-GMA) are two photo curable 36 monomers and are extensively used in dental composites as their toxicity is very low. Their mechanical strength properties depend on the filter content in the film. The photo curable monomers, photo initiators and photo-sensitizers that are generally used in dental sciences with visible light curing show promise for use in solvent less pharmaceutical coating. When evaluating the process and formulation factors of the photo curing process as described by Base and Bogner, the robustness of the UV cured siloxane material and visible light cured methacrylate material for pharmaceutical use were determined. The ratio of the amount of solid powder (S) pore-forming agent to volume of liquids (L) pre polymer/monomer (i.e. the S/L- ratio) was found to be the most significant parameter affecting coating efficiency and performance.

In addition, particle-size of the pore-forming agent played important role in the coating quality and process efficiency. The concentration of photo initiator and/or photo sensitizer, light intensity and exposure timer of light were found to allow the formation of the coating. In the optimized formulation, 60-70% conversion of pre polymer to polymer or monomer to polymer is obtained. This percent conversion is higher than reported in the literature for similar nonpharmaceutical photo curing applications. ^36-37Finally, the coatings (UV and visible light curable) were shown to be photo stable (according to ICH guideline) and could withstand normal handling stress. These methods represent physical approaches to achieve solvent-free coating. In some cases, the design space for these solvent less coating techniques is limited. However, ‘photo curing' provides a chemical approach to the formation of a coating at, or below, room temperature with an extremely rapid rate. Photo curing is a common solvent-free technique used in the paint, adhesive, and photo-imaging industries. It has a wide application in the dental and medical fields. Composite dental filling, preventive treatment for caries, the assembly of medical devices, and wound dressing are examples of medical and dental applications of photo curing. Although photo curing is used widely in the medical, dental, and chemical industries, it has few, if any, commercial applications in pharmaceutical manufacturing.

Photo curing systems generally consist of three major components: an ultraviolet (UV) or visible-light source specially functionalized liquid pre polymers or monomers, and an initiator. Photo curing involves a polymerization reaction which occurs by free-radical, cationic, or anionic mechanisms, depending on the functional groups of the pre polymers or monomers, and initiators or catalyst used. Among the photo curable materials that have been studied, acryl ate-functional pre polymers and monomers are the most widely used. Chemical reaction of the functionalized liquid pre polymers or monomers results in a transition from liquid to solid film. Oxygen can retard and/or reduce the extent of curing in some acrylate functionalized silicone systems by quenching excited states and scavenging free radicals from the initiator and the growing polymer network. Thus, photo curable systems are usually purged with nitrogen to reduce this complication. These prototype formulations for the solvent less, photo curable coating resulted in high yield, coating efficiency and good coating uniformity and provide pharmaceutical functionality including but not limited to immediate and sustained release. Moreover, this technique provide the flexibility to modified the release by changing the pore forming material, number of layers of coating as well as by mixing difference coating made by different pore forming agents. The processing time was short.

The solvent less coating techniques can overcome obvious disadvantages of aqueous and organic solvent based coating systems. Those pollution-free techniques are new compared to the traditional techniques. Further modification will be necessary to obtain optimized coatings. However, these techniques can potentially transform pharmaceuticals coating. At last comparisons of all solventless coating is depicted in Table 1.

3. SUMMARY AND CONCLUSION:

Over the last 75 years, coating techniques have improved greatly. However, the use of solvents in most matrix system, requires long processing times and solvent-removal systems. Solvent less process can bring significant advantages to the pharmaceutical industry, as solvent less system do not require any solvent recovery systems, and thus no explosion hazard or solvent exposure to production personnel or no residual solvent in the product. It also reduces time to coat. However, each solvent less process discussed above brings its own limitations. Further modifications will be necessary to improve these potentially useful processes.

In Table 1, all processes and their details (solvent, heat, equipment and method of preparation) are described. Most of the processes did not require any aid from solvents except for supercritical fluid spray coating and dry powder coating. On the other hand, some of the processes like hot melt coating, electrostatic spray powder and dry powder coating required heat to form the coating. Compression coating is the solvent less process that been in use in the pharmaceutical industry longest. This process is in use as a commercial process. The process is relatively slow when compared to other solvent less processes. The coatings are thick and not particularly well-suited for immediate release.

The hot-melt process is promising in terms of reduced processing time. The use of high heat for coating limits the use of hot-melt coating for many drug or active ingredient. The preparation of molten coating liquid and maintaining its temperature until the molten liquid is slowly sprayed onto the dosage forms is a challenge. However, the solid dispersion hot-melt coating has the potential to overcome this challenge.

Supercritical fluid spray coating can be performed near room temperature. Of all the methods reviewed, supercritical fluid spray coating appears to be best suited for coating very fine particle. Supercritical carbon dioxide is inexpensive. However, the core must be insoluble in supercritical fluid while the coating should be soluble. These two requirements will most likely limit solvent less supercritical coating.

Electrostatic spray powder coating is currently being investigated for use in the pharmaceutical industry, most notably by Phoqus. It involves unique equipment to charge the coating particles. The coating quality is reported to be an excellent and the processing time short.

However, until there is more information in the peer-reviewed literature of the product on the market, it will be difficult to objectively evaluate this potentially useful method.

Dry powder coating shows promise as a solvent less process. It is useful to coat water sensitive drugs. However, some of the process may require some solvent to promote film formation. Moreover, this process requires high temperatures and annealing or approximately 24 hours. Thus, this process is not suitable for heat –sensitive drugs.

Photo curing has wide applications in the chemical acid medical field, but has not been widely explored for pharmaceutical applications. Photo curing is a process which is free from thermal stress. A limitation of this method lies in the fact that some drugs are light sensitive. In addition, the UV-curable pre-polymers in this system are not GRAS listed. A solvent less photo curable coating system using medically used monomers and photo initiators which shows promise has been developed.

The solvent less coating techniques can overcome the obvious disadvantages of aqueous and organic solvent based coating systems. These pollution free techniques are new compared to obtain optimized coating. However, these techniques can potentially transform pharmaceutical coating.

4. ABBREVIATION:

1. pH: Negative log of [H+]

2. μm: Micro meter

3. gm: Gram

4. cm: Centimeter

5. SCF: Supercritical fluids

6. PC: Critical pressure

7. TC: Critical temperature

8. Ωm: Ohm meter

9. ESEM: Environmental scanning electron microscopy

10. Rpm: Round per minute

11. MAIC: Magnetically Assisted Impaction Coater

12. RFBC: Rotating Fluidized Bed Outer

13. TEGDMA: Tetraethyleneglycol dimethacrylate

14. Bis-GMA: Bisphenol A-glycidyl methacrylate

15. UV: Ultra violet

16. ICH: International conference harmonization

17. IR: Infrared

18. FDA: Food and drug administrative

19. THF: Tetrahrdofuran

20. DMAC: Dimethylacetamide

21. LED: Light emitting diode

22. Psi: Per square inch

23. kHz: Kilohertz

24. DES: Drug eluting stent

25. GRAS: Generally recognized as safe

5. ACKNOWLEDGEMENT

My heartily thanks to my beloved sir, Mr. Nrupal R. Modi, R and D Pharmacist of Sidmak lab (I) Pvt. Ltd. Valsad for providing his valuable guidance and support during my review work.

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Received on 12.02.2011 Modified on 10.03.2011

Research J. Pharm. and Tech. 4(6): June 2011; Page 851-860

Type of coating	Solvent	Heat	Equipment	Method of coating involves
Compression coating	No	No	Tablet press	Pressure
Hot melt coating	Sometime small quantities of solvent are added to reduce viscosity of coating material.	Yes	Top spray fluidized bed coater, conventional spray coater, rotary spray coater.	Heat
Supercritical fluid coating	Sometime small quantities of organic solvents are added to aid in solubility of coating material	Mild to moderate depending upon the required solvent powder.	High pressure vessels	Supercritical fluid
Electrostatic spray powder coating	No	Yes	Electrostatic powder coater with photo receptor drum	Electric charge and heat
Photo curing coating	No	No	Pan coater	Light