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Coating
By Dr. Robert O. (Bill) Williams and Ms. Vorapann Mahaguna
- Section
- Coating........................................................................................................................................... Table of Contents
- Table of Contents.......................................................................................................................
- General Introduction ..................................................................................................................
- Evolution of the Coating Process ..........................................................................................
- Purpose of Tablet Coating .....................................................................................................
- Types of Pharmaceutical Coating Processes ................................................................................
- Sugar Coating ............................................................................................................................
- Overview ................................................................................................................................
- Raw Materials ............................................................................................................................
- Coating Formers ....................................................................................................................
- Sucrose, Other Sugars, and Sugar Alcohols.....................................................................
- Binders ...............................................................................................................................
- Fillers..................................................................................................................................
- Colorants................................................................................................................................
- Flavors....................................................................................................................................
- Lubricants, Glidants and Antiadherants ................................................................................
- Smoothing Agents .................................................................................................................
- Polishing Agents ....................................................................................................................
- Suspension Stabilizers...........................................................................................................
- Processing Steps ....................................................................................................................... - Plain Sugar Coating ........................................................................................................... - Two-Component Coating or Lamination Process ............................................................. - Hot Sugar Coating .............................................................................................................
- Sealing (Protective Coating)...................................................................................................
- Subcoating .............................................................................................................................
- Liquid/Powder (Traditional Method)...................................................................................
- Suspension Method...........................................................................................................
- Smoothing..............................................................................................................................
- Coloring and Finishing ...........................................................................................................
- Polishing.................................................................................................................................
- Film Coating ...................................................................................................................................
- Advantages of Film Coating ......................................................................................................
- Typical Film Coating Formulation Components.........................................................................
- Polymers ................................................................................................................................
- Plasticizers .............................................................................................................................
- Polyols: Water Miscible......................................................................................................
- Organic Esters ...................................................................................................................
- Oils/Glycerides: Water Insoluble......................................................................................
- Pigments or Opacifiers ........................................................................................................
- Vehicles or Solvents.............................................................................................................
- Other Components ..............................................................................................................
- Types of Film coating ...................................................................................................................
- Organic Solvent Systems.........................................................................................................
- Overview ..............................................................................................................................
- Disadvantages .....................................................................................................................
- Aqueous Coating Systems ......................................................................................................
- Overview ..............................................................................................................................
- Immediate Release Coatings ...................................................................................................
- Pharmaceutical Applications ...............................................................................................
- Polymer Used for Conventional Film Coating .....................................................................
- Cellulose Ethers ...................................................................................................................
- Cellulosic Based Coatings ...................................................................................................
- Acrylic Polymers ..................................................................................................................
- Modified Release Film Coatings ..............................................................................................
- Polymers Used for Enteric Release Film Coating................................................................
- Cellulose Acetate Phthalate (CAP)...................................................................................
- Polyvinyl Acetate Phthalate (PVAP) .................................................................................
- Shellac .............................................................................................................................
- Methacrylic Acid Copolymers..........................................................................................
- Cellulose Acetate Trimellitate (CAT) .................................................................................
- Hydroxypropyl Methycellulose Phthalate (HPMCP) ........................................................
- Sustained Released Coatings..................................................................................................
- Polymers Used for Sustained Release Film Coating...........................................................
- Ethycellulose (EC) ............................................................................................................
- Methacrylate Ester Copolymers ......................................................................................
- Conclusion ...................................................................................................................................
- References ...................................................................................................................................
b). Binders:
The function of a binder is to increase the strength and elasticity of the coating by forming bonds and thus a coherent matrix. Examples of binders include polyvinyl acetate (PVA), polyvinyl pyrrolidone (PVP), acacia gum, gelatin, agar-agar, sodium alginate, carboxymethyl starch, dextrins, cellulose ethers, and starches.
c). Fillers:
A filler builds up the structure and adds mass to the coatings. Examples of fillers include kaolin, dextrin, precipitated calcium carbon- ate, powdered acacia, corn starch, talc and calcium sulfate.
Colorants
Flavors
Lubricants, Glidants, and Antiadherents
A colorant adds color to the coatings and covers imperfections which may appear in the tablet core. Examples of colorants include pigments (titanium dioxide or other inorganic coloring agents), dyes, and lakes.
Flavoring agents are used to improve and enhance the acceptability and palatability of the dosage form in order to maximize patient compliance. Examples include naturally and synthetically derived agents (cinnamon, fruit flavors, etc.).
These materials reduce friction between the individual sugar-coated cores and thus prevent dust formation during the drying step. Examples of lubricants, glidants and antiadherents include talc and colloidal silicon dioxide.
Types of Pharmaceutical Coating Processes
Overview
Coating Formers
Sugar Coating
Raw Materials
The sugar coat was developed primarily from technologies employed in the confectionery industry, which have been optimized over the years, and are still widely used today. Development of Brufen®^ by Boots (United Kingdom) was a major milestone in the develop- ment of sugar coating technology through the use of spray sugar coating. Sugar-coating processes result in nearly doubling the weight of the original tablet core; therefore batch sizes are calculated based on the finished tablet weight after coating. However, the use of modern spray- ing systems has resulted in a dramatic reduction in the final product weight. Moreover, the airflow velocity and processing temperature are very critical in achieving a pharmaceutically elegant finished product.^2
Coating formers, which form the coating due to their mass and cohesion, typically consist of sugars, binders and fillers.
a). Sucrose, other sugars, and sugar alcohols:
Sucrose is used primarily as a coating material in concentrations ranging between 50-60%, since syrups with a sugar content of less than 65% are stable at room temperature without crystallization occurring. Aqueous solubility of sucrose is increased by the use of heat.
Due to major concerns in using the products in diabetic patients, and the fact that they cause dental caries, other sugars and sugar alcohols are used to replace sucrose. These include glucose, lactose, maltitol, mannitol, isomalt, sorbitol, xylitol, and sugar mixtures such as invert sugar and starch sugars.
Smoothing Agents
Polishing Agents
Suspension Stabilizers
Sealing (Protective Coating)
Subcoating
The function of a smoothing agent is to smooth out the surface of the coatings by lubricating and binding the fines that may be created during the coating process. An example of a smoothing agent is a combination of syrup and acacia gum.
A polishing agent enhances the reflectivity and intensity of the color of the coatings. It can either be incorporated into the smoothing agent or applied onto the smooth surfaces of the coated product. Examples of polishing agents include beeswax and carnauba wax.
A suspension stabilizer prevents phase separation or sedimentation of the coating suspension while it is being applied during the coating process. Examples of suspension stabilizers used include surface active agents (emulsifying agents, bentonite) or thickening agents. However, the limitation of thickening agents is based on the viscosity of the coating suspension.
Processing Steps
Sugar coating layers are built up during process- ing by repetition of the application, distribution, and drying steps. Three types of sugar coating techniques are commonly used:
a). Plain sugar coating (application of syrup at room temperature):
This coating technique includes 3 steps: application of coating formulation onto the cores, distribution of formulation on the core surfaces, and drying to increase the strength of each coating layer. However, the time required for distribution and drying is critical to obtain a smooth even coating.
b). Two-component coating or lamination process (application of a syrup or binder solution first in a slight excess amount, and then dusting with a powder to bind the excess solution):
Compared to the plain sugar coating technique, the two-component coating is a more complicated technique involving two steps of application of solution and powder. In order to obtain a high volume increase within a short period of time, adjustment must be made between powder and liquid quantities and performed by skillful operators.
c). Hot sugar coating (application of heated syrup):
For the hot sugar coating technique, syrup is heated above room temperature to reduce the viscosity of the syrup. Therefore, a higher sugar content formulation can be used, with gelatin as a binder, and less water has to be removed during the drying process. However, the temperature used during the process must be controlled since the gelatin is prone to hydrolysis at temperatures above 60° C. Attempts to prevent sugar crystallization during processing may make this technique more complicated and more expensive since all equipment parts used must be insulated and heated. 1
The main purpose of the sealing layer application is to protect the cores from subsequent damage, especially for water-sensitive cores in which an additional protective film often is applied prior to subcoating, and for gastro-sensitive cores in which gastro-resistant layers are incorporated. In some cases, if the film layers are poor primers, a binder layer must be applied in order to ensure adhesion of the subsequent coatings. Seal coating materials include shellac, cellulose acetate phthalate (CAP), zein, and synthetic resins.
The main purpose of applying the subcoating layer is to facilitate rounding of the sharp edges of the cores. There are two techniques for the subcoating application:
Polishing
Example of pigmented syrups:^7
Ingredients % Color pigment 0-3. Acacia 1. Titanium dioxide 0-3. Sucrose 61. Water 33.
The main purpose of polishing is to obtain a transparent, glossy and reflective coating with no opalescence or cloudiness remaining from previous steps. Therefore, the polishing step can intensify the colors and eliminate white reflections visible from the tablet. Additionally, it makes the product more stable upon storage. The polishing step can be performed by incorporating waxes, fats, or lacquers into the final coating layer.
In some products, printing on the high-gloss surface is performed to provide unique product identification.
Example of polishing and finishing solutions:^8
Ingredients % Carnauba wax 0. Paraffin wax 0. PEG 0. Trichloroethylene 99.
In some cases, uniform coating layers may be applied using a combination of ingredients with different functions, as a single syrup formulation. This process is a more economical and practical way to coat different core shapes, and permits the use of pigments to provide a uniform color. In fact, uniform coloring can be obtained with only a few coating layers. A typical single syrup formulation for coating is;^1
Ingredients % Sucrose 58- Gelatin or acacia gum 0.5- Polyethylene glycol (PEG) or PEG fatty acid ester 1- Colloidal silica 0.5- Titanium dioxide 0.05-0. Dyes, pigments qs Water qs to 100.
is needed to complete the coloring step. A white pigment, titanium dioxide, is typically used in the coloring layers.
Ideal properties for polymers used in film coating include:
a) solubility in a wide range of solvent systems in order to allow flexibility in formulations b) ability to produce films with excellent mechanical properties c) stability against light, oxygen, hydrolysis d) low toxicity e) optimum dissolution in the gastrointestinal tract.^5
Coating polymers can be categorized into two types:
a) non-functional or conventional film coating polymers, which can be used as a coating to improve the appearance, improve the handling, and prevent dusting of dosage forms; b) functional coating polymers, which can be used to modify the pharmaceutical function of the dosage forms, especially with enteric or modified release coatings.
Characteristics of concern for polymers used during the coating process include solubility, solution viscosity, film permeability, mechanical properties (i.e. tensile strength, elastic modulus, work of failure, strain), and so on. For the coating application, the polymer frequently is dissolved in a suitable solvent, such as water or a non- aqueous organic solvent. However, some water- insoluble polymers are available commercially as an aqueous dispersion, which permits aqueous film coating, and are particularly useful for modified release coating applications. Based on the method of preparation, polymer dispersions can be classified into two types: true latexes and pseudolatexes.
Advantages of Film Coating
Typical Film Coating Formulation
Components
Polymers
Film Coating
A film coating is defined as a thin and uniform polymer based coat of about 20 to 100 m in thickness, which is applied to the surface of substrates such as tablets, granules, powder, capsules, multiparticulates or pellets.^5 Compared to sugar coating, film coating provides more flexibility with the ability to coat a variety of substrates, other than just com- pressed tablets. Although the first tablet film coating appeared in 1930, the first commercially available film coated tablet was not produced until 1954 by Abbott Laboratories using a fluidized bed coating column with a Wurster insert and an organic solvent system.^2
- Enhance the elegance and glossy appearance of the dosage form
- Obtain legible logo and product identification after coating. Product information can be engraved on the tablet core
- Improve mechanical integrity and resistance of the dosage form upon handling and shipping from manufacturing site to patients
- Modify the pharmaceutical function of the dosage form, especially for enteric or modified release coating
- Increase flexibility in types of formulations coated and processing equipment required
- Minimal weight increase (about 2-3 % of tablet core weight) compared to a sizeable increase when using a sugar coating (doubling the weight of tablet core)
- Significantly reduced processing time, with increased process efficiency and output
- Minimize dusting2,
Polymers are flexible linear macromolecules having a molecular weight range between 10, and several million daltons. Polymers consist of a number of repeating units in the structure.
c). Oils/glycerides: water insoluble Castor oil Distilled acetylated monoglycerides (AMG) Fractionated coconut oil
Pigments or Opacifiers
Vehicles or Solvents
Pigments or opacifiers are used in film coating to:
- Enable product identification
- Protect the active ingredient against light by optimizing the opacifying properties of pigments
- Modify the gas permeability of a film
- Decrease the risk of counterfeiting the product
However, the use of pigments and opacifiers could be omitted from the formulation if a clear coating is required.
Solvents and vehicles play an important role in carrying the coating materials to the surface of the product core. They include water, alcohols, ketones, esters, and chlorinated hydrocarbons. The type of vehicle or solvent used during the coating process can be used to classify the type of film coating into an organic film coating (non- aqueous film coating), or an aqueous film coat- ing. These types of coatings will be discussed in later sections. Necessarily, the solvent has to interact intimately with the selected polymer in order to allow both film adhesion and mechanical strength to be optimized.
Other Components
Other components are used occasionally in low concentrations for specific formulations such as processing auxiliary substances or drug release modifiers. Flavors may be included in some oral formulations to make them more palatable. Adhesion enhancers (e.g. saccharides such as polydextrose, maltodextrin, and lactose) are used to increase the adhesion of cellulosic systems to the substrate as well as improve stability towards light, for unstable colors).^11
Surfactants or dissolution enhancers (i.e. xanthan gum with Eudragit®^ NE30D coated theophylline granules)^12 , as well as pore-forming agents (e.g. sucrose or sodium chloride with ethylcellulose-coated salicylic acid tablets)^13 can be used to enhance the dissolution of the final dosage forms. Anti-tacking agents/glidants (e.g. talc, magnesium stearate, kaolin, glyceryl monostearate) typically are used to reduce sticking during film formation. Additionally, some film coatings may contain an active ingredient, such as preservative (i.e. sorbic acid), antifoaming agents (i.e. dimethylpolysiloxane), stabilizing agents, or waxes.
Types of Film Coating
Organic Solvent Systems
Aqueous Coating Systems
Immediate Release Coatings
Polymers Used for Conventional
Film Coating
Overview
Disadvantages
Pharmaceutical Applications
Cellulose Ethers
Overview
Due to environmental, safety and health-related concerns, the use of organic-based coatings has decreased recently with the advent of aqueous- based coatings. Additionally, the introduction of newly-developed coating equipment and the development of new film coating raw materials which can be applied in aqueous media, as solutions or dispersions, foster a more practical operation with aqueous-based coating systems. Similarly, some newer forms of older polymers previously used for organic-based systems have been transformed by manufacturers into different forms that allow the formulators to choose a more suitable form for aqueous-based coatings.
- Environmental, fire and toxicity hazards
- Requires flameproof equipment to reduce hazardous working environment for the operator.
- Residual solvent from coating process.
- Requires solvent recovery systems.
- High cost of the process due to the required use of special safety equipment with organic solvents.
Recently, the trend in coating has favored aqueous film coating since organic solvent systems require a high capital outlay in equipment and solvents, the limitation of chlorinated hydrocarbons use by regulatory authorities, the environmental concern for pollution, and the development of perforated coating pans and spraying systems, which allow application of more sophisticated coating materials.
- Mask the unpleasant taste and odor of drug;
- Protect the active drug substance from exposure to light, moisture and atmospheric oxygen;
- Enhance the elegance and glossy appearance of the dosage form;
- Improve mechanical integrity of the dosage forms upon handling from manufacturing site to patients;
- Prevent dosage forms from dusting.
Cellulose ethers are a major group of polymers used in the film coating process. Method of preparation, type of substitution groups, degree of substitution (DS), molar substitution (MS), polymer chain length, size and extent of branch- ing have significant effects on polymer properties with respect to their solubility, thermal gel point, molecular weight and solution viscosity. There are four types of cellulose ethers specified in the USP17: HPMC 2910, HPMC 2208, HPMC 2906, and HPMC 1828. The number designa- tions define the methoxy/hydroxypropoxy ranges of the respective HPMC.
Commonly used cellulose ethers for film coating and their properties are:
Hydroxypropyl methylcellulose (HPMC) HPMC is soluble in both aqueous and organic solvent. It provides aqueously clear soluble films. Color coating with addition of pigment is possible.
Hydroxypropyl cellulose (HPC) HPC is soluble in both aqueous and alcoholic solvents. HPC films tend to be tacky and weak, and are usually used in
CAP Coating Formulation
Ingredients %w/w CAP 5. Glycerol triacetate 1. Isopropyl alcohol 17. Dichloromethane 68. Water 8.
CAP is also available as a 30% solids dispersion (latex) as Aquacoat®^ CPD from FMC BioPolymer. Aquacoat CPD is employed as an aqueous enteric coating for tablets, beads, both hard and soft gelatin capsules and in wet granulation.
CAP Latex Coating Formulation
Ingredients Suspension (g) Solids (g) Aquacoat®^ CPD 100.0 30.0 (76.9%) DEP 9.0 9.0 (23.1%) Purified water 151.0 ----- 260.0 39.0 (100%)
Polyvinyl Acetate Phthalate (PVAP)
Methacrylic Acid Copolymers
Shellac
The USP has specified a total phthalate content Cellulose Acetate Trimellitate (CAT)
in PVAP of between 55-62 %w/w. The final poly- mer composition is also controlled by a viscosity specification and a limit of 5% water content. Compared to CAP, PVAP is less susceptible to hydrolysis, which minimizes or limits the content of free phthalic acid and other free acids. PVAP is soluble in methanol, methanol/methylene chloride, 95% ethanol, ethanol/water (85:15).
This naturally occurring polymer is produced from a purified resinous secretion of the insect Laccifer lacca. It can be modified to meet certain specifications. In the past shellac was used widely in a variety of applications, especially as a sealer coat prior to sugar coating, enteric coat- ing, or modified release coating. Due to its many drawbacks including inconsistent supply, varia- tion in quality (common with a natural product), and stability problems associated with an increase in disintegration and dissolution times upon storage, shellac is not often used
in coating today. Shellac is insoluble in water, but soluble in alkaline media, and moderately soluble in warm ethanol.
This group of polymers contains free carboxylic acid groups, and therefore can be used for enteric coating purposes by forming salts with alkalis. Methacrylic acid copolymers are soluble at pH values greater than 5.5.
Additives:
- Plasticizer is recommended.
- Pigments and opacifiers to reduce sticky nature of the polymers since they are likely to bind with large quantities of pigments.
- Polyethylene glycols (PEG) to provide a glossy appearance to the final product and stabilize the water-dispersible form (e.g. Eudragit®^ L30D).
The methacrylic acid copolymers are available as various grades of Eudragit®^ by Röhm Pharma.
CAT polymer has similar properties to CAP polymer, especially solubility. In addition, CAT has an additional carboxylic acid group on the aromatic ring and dissolves at a pH of 5.5.^14 To obtain the best enteric coating results from aqueous processing, ammoniated solutions of CAT in water are recommended.
Additives:
- Recommended plasticizers: triacetin, acetylated monoglyceride, diethyl phthalate (DEP)
CAT is available as a white powder from Eastman Chemical Co.
HPMCP characteristics, particularly at the pH where dissolution occurs, are determined by the degree of substitution of the three substituent groups (i.e. methoxy, hydroxypropoxy, and car- boxybenzoyl). Basically, this polymer is prepared from phthalic acid-treated HPMC. There are two types of substitution specified in the USP: HPMCP 200731 (20%w/w methoxy, 7%w/w hydroxypropoxy, and 31%w/w carboxybenzoyl) HPMCP 220824 (22%w/w methoxy, 8%w/w hydroxypropoxy, and 24%w/w carboxybenzoyl).
Solubility:
- insoluble in water
- soluble in aqueous alkaline media, acetone/water (95:5), acetone/methanol (1:1), acetone/-ethanol (1:1), or methylene chloride/ethanol (1:1)
Additives:
- Recommended plasticizers include triacetin, acetylated monoglyceride and DEP.
HPMCP is commercially available from Eastman Chemical Co. and Shin-Etsu.
Ethylcellulose Latex Coating Formulation
Ingredients Suspension (g) Solids (g) Aquacoat®^ ECD 100.0 30.0 (80.6%) DBS 7.2 7.2 (19.4%) Water 16.8 ------ 124.0 37.2 (100.%)
Sustained Released Coatings
Aqueous Dispersion
Ethycellulose (EC)
Polymers Used for Sustained Release
Film Coating
Ethylcellulose is insoluble in water. It was used extensively in organic solvent-based coatings in combination with other water soluble polymers, especially HPMC or polyethylene glycols (PEG), in order to provide a more hydrophilic nature to the EC film and promote drug diffusion through pores or channels. It provides additional gloss and shine to the tablet surface and optimizes film toughness to minimize surface imperfections caused by handling. It is preferred for modified release coatings because it is odorless, tasteless, and
Hydroxypropyl Methylcellulose Phthalate
(HPMCP)
has a high degree of stability to light and heat under normal storage conditions. The USP specifies an ethoxy content between 44.0-51. %w/w. The water dispersible form of EC provides significant advantages and makes processing of water insoluble polymers from an aqueous-based system possible.
Some commercially available products:
- Powder, Aqualon®, Aqualon Division, Hercules Inc. and Dow Chemical Co.
It is available in a wide range of viscosity and substitution types for a wide range of applications.
Aquacoat®^ ECD is a 30% by weight aqueous dispersion (latex) of ethylcellulose polymer. The dispersion contains ethylcellulose (polymer), cetyl alcohol (stablizer) and sodium lauryl sulfate (stabilizer/emulsifier). A plasticizer (e.g., DBS, DEP, Triacetin, Myvacet and TEC) is recom- mended. Aquacoat ECD, in addition to being used for sustained release film coating, can also be used for taste-masking and as a moisture barrier/sealant. The dispersion, in combination with water soluble polymers such as HPMC, can also be employed to produce elegant film coated tablets having all the positive attributes of aqueous film-coated tablets.
