Pulmonary Drug Delivery/Manufacture of Aerosol

How are Aerosols manufactured?

A.The manufacture of aerosol products takes place in two stages:

1.Manufacture of the concentrate and

2.Filling of the propellant

The aerosol concentrate consists of drug or combination of drugs, solvents, antioxidants and surfactants formulated as solution, suspension or foam systems. The aerosol concentrate is first prepared and filled into the container. The propellant is then filled into the container. Therefore, part of the manufacturing operation takes place during the filling operation which requires special quality control measures to ensure that both concentrate and propellant are brought together in the proper proportion. Filling operation is a unique step specific for aerosol products.

The equipments used for manufacture of aerosols can be classified into two classes:

1.Equipments used for compounding of liquids, suspensions, emulsions, creams and ointments. 2.Specialized equipments capable of handling and packaging materials at relatively low temperatures (above -40º F) or under high pressure.

Firstly, the aerosol concentrate is prepared according to the generally accepted procedure and a sample tested. Then it is filled into the container with or without the propellant. Lastly, the propellant is filled into the container. Three methods have been developed for filling of aerosol products:

1.Cold filling 2.Pressure filling 3.Compressed gas filling

Cold filling method:

The principle of cold filling method requires the chilling of all components including concentrate and propellant to a temperature of -30 to -40 º F. The propellant liquefies when chilled. First, the product concentrate is chilled and filled into already chilled container followed by the chilled liquefied propellant.

Process

Single head or multiple head rotary unit capable of vacuum crimping up to 120 can / min are available. The rotary unit requires air pressure (90 to 120 lbs / inch2) and vacuum.

1.The product is chilled to -30 ° to -40 ° C. 2.Propellant is also chilled to -30 ° to -40 ° C. The propellant is added to the chilled product in one or two stages depending on the amount. 3.A valve is placed either manually or automatically depending on the production rate required. The air is purged after which the valve is crimped in place ( about 24 inch of mercury and then seal the valve ) 4.The container passes through a heated water bath in which the contents of the container are heated to 130 º F to test for leaks and strength of the container. 5.The container is air dried, spray – tested, capped and labeled.

Apparatus for cold filling process

FIG 9:

Advantages

1.Easy process

Disadvantages

1.Chilling of the product, container and propellant is required. Aqueous products, emulsions and those products adversely affected by cold temperature cannot be filled by this method. This method is restricted to non-aqueous product and those products not affected by low temperature in the range of -40º F 2.Loss of propellant during air evacuation.

The cold filling aerosol line consists of: 1.Un-scrambler 2.Air-cleaner 3.Concentrate filler (capable of being chilled) 4.Propellant filler 5.Valve placer 6.Valve purger 7.Valve crimper 8.Heated water-bath 9.Labeler 10.Coder and packaging table

Pressure Filling Process

Pressure filling is carried out at R.T. under high pressure. The apparatus consists of a pressure burette capable of metering small volumes of liquefied gas under pressure into an aerosol container. The propellant is added through the inlet valve located at the bottom or top of the burette. Trapped air is allowed to escape through the upper valve. The desired amount of propellant is allowed to flow through the aerosol valve into the container under its own vapor pressure. When the pressure is equalized between the burette and the container (thus happens with low pressure propellant), the propellant stops flowing. To help in adding additional propellant, a hose leading to a cylinder of nitrogen or compressed is attached to the upper valve and the added nitrogen pressure causes the propellant to flow.

Process

1.The concentrate is added to the container at room temperature the valve is crimped in place, before crimping air in the container is purged out. 2.The propellant is added through the valve or ‘under the cap’. Since the valve contains extremely small openings (0.018 inch to 0.030inch) this step is slow and limits production. 3.Rotary filling machines and newer filling heads have developed, which allow propellant to be added around or through the valve stem and thus the speed has been increased. 4.After adding the propellant, the container passes through a heated water bath in which the contents of the container are heated to 130ºF to test for leaks and strength of container. 5.The container is air-dried, spray tested, capped and labeled.

Advantages

1.It is the preferred method because some solutions, emulsions, suspensions and other preparations cannot be chilled. 2.Lesser danger of contamination of product with the moisture 3.Less propellant is lost 4.With ‘under the cap’ filling process, higher production speed can be achieved. 5.No refrigeration is required, can be carried out at RT

Disadvantages

Incase of certain types of metering valves, filling can be done only by cold filling

Typical pressure filling aerosol line consists of: 1.Un-scrambler 2.Air cleaner 3.Concentrate filler (capable of being chilled) 4.Valve placer 5.Valve plunger 6.Valve crimper 7.Pressure filler 8.Heated water-bath 9.Labeler 10.Coder and packaging table

Where ‘under the cap’ filling is used, the purger, vacuum crimper and pressure filler are replaced with a single unit.

Compressed Gas Filling

Compressed gases are present under high pressure in cylinders. These cylinders are fitted with a pressure reducing valve and a delivery gauge. The delivery gauge in turn fitted with flexible hose capable of withstanding about 150 lbs per square inch gauge pressure and a filling head.

Process

1.The concentrate is placed in the container 2.The valve is crimped in place 3.Air is evacuated by means of vacuum pump 4.The filling head is inserted into the valve opening, valve depressed and gas is allowed to flow into the container. 5.When the pressure inside the container is equal to the delivering pressure, the gas stops flowing. For those products requiring an increased amount of gas or those in which the solubility of gas in the product is necessary, carbon dioxide and nitrous oxide can be used. To obtain maximum solubility of the gas in the product, the container is shaken manually during and after the filling operation by mechanical shakers.

Advantages

1.Easy process 2.Can be carried out at RT

Disadvantages

Compressed gas is used as a propellant in topical preparations and not used in oral inhalation products used for pulmonary delivery.

Effervescent tablet

As per revised definition proposed to US FDA, Effervescent tablet is a tablet intended to be dissolved or dispersed in water before administration.

It generally contains in addition to active ingredients, mixture of acids/acid salts (citric, tartaric, malic acid or any other suitable acid or acid anhydride) and carbonate and hydrogen carbonates (sodium, potassium or any other suitable alkali metal carbonate or hydrogen carbonate) which release carbon dioxide when mixed with water. Occasionally, active ingredient itself could act as the acid or alkali metal compound necessary for effervescent reaction.

Effervescent tablets are uncoated tablets that generally contain acid substances and carbonates or bicarbonates and which react rapidly in the presence of water by releasing carbon dioxide. They are intended to be dissolved or dispersed in water before use.

Contents [hide] 1 INTRODUCTION 1.1 Background 1.2 The Effervescent Reaction (1,3) 1.3 Active Ingredients (4) 1.3.1 1.Drugs difficult to digest or disruptive to the stomach 1.3.2 2.pH-sensitive drugs such as amino acids and antibiotics 1.3.3 3. Drugs requiring a large dose 1.4 Advantages Of Effervescent Tablets (4,5,6) 1.5 Possible Drawbacks 1.6 Applications Of Effervescent Tablets 1.7 Monographs Of Effervescent Tablets In Pharmacopeias 1.8 See also 2 REFERENCES 3 Authors

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INTRODUCTION

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Background

Effervescent mixtures have been known for over 250 years. The famous Rochelle salt (potassium sodium tartrate) dates back to 1731 in conjunction with such a mixture. In the 18th century, effervescent powders as saline cathartics were listed as “Seidlitz powders” in the official compendia.

In the 1930s, the effervescent products gained much importance with the technology of Alka Seltzer. These mixtures have been moderately popular over the years since along with medicinal activity they are attractive dosage form for the patients. Effervescent reactions have been used alternatively preparation of other dosage forms, such as suppositories (for laxative effect), vaginal suppositories (for contraceptive effect) and drug delivery system (floating system and orally disintegrating tablets) (1).

Effervescent tablet

Effervescence has also proved its utility as an oral drug delivery system in the pharmaceutical and dietary industries for decades. In Europe, effervescent dosage forms are widespread, and their use is growing in the US because they offer pharmaceutical and nutraceutical companies a way to extend their market share.

A wide range of effervescent tablets have been formulated over the years. These include dental compositions containing enzymes, contact lens cleaners, washing powder compositions, beverage sweetening tablets, chewable dentifrice, dental cleansers, surgical instrument sterilizers, analgesics and effervescent candies as well as many preparations of prescription pharmaceuticals such as antibiotics, ergotamines, digoxin, methadone and L- dopa. Preparations for veterinary use have also been developed.

Soluble effervescent tablets are prepared by compression. In addition to active ingredients, they contain mixtures of acids (like citric, tartaric, malic and fumaric acid) and carbonates like sodium, potassium bicarbonate that release carbon dioxide when dissolved in water.

Storage: Effervescent products should be stored in tightly closed containers or moisture proof packs. They should be preserved in air tight containers and protected from excessive moisture. Desiccants are usually added to the containers.

Labeling: It should be labeled that these products are not to be swallowed directly (2). The label should state that when the tablets are packaged in individual pouches, the label instructs the user not to open until time of use. The label also states that the tablets are to be dissolved in water before being taken.

Directions for use may be mentioned on the label as follows:

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The Effervescent Reaction (1,3)

Effervescence is the evolution of gas bubbles from a liquid, as the result of a chemical reaction. The most common reaction for pharmaceutical purpose is the acid base reaction between sodium bicarbonate and citric acid. Acid-base reactions between alkali metal bicarbonates and citric or tartaric acid have been used for many years to produce pharmaceutical preparations that effervesce as soon as water is added.

3NaHCO3(aq) + H3C6H5O7(aq) 3H2O+CO2 + 3Na3C6H5O7(aq)

This reaction starts in presence of water, even with small amount as catalyzing agent, and because water is one of the reaction products, it will accelerate the rate of reaction, leading to difficulty in stopping the reaction. For this reason, the whole manufacturing and storage of effervescent products is planned by minimizing the contact with water. In such systems, it is practically impossible to achieve much more than an atmospheric saturation of the solution with respect to released CO2. If the acid dissolves first, then the bulk of the reaction takes place in the saturated solution in close proximity to the undissolved bicarbonate particles. If the bicarbonate dissolves faster, the reaction essentially takes place near the surface of the undissolved acid. Such suspension systems do not favor supersaturation with respect to carbon dioxide because the particulate solids act as nuclei for bubble formation. The physical and chemical basis of the formulation depends on essentially the total dissolution of bicarbonate salts and the acids prior to formation of free acids.

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Active Ingredients (4)

There are several categories of active ingredients, which would be advantageous if formulated as effervescent tablet.

These include the following:

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1.Drugs difficult to digest or disruptive to the stomach

A classic example is calcium carbonate tablets, the most widely used form of calcium. In a conventional tablet or powder, the calcium carbonate dissolves in the acidic pH of the stomach and is carried into the digestive system for absorption. However, calcium carbonate releases carbon dioxide when it dissolves in the gastrointestinal tract, which usually produces gas in the stomach. On the other hand, as people age, they have less amount of acid in the stomach, and thus a calcium carbonate tablet may pass undissolved through the stomach.

That, in turn, may lead to constipation. However, if the calcium carbonate is taken in an effervescent formulation, the calcium dissolves in water, is readily available for the body to absorb, and there is no risk of excessive gas in the stomach or of constipation.

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2.pH-sensitive drugs such as amino acids and antibiotics

The low pH of the stomach can cause active ingredients to become denatured, lose activity, or cause them to remain inactive. Effervescent ingredients, however, can buffer the water-active solution so that the stomach pH increases (becomes less acidic) and thus prevent the degradation or inactivation of the active ingredient. This buffering effect (via carbonation) induces the stomach to empty quickly—usually within 20 min into the small intestine and results in maximum absorption of the active ingredient.

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3. Drugs requiring a large dose

A typical effervescent tablet (1 inch in diameter weighing 5 g in total weight) can include more than 2 g of water-soluble active ingredients in a single dose. If the required dose is larger than that, the sachet (powder form) is the common means of delivery

Effervescent delivery can be highly beneficial in the following treatments:

• Arthritis, inflammation and pain management

• Ulcers and gastrointestinal

• Allergies

• Osteoporosis

Drugs and drug compositions used as effervescent products

• Acetylsalicylic acid (Aspirin)

• Paracetamol (Acetaminophen)

• Ibuprofen

• Antacid preparations

• Ascorbic acid and other Vitamins

• Calcium

• Acetylcysteine, a mycolytic agent used as an antidote for paracetamol overdosage.

• Activated charcoal preparations used in the management of theophylline poisoning

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Advantages Of Effervescent Tablets (4,5,6)

1.Fast onset of action

Effervescent tablets have major advantage that the drug product is already in solution at the time it is consumed. Thus, the absorption is faster and more complete than with conventional tablet. This is particularly helpful in treating acute symptoms of pain. Faster absorption means faster onset of action, critical in treating acute symptoms such as pain. Buffered preparations with adjustable stomach pH optimize formula performance characteristics.

Effervescent drugs are delivered to the stomach at a pH that is just right for absorption. Many medications travel slowly through the gastrointestinal tract or have absorption that is hampered by food or other drugs. To achieve desired absorption levels, such drugs have to be often administered as injections or with increased dosages.

2.No need to swallow tablets

Effervescent medications are administered in liquid form so they are easy to take as compared to tablets or capsules. The number of people who cannot swallow tablets or who dislike swallowing tablets and capsules is growing. Many diseased conditions require the patient or customer to swallow several tablets at a time. The elderly, in particular, have difficulty in swallowing tablets. With an effervescent dosage form, one dose can usually be delivered in just 3 or 4 ounces of water. The amount used when someone swallows a conventional tablet or capsule.

3.Good stomach and intestinal tolerance

Effervescent tablets dissolve fully in a buffered solution. Reduced localized contact in the upper gastrointestinal tract leads to less irritation and greater tolerability. Buffering also prevents gastric acids from interacting with the drugs themselves, which can be a major cause of stomach and esophageal upsets.

4.More portability

Effervescent tablets are more easily transported than liquid medication because no water is added until it's ready to use. .

5.Improved palatability

Drugs delivered with the effervescent base, taste better than most liquids, mixtures and suspensions. Superior taste masking is achieved by limiting objectionable characteristics and complementing formulations with flavors and fragrances. Effervescent pharmaceuticals retain their flavor after lengthy storage. The effervescent tablets essentially include flavorings so they taste much better than a mixture of a non-effervescent powder in water. Moreover, they produce fizzy tablets, which may have better consumer appeal than the traditional dosage forms.

6. Superior stability

Excellent stability is inherent with effervescent formulations, particularly surpassing liquid forms.

7. More consistent response

Drugs delivered using effervescent technology have predictable and reproducible pharmacokinetic profiles that are much more consistent than tablets or capsules.

8. Incorporation of large amounts of active ingredients

In many cases, one effervescent tablet will equal to three conventional tablets in active dose amounts.

9. Accurate dosing

Researchers have shown that effervescent tablets enhance the absorption of a number of active ingredients (e.g. disulfiram and caffeine), compared to conventional formulations. This is because the carbon dioxide created by the effervescent reaction can induce enhanced active-ingredient permeability due to an alteration of the paracellular pathway. The paracellular pathway is the primary route of absorption for hydrophilic active ingredients in which the solutes diffuse into the intercellular space between epithelial cells. It is postulated that the carbon dioxide widens the intercellular space between cells, which leads to greater absorption of active ingredients (both hydrophobic and hydrophilic). The increased absorption of hydrophobic active ingredients could be due to the non-polar carbon dioxide gas molecules partition into the cell membrane, thus creating an increased hydrophobic environment, which would allow the hydrophobic active ingredients to be absorbed.

10. Improved therapeutic effect

The effervescent components aid in improving the therapeutic profiles of the active ingredients. They also help in solubilization of poorly soluble drugs.

Other Considerations:

• Convenient and easy administration than other liquid medicines to administer

• Less chance of misuse

• Ability to combine multiple active ingredients, if therapeutically appropriate

• Innovative, yet less risky than unproven technology

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Possible Drawbacks

1. Unpleasant taste of some active ingredients Some active ingredients have unpleasant taste that cannot be masked by flavors and sweeteners. This will lead to an unacceptable product.

2. Disintegration time In a tablet form, disintegration can take up to 5 min. This depends mainly on the temperature of the water and the active ingredients present.

3. Relatively expensive to produce due to large amount of more or less expensive excipients and special production facilities.

4. Larger tablets requiring special packaging materials.

5. Clear solution is preferred for administration, although a fine dispersion is now universally acceptable

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Applications Of Effervescent Tablets

1.Effervescence induces penetration enhancement of broad range of compounds ranging in size structure and other physiological properties across rat and rabbit small intestinal epithelium.

Eichman and Robinson demonstrated that effervescence could be used as a penetration enhancer. These researchers passed a large volume of CO2 through the donor compartment of a modified using diffusion apparatus and were able to demonstrate enhanced permeation of drugs through rabbit epithelium placed between the cells. The effervescence-induced enhancement is mediated via the following effects:

•A solvent drag effect due to increased fluid flow

•Opening of tight junctions

•Increasing the hydrophobic nature of the cell membrane

The suggested reason for penetration enhancement is the carbon dioxide bubbling directly onto epithelium and induces enhanced drug permeability due to an alteration of the paracellular pathway (7,8).

2. Effervescent blend can be used to obtain programmed drug delivery from hard gelatin capsules containing a hydrophilic plug (9).

3. A controlled release effervescent osmotic pump tablets have also been used since long time for traditional Chinese medicine (10).

4. Floating drug delivery systems based on a reservoir system consisting of a drug containing effervescent core and polymeric coating. The concentration of effervescent agents significantly affects the floating time (11).

5. It is helpful in pulsatile system; a quick releasing core was formulated in order to obtain rapid drug release after the rupture of the polymer coating (12).

6. In design of simple zero order release system by incorporation of low levels of effervescent mixtures within the tablet matrix can be done (13).

7. In remote areas, especially where parenteral forms are not available due to prohibitive cost, lack of qualified medical staff, effervescent tablets could become an alternative. The use of Chloroquine phosphate effervescent tablet for epidemic disease like malaria and viral fever is an example of this type (14).

8. To solve the problems of physicochemical stability and high cost of transporting syrups, effervescent tablets provide a realistic solution.

9. A new dosage form of levodopa, which has the characteristic of loading high concentration at the upper part of the intestine, has been developed to improve bioavailability. Effervescent tablet formulation, coated with HPMC phthalate, as the enteric material is suitable for the purpose of dissolution (15).

10. Cosmetic effervescent tablets have different applications like bath as an existing perfumed line extension, bath including essential oils and hydrating agents, foot care including essential oils and/or hydrating agents, hand care with hydrating agents and nail care products (14).

Patents On varied applications of Effervescent Tablets

•Levamisole effervescent tablets which comprise a composition characterized by excellent solubility yielding crystal clear solutions in water, good storage stability, and ease of use. There are also methods for the oral administration of levamisole to swine in predetermined dosages via the drinking water offered to animals utilizing the aforesaid levamisole effervescent tablets. It gives detailed information related to levamisole effervescent tablet containing levamisole hydrochloride, alkali metal bicarbonate, adipic or fumaric acid, lubricant and dye (16).

•A pharmaceutical dosage form incorporates microparticles which are susceptible to rupture upon chewing or which are adapted to provide substantially immediate release of the pharmaceutical ingredient contained in the microparticles. These microparticles are provided in a tablet with an effervescent disintegration agent. When the tablet is taken orally, the effervescent disintegration agent aids in rapid dissolution of the tablet and hence permits release of the microparticles, and swallowing of the microparticles, before the pharmaceutical ingredient is released from the microparticles. The system therefore provides particularly effective taste masking (17).

• An oral pediatric vitamin supplement comprising: a mixture of at least one effervescent disintegration agent, and a pediatrically effective amount of at least one intended ingredient selected from the group consisting of vitamins and minerals and mixtures thereof, wherein said mixture is present in the form of a compressed tablet of a size and shape adapted for direct oral administration to children and which will rapidly and completely disintegrate when administered; and wherein said effervescent disintegration agent is present in a amount which is effective to both aid in rapid disintegration of said tablet and to provide a positive organoleptic sensation to children (18).

• The invention relates to effervescent tablets and granules comprising a shell material, a basic sparkling component, an acidic sparkling component, and a sweetening agent, macro and microelements and vitamins as active agents. The effervescent tablets and granules comprise 20-50% by mass of mannitol as shell material, 8-25% by mass of potassium hydrogen carbonate as basic sparkling component, 9-27% by mass of malic acid as acidic sparkling component, and 0.4-2.2% by mass of aspartame as sweetening agent. Furthermore, the invention relates to a process for preparing the above-described effervescent tablets and granules (19).

• An effervescent composition and tablet made from acidic effervescent component for direct tabletting of effervescent tablet and process for its preparation are described in the patent (20).

• A pharmaceutical composition containing effervescent acid-base couple comprising active ingredient and sodium glycine carbonate and acid capable of reacting with sodium glycine carbonate to release carbon dioxide (21).

• An effervescent rapidly disintegrating oral dosage form of alkali sensitive agents includes active ingredient Selegiline HCl which is sensitive to effervescent base like sodium bicarbonate, sodium carbonate and sodium hydrogen citrate (22).

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Monographs Of Effervescent Tablets In Pharmacopeias

USP29 NF24 Aspirin effervescent tablet for oral solution Potassium bicarbonate effervescent tablets for oral solutions Potassium chloride, potassium bicarbonate and potassium citrate effervescent tablets for oral solutions.

BP 2005 Effervescent Soluble Aspirin Tablets Effervescent Co-codamol Tablets Soluble Paracetamol tablets

Commercial products of effervescent tablets

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See also

Manufacuring of Effervescent tablets

Commercial Products Of Effervescent Tablets

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REFERENCES

1. Swarbrick J. and Boylan J., Encyclopedia of Pharmaceutical Technology; Volume -1,1037-1049 (2002), Marcel dekker Inc., New York.

2. Mohrle R., Effervescent tablets in Liberman H., Lachman L. and Schwartz, J., Pharmaceutical dosage forms: Tablets, Volume - 1:285-292, First Indian Reprint (2005) Marcel dekker Inc., New York.

3. Parikh D M, Handbook of Pharmaceutical granulation technology; 2nd Edition, 154:365-383 (2005), Taylor & Francis, New York.

4. Robert, L. E., Amerilab technologies, Effervescent tablets.

5. Effervescent formulations.

6. Effervescent tablets, .

7. Enhanced buccal delivery of fentanyl using Oravescent drug delivery system, 1(1), 2001.

8. Jonathan, E., Joseph, R., Pharm. Res., Mechanistic studies on effervescent induced permeability enhancement, 15(6),925-930 (1998).

9. Gohel, M., Manhapra, S., Modulation of active pharmaceutical material release from novel tablet in capsule system containing effervescent blend, J. Cont. Rel., 79(1-3),157-164 (2002).

10. Xian L., Wei-San P., Studies on controlled release effervescent osmotic pump tablets from traditional Chinese medicine compound recipe, J. of Control. Rel., 96(3), 359-367 (2004). 11. Ina, K., Bodmeier, R., Floating or pulsatile drug delivery systems based on coated effervescent cores, Int. J. Pharm., 187, 175-184, (1999).

12. Hashim H., Li, P., Improving the release characteristics of water soluble drugs from hydrophilic sustained release matrices by in situ gas generation, Int. J. Pharm., 35(3), 201-209 (1987).

13. Yanze F., Duru, C., Rapid therapeutic response onset of a new pharmaceutical form of chloroquine phosphate 300 mg effervescent tablet, Tropical Medicine and International Health, 6(3),196-201 (2001).

14. Nishimura K., Sasahara K., J. Pharm. Sci., Dosage form design for improvement of bioavailability of levo-dopa: Formulation of effervescent enteric coated tablets, 13(7), 942-946 (1984).

15. laboratoire-du-bain.com

16. U.S. Patent 4,153,678, (1979)

17. U.S. Patent 5,178,878, (1993)

18. U.S. Patent 5,223,264, (1993)

19. U.S. Patent 5,707,654, (1998)

20. U.S. Patent 5,762,951, (1998)

21. U.S. Patent 6,667,056, (2003)

22. U.S. Patent 6,242,002, (2001)

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Authors

Dr.Avani , Tejal Shah, Reena Dua and Renuka

Tablet coating

Pharmpedia
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Tablet:Tablet coating
From Pharmpedia
Next Page: Problems in tablet manufacturingPrevious Page: Tablet Manufacturing methods
Contents[hide]
1 Introduction
2 Aspects of tablet coating
3 Basic principle of tablet coating
4 Type of tablet coating process
4.1 Sugar coating
4.1.1 Sealing/Water proofing
4.1.2 Subcoating
4.1.3 Grossing/ smoothing
4.1.4 Colour coating
4.1.5 Polishing
4.2 Film Coating
4.2.1 Process description
4.2.2 Process details
4.2.3 Basic process requirements for film coating
4.2.4 Coating formula optimization
4.2.5 Materials used in film coating
4.3 Enteric coating
4.3.1 = Enteric sugar coating
4.3.2 Enteric film coating
4.3.3 Controlled release coating
4.4 Specialized coating
4.4.1 Compressed coating
4.4.2 Electrostatic coating
4.4.3 Dip coating
4.4.4 Vacuum film coating
5 Equipments
6 Process parameters
6.1 Air capacity
6.2 Coating composition
6.3 Tablet surface area
6.4 Equipment efficiency
7 Key Phrases
//

Introduction
(1-3,5)
Coated tablets are defined as “tablets covered with one or more layers of mixture of various substances such as natural or synthetic resins ,gums ,inactive and insoluble filler, sugar, plasticizer, polyhydric alcohol ,waxes ,authorized colouring material and some times flavoring material .
Coating may also contain active ingredient. Substances used for coating are usually applied as solution or suspension under conditions where vehicle evaporates.

Aspects of tablet coating
I. Therapy
i) Avoid irritation of oesophagus and stomach
ii) Avoid bad taste
iii) Avoid inactivation of drug in the stomach
iv) Improve drug effectiveness
v) Prolong dosing interval
vi) Improve dosing interval
vii) Improve patient compliance
II. Technology
i) Reduce influence of moisture
ii) Avoid dust formation
iii) Reduce influence of atmosphere
iv) Improve drug stability
v) Prolong shelve life
III. Marketing
i) Avoid bad taste
ii) Improve product identity
iii) Improve appearance and acceptability

Basic principle of tablet coating
The principle of tablet coating is relatively simple. Tablet coating is the application of coating composition to moving bed of tablets with concurrent use of heated air to facilitate evaporation of solvent.
Basic principles involve
i) Insulation which influences the release pattern as little as possible and does not markedly change the appearance.
ii) Modified release with specific requirement and release mechanism adapted to body function in the digestive tract.
iii) Colour coating which provides insulation or is combined with modified release coating.

Type of tablet coating process

Sugar coating
(1,3,5)
Compressed tablets may be coated with coloured or uncoloured sugar layer. The coating is water soluble and quickly dissolves after swallowing. The sugarcoat protects the enclosed drug from the environment and provides a barrier to objectionable taste or order. The sugar coat also enhances the appearance of the compressed tablet and permit imprinting manufacturing’s information. Sugar coating provides a combination of insulation, taste masking, smoothing the tablet core, colouring and modified release. The disadvantages of sugar coating are the time and expertise required in the coating process and thus increases size, weight and shipping costs.
Sugar coating process involves five separate operations:
I. Sealing/Water proofing: provides a moisture barrier and harden the tablet surface.
II. Subcoating: causes a rapid buildup to round off the tablet edges.
III. Grossing/Smoothing: smoothes out the subcoated surface and increases the tablet size to predetermine dimension.
IV. Colouring: gives the tablet its colour and finished size.
V. Polishing: produces the characteristics gloss.

Sealing/Water proofing
Prior to applying any sugar/water syrup, the tablet cores must be sealed, thoroughly dried and free of all residual solvents.
The seal coat provides a moisture barrier and hardness the surface of the tablet in order to minimize attritional effects. Core tablets having very rapid disintegration rates conceivably could start the disintegration process during the initial phase of sugar coating. The sealants are generally water-insoluble polymers/film formers applied from an organic solvent solution. The quantities of material applied as a sealing coat will depend primarily on the tablet porosity, since highly porous tablets will tend to soak up the first application of solution, thus preventing it from spreading uniformly across the surface of every tablet in the batch. Hence, one or more further application of resin solution may be required to ensure that the tablet cores are sealed effectively.
Common materials used as a sealant include Shellac, Zine, Cellulose acetate phthalate (CAP), Polyvinylacetate phthalate, Hyroxylpropylcellulose, Hyroxypropylmethylcellulose etc.

Subcoating
Subcoating is the actual start of the sugar coating process and provides the rapid buildup necessary to round up the tablet edge. It also acts as the foundation for the smoothing and colour coats.
Generally two methods are used for subcoating:
i)The application of gum based solution followed by dusting with powder and then drying. This routine is repeated until the desired shape is achieved.
ii)The application of a suspension of dry powder in gum/sucrose solution followed by drying.
Thus subcoating is a sandwich of alternate layer of gum and powder. It is necessary to remove the bulk o the water after each application of coating syrup.
TABLE.23. TYPICAL BINDER SOLUTION FORMULATION FOR SUBCOATING(1)

%W/W
%W/W
Gelatin
6
3.3
Gum acacia (powdered)
8
8.7
Sucrose (powdered)
45
55.3
Distilled water
to 100
to 100
TABLE.24. TYPICAL DUSTING POWDER FORMULATION FOR SUBCOATING(1)

%W/W
%W/W
Calcium carbonate
40.0
-
Titanium dioxide
5.0
1.0
Talc, asbestos free
25.0
61.0
Sucrose( powdered )
28.0
38.6
Gum acacia (powdered)
2.0
-
TABLE.25. TYPICAL SUSPENSION SUBCOATING FORMULATION(1)

%W/W
Sucrose
40.0
Calcium carbonate
20.0
Talc, asbestos free
12.0
Gum acacia(powdered)
2.0
Titanium dioxide
1.0
Distilled water
25.0

Grossing/ smoothing
The grossing/smoothing process is specifically for smoothing and filing the irregularity on the surface generated during subcoating. It also increases the tablet size to a predetermined dimension.
If the subcoating is rough with high amount of irregularities then the use of grossing syrup containing suspended solids will provide more rapid buildup and better filling qualities. Smoothing usually can be accomplished by the application of a simple syrup solution (approximately 60-70 % sugar solid). This syrup generally contains pigments, starch, gelatin, acacia or opacifier if required.
Small quantities of colour suspension can be applied to impart a tint of the desired colour when there are irregularities in coating.

Colour coating
This stage is often critical in the successful completion of a sugar coating process and involves the multiple application of syrup solution (60-70 % sugar solid) containing the requisite colouring matter. Mainly soluble dyes were used in the sugar coating to achieve the desired colour, since the soluble dye will migrate to the surface during drying. But now a days the insoluble certified lakes have virtually replaced the soluble dyes in pharmaceutical tablet coating. The most efficient process for colour coating involves the use of a predispersed opacified lake suspension.

Polishing
Sugar-coated tablets needs to be polished to achieve a final elegance. Polishing is achieved by applying the mixture of waxes like beeswax, carnubawax, candelila wax or hard paraffin wax to tablets in polishing pan.

Film Coating
Film coating is more favored over sugar coating.
TABLE.26. COMPARISON BETWEEN FILM COATING AND SUGAR COATING(1)
FEATURES
FILM COATING
SUGAR COATING
Tablet:
Appearance



Weight increase because of coating material

Logo or ‘break lines’

Retain contour of original core. Usually not as shiny as sugar coat type


2-3%


Possible

Rounded with high degree of polish



30-50%


Not possible
Process
Operator training required


Adaptability to GMP

Process stages

Functional coatings

Process tends itself to automation and easy training of operator

High

Usually single stage

Easily adaptable for controlled release

Considerable



Difficulty may arise

Multistage process

Not usually possible apart from enteric coating

Process description
(1)
Film coating is deposition of a thin film of polymer surrounding the tablet core. Conventional pan equipments may be used but now a day’s more sophisticated equipments are employed to have a high degree of automation and coating time. The polymer is solubilized into solvent. Other additives like plasticizers and pigments are added. Resulting solution is sprayed onto a rotated tablet bed. The drying conditions cause removal of the solvent, giving thin deposition of coating material around each tablet core.

Process details
(1)
Usually spray process is employed in preparation of film coated tablets. Accela cota is the prototype of perforated cylindrical drum providing high drying air capacity. Fluidized bed equipment has made considerable impact where tablets are moving in a stream of air passing through the perforated bottom of a cylindrical column. With a smaller cylindrical insert, the stream of cores is rising in the center of the device together with a spray mist applied in the middle of the bottom. For fluidized bed coating, very hard tablets (hardness > 20 N) have to be used.

Basic process requirements for film coating
(2)
The fundamental requirements are independent of the actual type of equipments being used and include adequate means of atomizing the spray liquid for application to the tablet core, adequate mixing and agitation of tablet bed, sufficient heat input in the form of drying air to provide the latent heat of evaporation of the solvent. This is particularly important with aqueous-based spraying and good exhaust facilities to remove dust and solvent laden air.
Development of film coating formulations (1)
If the following questions are answered concomitantly then one can go for film coating:
i) Is it necessary to mask objectionable taste, colour and odor?
ii) Is it necessary to control drug release?
iii) What tablets size, shape, or colour constrains must be placed on the developmental work?
Colour, shape and size of final coated tablet are important for marketing and these properties have a significant influence on the marketing strategies. An experienced formulator usually takes the pragmatic approach and develops a coating formulations modification of one that has performed well in the past. Spraying or casting films can preliminarily screen film formulations. Cast films cab is prepared by spreading the coating composition on teflon, glass or aluminum foil surface using a spreading bar to get a uniform film thickness. Sprayed films can be obtained by mounting a plastic-coated surface in a spray hood or coating pan.

Coating formula optimization
(1)
Basic formula is obtained from past experience or from various sources in the literature. Modifications are required to improve adhesion of the coating to the core, to decrease bridging of installations, to increase coating hardness, etc. Usually concentration of colorant and opaquant are fixed to get predetermined shade. Common modification is to alter polymer-to-plasticizer ratio or addition of different plasticizer/ polymer. Experimentation of this type can be best achieved by fractional factorial study.

Materials used in film coating
(1,13)
I.Film formers, which may be enteric or nonenteric
II.Solvents
III.Plasticizers
IV.Colourants
V.Opaquant-Extenders
VI. Miscellaneous coating solution components
I.Film formers (1)
Ideal requirements of film coating materials are summarized below:
i) Solubility in solvent of choice for coating preparation
ii) Solubility requirement for the intended use e.g. free water-solubility, slow water-solubility or pH -dependent solubility
iii) Capacity to produce an elegant looking product
iv) High stability against heat, light, moisture, air and the substrate being coated
v) No inherent colour, taste or odor
vi) High compatibility with other coating solution additives
vii) Nontoxic with no pharmacological activity
viii) High resistance to cracking
ix) Film former should not give bridging or filling of the debossed tablet
x) Compatible to printing procedure
Commonly used film formers are as follow
i.Hydroxy Propyl Methyl Cellulose (HPMC)
It is available in different viscosity grades. It is a polymer of choice for air suspension and pan spray coating systems because of solubility characteristic in gastric fluid, organic and aqueous solvent system. Advantages include: it does not affect tablet disintegration and drug availability, it is cheap, flexible, highly resistant to heat, light and moisture, it has no taste and odor, colour and other additives can be easily incorporated.
Disadvantage includes: when it is used alone, the polymer has tendency to bridge or fill the debossed tablet surfaces. So mixture of HPMC and other polymers/ plasticizers is used.
ii.Methyl Hydroxy Ethyl Cellulose (MHEC)
It is available in wide variety of viscosity grades. It is not frequently used as HPMC because soluble in fewer organic solvents.
iii. Ethyl Cellulose (EC)
Depending on the degree of ethoxy substitution, different viscosity grades are available. It is completely insoluble in water and gastric fluids. Hence it is used in combination with water-soluble additives like HPMC and not alone. Unplasticized ethyl cellulose films are brittle and require film modifiers to obtain an acceptable film formulation. Aqua coat is aqueous polymeric dispersion utilizing ethyl cellulose. These pseudolatex systems contain high solids, low viscosity compositions that have coating properties quite different from regular ethyl cellulose solution.
iv.Hydroxy Propyl Cellulose (HPC)
It is soluble in water below 40oc (insoluble above 45 oC), gastric fluid and many polar organic solvents. HPC is extremely tacky as it dries from solution system. It is used for sub coat and not for colour or glass coat. It gives very flexible film.
v. Povidone
Degree of polymerization decides molecular weight of material. It is available in four viscosity grades i.e. K-15, K-30, K-60 and K-90. Average molecular weight of these grades is 10000, 40000, 160000 and 360000 respectively. K-30 is widely used as tablet binder and in tablet coating. It has excellent solubility in wide variety of organic solvents, water, gastric and intestinal fluids. Povidone can be cross-linked with other materials to produce films with enteric properties. It is used to improve dispersion of colourants in coating solution.
vi. Sodium carboxy methyl cellulose
It is available in medium, high and extra high viscosity grades. It is easily dispersed in water to form colloidal solutions but it is insoluble in most organic solvents and hence not a material of choice for coating solution based on organic solvents. Films prepared by it are brittle but adhere well to tablets. Partially dried films of are tacky. So coating compositions must be modified with additives.
viii. Polyethylene glycols (PEG)
Lower molecular weights PEG (200-600) are liquid at room temperature and are used as plasticizers. High molecular weights PEG (900-8000series) are white, waxy solids at room temperature. Combination of PEG waxes with CAP gives films that are soluble in gastric fluids.
ix. Acrylate polymers
It is marketed under the name of Eudragit. EudragitE is cationic co-polymer. Only EudragitE is freely soluble in gastric fluid up to pH 5 and expandable and permeable above pH 5. This material is available as organic solution (12.5% in isopropanol/acetone), solid material or 30% aqueous dispersion. EudragitRL & RS are co-polymers with low content of quaternary ammonium groups. These are available only as organic solutions and solid materials. They produce films for delayed action (pH dependent).
II.Solvents (1)
Solvents are used to dissolve or disperse the polymers and other additives and convey them to substrate surface.
Ideal requirement are summarized below:
i) Should be either dissolve/disperse polymer system
ii) Should easily disperse other additives into solvent system
iii) Small concentration of polymers (2-10%) should not in an extremely viscous solution system creating processing problems
iv) Should be colourless, tasteless, odorless, inexpensive, inert, nontoxic and nonflammable
v) Rapid drying rate
vi) No environmental pollution
Mostly solvents are used either alone or in combination with water, ethanol, methanol, isopropanol, chloroform, acetone, methylene chloride, etc. Water is more used because no environmental and economic considerations. For drugs that readily hydrolyze in presence of water, non aqueous solvents are used.
III. Plasticizers (1)
As solvent is removed, most polymeric materials tend to pack together in 3-D honey comb arrangement. “Internal” or “External” plasticizing technique is used to modify quality of film. Combination of plasticizer may be used to get desired effect. Concentration of plasticizer is expressed in relation to the polymer being plasticized. Recommended levels of plasticizers range from 1-50 % by weight of the film former. Commonly used plasticizers are castor oil, PG, glycerin, lower molecular weight (200-400 series), PEG, surfactants, etc. For aqueous coating PEG and PG are more used while castor oil and spans are primarily used for organic-solvent based coating solution. External plasticizer should be soluble in the solvent system used for dissolving the film former and plasticizer. The plasticizer and the film former must be at least partially soluble or miscible in each other.
IV.Colourants (1)
Colourants can be used in solution form or in suspension form. To achieve proper distribution of suspended colourants in the coating solution requires the use of the powdered colourants (<10 microns). Most common colourants in use are certified FD & C or D & C colourants. These are synthetic dyes or lakes. Lakes are choice for sugar or film coating as they give reproducible results. Concentration of colourants in the coating solutions depends on the colour shade desired, the type of dye, and the concentration of opaquant-extenders. If very light shade is desired, concentration of less than 0.01 % may be adequate on the other hand, if a dark colour is desired a concentration of more than 2.0 % may be required. The inorganic materials (e.g. iron oxide) and the natural colouring materials (e.g. anthrocyanins, carotenoids, etc) are also used to prepare coating solution. Magenta red dye is non absorbable in biologic system and resistant to degradation in the gastro intestinal track. Opasray (opaque colour concentrate for film coating) and Opadry (complete film coating concentrate) are promoted as achieving less lot-to-lot colour variation.
V.Opaquant-Extenders (1)
These are very fine inorganic powder used to provide more pastel colours and increase film coverage. These inorganic materials provide white coat or mask colour of the tablet core. Colourants are very expensive and higher concentration is required. These inorganic materials are cheap. In presence of these inorganic materials, amount of colourants required decreases. Most commonly used materials are titanium dioxide, silicate (talc &aluminum silicates), carbonates (magnesium carbonates), oxides (magnesium oxide) & hydroxides (aluminum hydroxides). Pigments were investigated in the production of opaque films and it was found that they have good hiding power and film-coated tablets have highlighted intagliations.
VI. Miscellaneous coating solution component (1)
Flavors, sweeteners, surfactants, antioxidants, antimicrobials, etc. may be incorporated into the coating solution.

Enteric coating
(1, 2, 13)
This type of coating is used to protect tablet core from disintegration in the acid environment of the stomach for one or more of the following reasons:
i) To prevent degradation of acid sensitive API
ii) To prevent irritation of stomach by certain drugs like sodium salicylate
iii) Delivery of API into intestine
iv) To provide a delayed release component for repeat action tablet
Several kinds of enteric layer systems are now available
One layer system - The coating formulation is applied in one homogeneous layer, which can be whites-opaque or coloured. Benefit is only one application needed.
Two layer system - To prepare enteric tablets of high quality and pleasing appearance the enteric formulation is applied first, followed by coloured film. Both layers can be of enteric polymer or only the basic layer contains enteric polymer while top layer is fast disintegrating & water-soluble polymer
Ideal properties of enteric coating material are summarized as below
i) Resistance to gastric fluids
ii) Susceptible/permeable to intestinal fluid
iii) Compatibility with most coating solution components and the drug substrate
iv) Formation of continuous film
v) Nontoxic, cheap and ease of application
vi) Ability to be readily printed
Polymers used for enteric coating are as follow
i.Cellulose acetate phthalate (CAP)
It is widely used in industry. Aquateric is reconstituted colloidal dispersion of latex particles. It is composed of solid or semisolid polymer spheres of CAP ranging in size from 0.05 - 3 microns. Cellulose acetate trimellitate (CAT) developed as an ammoniated aqueous formulation showed faster dissolution than a similar formulation of CAP. Disadvantages include: It dissolves above pH 6 only, delays absorption of drugs, it is hygroscopic and permeable to moisture in comparison with other enteric polymer, it is susceptible to hydrolytic removal of phthalic and acetic acid changing film properties. CAP films are brittle and usually used with other hydrophobic film forming materials.
ii. Acrylate polymers
Eudragit®L & Eudragit®S are two forms of commercially available enteric acrylic resins. Both of them produce films resistant to gastric fluid. Eudragit®L & S are soluble in intestinal fluid at pH 6 & 7 respectively. Eudragit®L is available as an organic solution (Isopropanol), solid or aqueous dispersion. Eudragit®S is available only as an organic solution (Isopropanol) and solid.
iii Hydroxy propyl methyl cellulose phthalate
HPMCP 50, 55 & 55-s (also called HP-50, HP-55 & HP-55-s) is widely used. HP-55 is recommended for general enteric preparation while HP-50 & HP-55-s for special cases. These polymers dissolve at a pH 5-5.5.
iii. Polyvinyl acetate phthalate
It is similar to HP-55 in stability and pH dependent solubility.

= Enteric sugar coating
(2)
Here the sealing coat is tailored to include one of the enteric polymers in sufficient quantity to pass the enteric test for disintegration. The sub coating and subsequent coating steps are then as for conventional sugar coating.

Enteric film coating
(2)
Enteric polymers are capable of forming a direct film in a film coating process. Sufficient weight of enteric polymer has to be used to ensure an efficient enteric effect. Enteric coating can be combined with polysaccharides, which are enzyme degraded in colon e.g. Cyclodextrin & galactomannan.

Controlled release coating
(2)
Polymers like modified acrylates, water insoluble cellulose (ethyl cellulose), etc. used for control release coating.

Specialized coating
(1)
Compressed coating
This type of coating requires a specialization tablet machine. Compression coating is not widely used but it has advantages in some cases in which the tablet core cannot tolerate organic solvent or water and yet needs to be coated for taste masking or to provide delayed or enteric properties to the finished product and also to avoid incompatibility by separating incompatible ingredients.

Electrostatic coating
Electrostatic coating is an efficient method of applying coating to conductive substrates. A strong electrostatic charge is applied to the substrate. The coating material containing conductive ionic species of opposite charge is sprayed onto the charged substrate. Complete and uniform coating of corners and adaptability of this method to such relatively nonconductive substrate as pharmaceutical is limited.

Dip coating
Coating is applied to the tablet cores by dipping them into the coating liquid. The wet tablets are dried in a conventional manner in coating pan. Alternative dipping and drying steps may be repeated several times to obtain the desired coating. This process lacks the speed, versatility, and reliability of spray-coating techniques. Specialized equipment has been developed to dip-coat tablets, but no commercial pharmaceutical application has been obtained.

Vacuum film coating
Vacuum film coating is a new coating procedure that employs a specially designed baffled pan. The pan is hot water jacketed, and it can be sealed to achieve a vacuum system. The tablets are placed in the sealed pan, and the air in the pan is displaced by nitrogen before the desired vacuum level is obtained. The coating solution is then applied with airless spray system. The evaporation is caused by the heated pan, and the vapour is removed by the vacuum system. Because there is no high-velocity heated air, the energy requirement is low and coating efficiency is high. Organic solvent can be effectively used with this coating system with minimum environmental or safety concerns.

Equipments
Three general types of equipments are available
1.Standard coating pan
e.g., Pellegrin pan system
Immersion sword system
Immersion tube system
2.Perforated pan system e.g.,Accela cota system
Hicoater system
Glattcoater system
Driacoated system
3.Fluidized bed coater

Process parameters

Air capacity
This value represents the quantity of water or solvent that can be removed during the coating process which depends on the quantity of air flowing through the tablet bed, temperature of the air and quantity of water that the inlet air contains.

Coating composition
The coating contains the ingredients that are to be applied on the tablet surface and solvents which act as carrier for the ingredients.

Tablet surface area
It plays an important role for uniform coating. The total surface area for unit weight decreases significantly from smaller to larger tablets. Application of a film with the same thickness requires less coating composition. In the coating process only a portion of the total surface is coated. Continuous partial coating and recycling eventually results in fully coated tablets.

Equipment efficiency
Tablet coaters use the expression “coating efficiency” a value obtained by dividing the net increase in coated tablet weight by the total nonvolatile coating weight applied to the tablet. Ideally 90-95 % of the applied film coating should be on the tablet surface. Coating efficiency for conventional sugar coating is much less and 60% would be acceptable. The significant difference in coating efficiency between film and sugar coating relates to the quantity of coating material that collects on the wall.

Key Phrases
The sugar coating involves several steps like, sealing, subcoating, colour coating and printing.
Sugar coating process yields elegant and highly glossed tablet.
Newer techniques utilize spraying systems and varying degree of automation to improve coating efficiency and product uniformity.
Film coating is deposition of a thin film of polymer surrounding the tablet core.
Film coating is more favored than sugar coating because weight increase is 2-3%, single stage process, easily adaptable to controlled release, it retains colour of original core, high adaptability to GMP, automation is possible, etc.
Accela cota and fluidized bed equipments are widely used for film coating.
Basic formula is obtained from past experience or from literature and modifications are made accordingly. Common modifications are to alter polymer-to-plasticizer ratio or addition of different plasticizer/polymer. Experimentation of this type can be best achieved by fractional factorial study.
Materials used in film coating include film formers, solvents, plasticizers, colourants, opaquant-extenders, surfactant, anti oxidant, etc.
Widely used film formers are Hydroxy Propyl Methyl Cellulose (HPMC),Methyl Hydroxy Ethyl Cellulose (MHEC), Ethyl Cellulose (EC), Hydroxy Propyl Cellulose (HPC), Povidone (four grades available i.e. K-15, K-30, K-60and K-90), Sodium carboxy methyl cellulose, Polyethylene glycols (PEG) and Acrylate polymers (Eudragit®, Eudragit®RL, Eudragit®RS, Eudragit®E) are used for film coating. Eudragit®L & S are used for enteric coating. Eudragit®RL, Eudragit®RS, Eudragit®S are available as organic solution and solid while Eudragit®L and Eudragit®E are available as organic, solid or aqueous dispersion.
Quality of film can be modified by plasticizer. Commonly used plasticizers include PG, glycerin, low molecular weight PEG, castor oils, etc. Castor oil and spans are more used for organic-solvent based coating solution while PE and PEG are used for aqueous coating.
FD & C or D & C certified colourants are used. Lakes are choice for film coating as they give reproducible results. Opaspray® (opaque colour concentrate for film coating) and Opadry® (complete film coating concentrate) are promoted as achieving less lot-to-lot variation.
Colourants are expensive and higher concentration is required. So materials like titanium dioxides, silicates, and carbonates are used to provide more pastel colours and increase film coverage.
Enteric Coating:
Enteric coating is used to protect tablet core from disintegration in the acid environment of stomach to prevent degradation of acid sensitive API, prevent irritation to stomach by certain drugs, delivery of API into intestine, to provide a delayed release components for repeat action, etc.
Several kinds of enteric layer systems are available like one layer system and two-layer system. Polymers used for enteric coating are cellulose Acetate Phthalate (CAP), Acrylates (Eudragit®L and Eudragit®S, Hydroxy Propyl Methyl Cellulose Phthalate (HPMCP50, HPMCP55 & HPMCP 55s) and polyvinyl acetate phthalate
Enteric sugar coating:
Here sealing coat is modified to comprise one of the enteric polymers in sufficient quantity to pass the enteric test for disintegration. The sub coating and subsequent coating steps are then as for conventional sugar coating.
Enteric polymers are capable of forming a direct film in a film coating process. Sufficient weight of enteric polymer has to be used to ensure an efficient enteric effect.
Enteric coating can be combined with polysaccharides, which are enzymatically degraded in colon. For example, Cyclodextrin & Galactomannan.
Controlled release coating:

GUIDE TO INSPECTIONS ORAL SOLUTIONS AND SUSPENSIONS

I. INTRODUCTION
The manufacture and control of oral solutions and oral suspensions has presented some problems to the industry. While bioequivalency concerns are minimal (except for the antiseptic products such as phenytoin suspension), there are other issues which have led to recalls. These include microbiological, potency and stability problems. Additionally, because the population using these oral dosage forms includes newborns, pediatrics and geriatrics who may not be able to take oral solid dosage forms and may be compromised, defective dosage forms can pose a greater risk because of the population being dosed. Thus, this guide will review some of the significant potential problem areas and provide direction to the investigator when giving inspectional coverage.
II. FACILITIES
The design of the facilities are largely dependent upon the type of products manufactured and the potential for cross-contamination and microbiological contamination. For example, the facilities used for the manufacture of OTC oral products might not require the isolation that a steroid or sulfa product would require.
Review the products manufactured and the procedures used by the firm for the isolation of processes to minimize contamination. Observe the addition of drug substance and powdered excipients to manufacturing vessels to determine if operations generate dust. Observe the systems and the efficiency of the dust removal system.
The firm's HVAC (Heating Ventilation and Air Conditioning) system may also warrant coverage particularly where potent or highly sensitizing drugs are processed. Some manufacturers recirculate air without adequate filtration. Where air is recirculated, review the firm's data which demonstrates the efficiency of air filtration such should include surface and/or air sampling.
III. EQUIPMENT
Equipment should be of sanitary design. This includes sanitary pumps, valves, flow meters and other equipment which can be easily sanitized. Ball valves, packing in pumps and pockets in flow meters have been identified as sources of contamination.
In order to facilitate cleaning and sanitization, manufacturing and filling lines should be identified and detailed in drawings and SOPs. In some cases, long delivery lines between manufacturing areas and filling areas have been a source of contamination. Also, SOPs, particularly with regard to time limitations between batches and for cleaning have been found deficient in many manufacturers. Review cleaning SOPs, including drawings and validation data with regard to cleaning and sanitization.
Equipment used for batching and mixing of oral solutions and suspensions is relatively basic. Generally, these products are formulated on a weight basis with the batching tank on load cells so that a final Q.S. can be made by weight. Volumetric means, such as using a dip stick or line on a tank, have been found to be inaccurate.
In most cases, manufacturers will assay samples of the bulk solution or suspension prior to filling. A much greater variability has been found with batches that have been manufactured volumetrically rather than by weight. For example, one manufacturer had to adjust approximately 8% of the batches manufactured after the final Q.S. because of failure to comply with potency specifications. Unfortunately, the manufacturer relied solely on the bulk assay. After readjustment of the potency based on the assay, batches occasionally were found out of specification because of analytical errors.
The design of the batching tank with regard to the location of the bottom discharge valve has also presented problems. Ideally, the bottom discharge valve is flush with the bottom of the tank. In some cases valves, including undesirable ball valves, have been found to be several inches to a foot below the bottom of the tank. In others, drug or preservative was not completely dissolved and was lying in the "dead leg" below the tank with initial samples being found to be subpotent. For the manufacture of suspensions, valves should be flush. Review and observe the batching equipment and transfer lines.
With regard to transfer lines, they are generally hard piped and easily cleaned and sanitized. In some cases manufacturers have used flexible hoses to transfer product. It is not unusual to see flexible hoses lying on the floor, thus significantly increasing the potential for contamination. Such contamination can occur by operators picking up or handling hoses, and possibly even placing them in transfer or batching tanks after they had been lying on the floor. It is also a good practice to store hoses in a way that allows them to drain rather than be coiled which may allow moisture to collect and be a potential source of microbial contamination. Observe manufacturing areas and operator practices, particularly when flexible hose connection are employed.
Another common problem occurs when a manifold or common connections are used, especially in water supply, premix or raw material supply tanks. Such common connections have been shown to be a source of contamination.
IV. RAW MATERIALS
The physical characteristics, particularly the particle size of the drug substance, are very important for suspensions. As with topical products in which the drug is suspended, particles are usually very fine to micronized (less than 25 microns). For syrups, elixir or solution dosage forms in which there is nothing suspended, particle size and physical characteristics of raw materials are not that important. However, they can affect the rate of dissolution of such raw materials in the manufacturing process. Raw materials of a finer particle size may dissolve faster than those of a larger particle size when the product is compounded.
Examples of a few of the oral suspensions in which a specific and well defined particle size specification for the drug substance is important include phenytoin suspension, carbamazepine suspension, trimethoprim and sulfamethoxazole suspension, and hydrocortisone suspension. Review the physical specifications for any drug substance which is suspended in the dosage form.
V. COMPOUNDING
In addition to a determination of the final volume (Q.S.) as previously discussed, there are microbiological concerns. For oral suspensions, there is the additional concern with uniformity, particularly because of the potential for segregation during manufacture and storage of the bulk suspension, during transfer to the filling line and during filling. Review the firm's data that support storage times and transfer operations. There should be established procedures and time limits for such operations to address the potential for segregation or settling as well as other unexpected effects that may be caused by extended holding or stirring.
For oral solutions and suspensions, the amount and control of temperature is important from a microbiological as well as a potency aspect. For those products in which temperature is identified as a critical part of the operation, the firm's documentation of temperature, such as by control charts, should be reviewed.
There are some manufacturers that rely on heat during compounding to control the microbiological levels in product. For such products, the addition of purified water to final Q.S., the batch, and the temperatures during processing should be reviewed.
In addition to drug substances, some additives, such as the parabens are difficult to dissolve and require heat. The control and assurance of their dissolution during the compounding stage should be reviewed. From a potency aspect, the storage of product at high temperatures may increase the level of degradants. Storage limitations (time and temperature) should be justified by the firm and evaluated during your inspection.
There are also some oral liquids which are sensitive to oxygen and have been known to undergo degradation. This is particularly true of the phenothiazine class of drugs, such as perphenazine and chlorpromazine. The manufacture of such products might require the removal of oxygen such as by nitrogen purging. Additionally, such products might also require storage in sealed tanks, rather than those with loose lids. Manufacturing directions for these products should be reviewed.
VI. MICROBIOLOGICAL
QUALITY
There are some oral liquids in which microbiological contamination can present significant health hazards. For example, some oral liquids, such as nystatin suspension are used in infants and immuno-compromised patients, and microbiological contamination with organisms, such as Gram-negative organisms, is objectionable. There are other oral liquid preparations such as antacids in which Pseudomonas sp. contamination is also objectionable. For other oral liquids such as cough preparations, the contamination with Pseudomonas sp. might not present the same health hazard. Obviously, the contamination of any preparation with Gram-negative organisms is not desirable.
In addition to the specific contaminant being objectionable, such contamination would be indicative of a deficient process as well as an inadequate preservative system. The presence of a specific Pseudomonas sp. may also indicate that other plant or raw material contaminants could survive the process. For example, the fact that a Pseudomonas putida contaminant is present could also indicate that Pseudomonas aeruginosa, a similar source organism, could also be present.
Both the topical and microbiological inspection guides discuss the methods and limitations of microbiological testing. Similar microbiological testing concepts discussed apply to the testing of oral liquids for microbiological contamination. Review the microbiological testing of raw materials, including purified water, as well as the microbiological testing of finished products. Since FDA laboratories typically utilize more sensitive test methods than industry, consider sampling any oral liquids in which manufacturers have found microbiological counts, no matter how low. Submit samples for testing for objectionable microorganisms.
VII. ORAL SUSPENSIONS
UNIFORMITY
Those liquid products in which the drug is suspended (and not in solution) present manufacturer and control problems.
Those liquid products in which the drug is suspended (and not in solution) present manufacture and control problems. Depending upon the viscosity, many suspensions require continuous or periodic agitation during the filling process. If delivery lines are used between the bulk storage tank and the filling equipment, some segregation may occur, particularly if the product is not viscous. Review the firm's procedures for filling and diagrams for line set-up prior to the filling equipment.
Good manufacturing practice would warrant testing bottles from the beginning, middle and end to assure that segregation has not occurred. Such samples should not be composited.
In-process testing for suspensions might also include an assay of a sample from the bulk tank. More important, however, may be testing for viscosity.
VIII. PRODUCT
SPECIFICATIONS
Important specifications for the manufacture of all solutions include assay and microbial limits. Additional important specifications for suspensions include particle size of the suspended drug, viscosity, pH, and in some cases dissolution. Viscosity can be important from a processing aspect to minimize segregation. Additionally, viscosity has also been shown to be associated with bioequivalency. pH may also have some meaning regarding effectiveness of preservative systems and may even have an effect on the amount of drug in solution. With regard to dissolution, there are at least three products which have dissolution specifications. These products include phenytoin suspension, carbamazepine suspension, and sulfamethoxazole and trimethoprim suspension. Particle size is also important and at this point it would seem that any suspension should have some type of particle size specification. As with other dosage forms, the underlying data to support specifications should be reviewed.
IX. PROCESS VALIDATION
As with other products, the amount of data needed to support the manufacturing process will vary from product to product. Development (data) should have identified critical phases of the operation, including the predetermined specifications, that should be monitored during process validation.
For example, for solutions the key aspects that should be addressed during validation include assurance that the drug substance and preservatives are dissolved. Parameters, such as heat and time should be measured. Also, in-process assay of the bulk solution during and/or after compounding according to predetermined limits are also an important aspects of process validation. For solutions that are sensitive to oxygen and/or light, dissolved oxygen levels would also be an important test. Again, the development data and the protocol should provide limits. Review firm's development data and/or documentation for their justification of the process.
As discussed, the manufacture of suspensions presents additional problems, particularly in the area of uniformity. Again, development data should have addressed the key compounding and filling steps that assure uniformity. The protocol should provide for the key in-process and finished product tests, along with their specifications. For oral solutions, bioequivalency studies may not always be needed. However, oral suspensions, with the possible exception of some of the antacids, OTC products, usually require a bioequivalency or clinical study to demonstrate effectiveness. As with oral solid dosage forms, comparison to the biobatch is an important part of validation of the process.
Review the firm's protocol and process validation report and, if appropriate, compare data for full scale batches to biobatch, data and manufacturing processes.
X. STABILITY
One area that has presented a number of problems includes the assurance of stability of oral liquid products throughout their expiry period. For example, there have been a number of recalls of the vitamins with fluoride oral liquid products because of vitamin degradation. Drugs in the phenothiazine class, such as perphenazine, chlorpromazine and promethazine have also shown evidence of instability. Good practice for this class of drug products would include quantitation of both the active and primary degradant. Dosage form manufacturers should know and have specifications for the primary degradant. Review the firm's data and validation data for methods used to quantitate both the active drug and degradant.
Because interactions of products with closure systems are possible, liquids and suspensions undergoing stability studies should be stored on their side or inverted in order to determine whether contact of the drug product with the closure system affects product integrity.
Moisture loss which can cause the remaining contents to become superpotent and microbiological contamination are other problems associated with inadequate closure systems.
XI. PACKAGING
Problems in the packaging of oral liquids have included potency (fill) of unit dose products, accurate calibration of measuring devices such as droppers that are often provided. The USP does not provide for dose uniformity testing for oral solutions. Thus, for unit dose solution products, they should deliver the label claim within the limits described in the USP. Review the firm's data to assure uniformity of fill and test procedures to assure that unit dose samples are being tested.
Another problem in the packaging of Oral Liquids is the lack of cleanliness of containers prior to filling. Fibers and even insects have been identified as debris in containers, and particularly plastic containers used for these products. Many manufacturers receive containers shrink-wrapped in plastic to minimize contamination from fiberboard cartons. Many manufacturers utilize compressed air to clean containers. Vapors, such as oil vapors, from the compressed air have occasionally been found to present problems. Review the firm's systems for the cleaning of containers.
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starch

1. A naturally abundant nutrient carbohydrate, (C₆H₁₀O₅)_n, found chiefly in the seeds, fruits, tubers, roots, and stem pith of plants, notably in corn, potatoes, wheat, and rice, and varying widely in appearance according to source but commonly prepared as a white amorphous tasteless powder.
2. Any of various substances, such as natural starch, used to stiffen cloth, as in laundering.
3. starches Foods having a high content of starch, as rice, breads, and potatoes.
4. 1. Stiff behavior.
   2. Vigor; mettle: “Business travel can take the starch out of the most self-assured corporate titan” (Lisa Faye Kaplan).

tr.v., starched, starch·ing, starch·es.

To stiffen with starch.

[Middle English starche, substance used to stiffen cloth (sense uncertain), from sterchen, to stiffen, from Old English *stercan.]

Polysaccharide, a polymer of glucose units; the form in which carbohydrate is stored in the plant; it does not occur in animal tissue. (Glycogen is sometimes referred to as animal starch.) Starch is broken down by acid or enzymic hydrolysis (amylase), or during digestion, first to maltose and then glucose; it is the principal carbohydrate of the diet and hence the major source of energy. Starches from different sources (e.g. potato, maize, cereal, arrowroot, sago, etc.) have different structures, and contain different proportions of two major forms: amylose, which is a linear polymer and amylopectin, which has a branched structure. The mixture of dietary starches consists of about one-quarter amylose and three-quarters amylopectin.
A complex carbohydrate (polysaccharide) made of many glucose units. Uncooked starch is very difficult to digest, but heat opens out starch molecules so that they form a gel-like structure which is more accessible to digestive enzymes. During digestion, enzymes in the gut help to break down the starch into dextrins, and then glucose molecules which are absorbed into the blood. Starch takes much longer to digest than simple sugars, such as sucrose (table sugar). Consequently, starch provides a steady stream of glucose into the bloodstream and is less likely than sucrose to cause blood glucose swings which can provoke the secretion of excess insulin.

High quantities of starch are found in bananas which are still green at their tips (in brown bananas, most of the starch is converted to sugars), breads, corn, oats, pasta, potatoes, rice, and yams. Unrefined forms of these foods also contain other nutrients, especially vitamins, trace minerals, and fibre. They are a much better source of carbohydrates than manufactured, sweet products containing little other than su

Starch is a highly organized mixture of two carbohydrate polymers, amylose and amylopectin, which are synthesized by plant enzymes and simultaneously packed into dense water-insoluble granules. Starch granules vary in size (1 to 100 microns [μ m] in diameter) and shape, which are characteristic of their specific plant origin. Starch is the major energy reserve for plants; it is located mainly in the seeds, roots or tubers, stem pith, and fruit. Starch amylose is primarily a linear chain of glucose units. Amylose chains can coil into double helices and become insoluble in cold water. Amylopectin also is composed of chains of glucose units, but the chains are branched. This branched structure renders amylopectin soluble in cold water. The molecular architecture of the amylopectin and amylose within the granules is not entirely understood, but the granules are insoluble in cold water. The functional properties of native starch are determined by the granule structure. Both the appearance of the granules and their functional properties vary with the plant source.

Physical and Functional Properties

In home cooking and in commercial food processing native starches are used for their thickening properties. Starch granules when heated in water gradually absorb water and swell in size, causing the mixture to thicken. With continued heating however, the swollen granules fragment, the mixture becomes less thick, and the amylose and amylopectin become soluble in the hot mixture. This process of granule swelling and fragmenting is called gelatinization. Once gelatinized the granules cannot be recreated and the starch merely behaves as a mixture of amylose and amylopectin. Because of the larger size of the swollen granules compared to the size of amylose and amylopectin, the viscosity of the swollen granule mixture is much higher than the viscosity (the resistance to flow or a liquid or semi-liquid mixture) of the amylose/amylopectin mixture. Starches from different plant sources vary in their gelatinization temperatures, rate of gelatinization, maximum viscosity, clarity of the gelatinized mixture, and ability to form a solid gel on cooling.

The texture of heat-gelatinized starch mixtures is variable. Some gelatinized starch mixtures have a smooth creamy texture, while others are more pastelike. Some starches form gels after cooking and cooling. These starch gels may lack stability and slowly exude water through the gel surface. A similar breakdown of the gelatinized starch occurs in some frozen foods during thawing and refreezing. Although amylose is soluble in the hot gelatinized starch mixture, it tends to become insoluble in the cooled mixture. This phenomenon is called retrogradation and it occurs when the amylose chains bind together in helical and double helical coils. Retrogradation affects the texture of the food product and it also lowers the digestibility of the product. The proper starches must be employed for the different food products to minimize these problems. Certain starches are good film formers and can be used in coatings or as film barriers for protection of the food from oil absorption during frying.

Native and Modified Starches

The predominant commercial starches are those from field corn (maize), potato, cassava (tapioca), wheat, rice, and arrowroot. Field cornstarch (27 percent amylose and 73 percent amylopectin) is the major commercial starch worldwide. Genetic variants of field corn include waxy maize, which produces a starch with 98 to 100 percent amylopectin, and high-amylose starches, which have amylose contents of 55 percent, 70 percent, and higher. Waxy starch does not form gels and does not retrograde readily. High-amylose starches retrograde more extensively than normal starches and are less digestible. Their linear structure enables them to form films.

From the 1940s on the demand for convenience foods, dry mixes, and various processed foods has led to the modification of starches for food use and for other commercial products. These modified starches improve the textural properties of food products and may be more suitable for use in modern processing equipment. The Food and Drug Administration regulates use of the various modified food starches by stipulating the types of modification allowed, the degree of modification, and the reagents used in chemical modification. However, the food label is required only to state that "modified starch" is present. Only a small fraction of the sites available for modification of the food starches are actually modified. Although the degree of modification is small, the properties of the starches are significantly improved. This small degree of modification is sufficient to give a more soluble and stable starch after cooking. The clarity of the gelatinized starch as well as the stability of the cooked starch and starch gels are improved. The modification procedures are carried out under mild conditions that do not cause gelatinization of the native starch granules, and therefore the functional properties of the granule are preserved. The emulsifying properties of starch also may be improved by proper modification, improving the stability of salad dressings and certain beverages.

Physically modified starches include a pregelatinized starch that is prepared by heat-gelatinization and then dried to a powder. This instant starch is water-soluble and doesn't require further cooking. Because of its lower viscosity resulting from loss of granule structure, the starch can be used at higher concentrations. Certain confectionaries require high levels of starch to give structure to their products. These gelatinized instant starches serve this role. Cold water swelling starches represent a different type of instant starch. They are made by a proprietary process that retains the granule structure but lowers the granule strength. These cold water swelling starches give higher viscosities than the other instant starches. They are used in instant food mixes and for products such as low-fat salad dressings and mayonnaise.

Plant breeding has led to specialty starches with atypical proportions of amylose and amylopectin. Waxy maize starch with nearly 100 percent amylopectin is inherently stable to retrogradation. Chemically cross-linked waxy maize starch is a very high-quality modified starch. High-amylose starches have become available more recently and have led to lower caloric starches. Because of the crystallinity of these starches they are partially resistant to digestion by intestinal amylases and behave as dietary fiber when analyzed by the official methods of analysis for dietary fiber. Some of these high-amylose starches contain as high as 60 percent dietary fiber when analyzed.

The nutritional value of uncooked (ungelatinized) starchy foods (cereal grains, potato, peas, and beans) is relatively poor. Our digestive enzymes do not readily convert the native granular starch of uncooked fruits and vegetables into glucose that would be absorbed in the small intestine. Undigested starch passes into the large intestine where, along with dietary fiber, it is broken down to glucose and fermented to short-chain fatty acids. Some of these short-chain acids are absorbed from the large intestine resulting in recovery of some of the caloric value of the native starch.

Starch-Derived Dextrins and Corn Syrups

Modified starches as described above were developed to improve starch functionality in foods as well as their ability to withstand the physical forces of modern food processing systems. In addition to the food applications of starches and modified starches, the native starches are also converted into other products that serve food and other industries. These products do not require the granular character of native starches, which is lost by chemical or enzymic action during processing of the starch.

Dextrinization, a process requiring high temperatures and acid that has been in use since the early 1800s, converts native starch into dextrins that are composed of amylose and amylopectin chains of smaller sizes and altered structure. Consequently, food and nonfood industries have access to a range of dextrins of varying molecular sizes, solubility, and viscosity, but without the granular characteristics described above. Corn syrups are made in the same way as the dextrins, but they are converted to a higher degree such that glucose is a major ingredient. The more recent availability of an enzyme that converts glucose into fructose has led to a new industry in high-fructose corn syrups, which have found a strong market in beverages.

Bibliography

Frazier, Peter J., Peter Richmond, and Athene M. Donald, eds. Starch Structure and Functionality. Cambridge, U.K.: Royal Society of Chemistry, 1997.

Light, Joseph M. "Modified Food Starches: Why, What, Where, and How." Cereal Foods World 35 (1990): 1081–1092.

Murphy, Pauline. "Starch." In Handbook of Hydrocolloids, edited by Glyn O. Phillips and Peter A. Williams. Cambridge, U.K.: Woodhead Publishing; Boca Raton, Fla.: CRC Press LLC, 2000.

Thomas, David J., and William A. Atwell. Starches. St. Paul, Minn.: Eagan Press, 1999.

—Betty A. Lewis

gar. For example, wholemeal pasta contains high levels of carbohydrate and significant amounts of dietary fibre, minerals, and B complex vitamins. This makes it a favourite pre-race food for many marathon runners: the carbohydrate helps to boost muscle glycogen stores, and the other components help to maintain the health and efficiency of the runner. See also resistant starch.