LIQUID ORALS

By---DEEPAK

Liquid orals contain one or more chemical substances dissolved in a suitable solvent or solvents. Oral solutions, syrups and elixirs. Oral use of liquid pharmaceuticals has been on the basis of ease of administration to those individuals who have difficulty swallowing solid dosage forms.

classification

Solutions can be formulated for different routes of administration

Orally: Syrups, elixirs, drops In mouth and throat: Mouth washes, gargles, throat sprays. In body cavities: Douches, enemas, ear drops, nasal sprays. On body Surfaces: Collodions, lotions.

Advantages of SoIutions
(1) Easier to swallow therefore easier for: children - old age - unconscious people. (2) More quickly effective than tablets and capsules. (3) Homogenous therefore give uniform dose than suspension or emulsion which need shaking. (4) Dilute irritant action of some drugs (aspirin, Kl, KBr) minimize adverse effects in the GIT like KCl.

Disadvantages of SoIutions
(1) Bulky therefore difficult to transport and store.

(2) Unpleasant taste or odors are difficult to mask.

(3) Needs an accurate spoon to measure the dose. (4) Less stable than solid dosage forms. major signs of instability: color change, precipitation microbial growth chemical gas formation

Additives
Buffers To resist any change in pH
Isotonicity modifiers Solutions for injection Application to mucous membrane Large-volume solutions for ophthalmic application

Most widely used isotonicity modifiers are: dextrose and NaCl

Viscosity enhancement It is difficult for aqueous-based topical solutions to remain on the skin or in the eye therefore low concentrations of jelling agents are added to increase the viscosity of the product.

 Preservatives
Solution may become contaminated for a number of reasons: 1. Raw materials used in the manufacture of solutions are excellent growth media for bacterial substances such as gums, dispersing agents, sugars and flavors 2. Equipment, environment and personnel contribute to product contamination. 3. Consumer use may result in the introduction of microorganism. a preservative should be added to the product
Preservative used should be: 1. effective against a wide spectrum of microorganisms 2. stable for its shelf life 3. non toxic, non sensitizing 4. compatible with the ingredients in the dosage form 5. free of taste and odour

Preservatives may be used alone or in combination to prevent the growth of microorganisms. Alcohols Ethanol is useful as a preservative when it is used as a solvent. It needs a relatively high concentration (> 10%) to be effective. Propylene glycol also used as a solvent in oral solutions and topical preparations. It can function as a preservative in the range of 15 to 30%. It is not volatile like ethanol. Acids Benzoic acid and sorbic acid have low solubility in water.

They are used in a concentration range from 0.1 % to 0.5%. Only the non-ionized form is effective and therefore its use is restricted to preparations with a pH below 4.5

Antioxidants
Vitamins, essential oils & almost all fats and oils can be oxidized. Oxidation reaction can be initiated by: 1. heat: maintain oxidizable drugs in a cool place 2. light: use of light- resistant container 3. heavy metals (e.g. Fe, Cu): effect of trace metals can be minimized by using citric acid or ethylenediamine tetraacetic acid (EDTA) i.e. sequestering agent . Antioxidants as propyl & octyl esters of gallic acid, tocopherols or vitamin E, sodium sulfite, ascorbic acid (vit. C) can be used.

Sweetening agents
Sucrose is the most widely used sweetening agent. Advantages: Colourless, highly water soluble, stable over a wide pH range (4-8), increase the viscosity, masks both salty and bitter taste, has soothing effect on throat. Polyhydric alcohols (sorbitol, mannitol and glycerol) possess sweetening power and can be used for diabetic preparations.

Flavours and perfumes

- Mask unpleasant taste or odour -Enable the easy identification of the product. -Natural products: fruit juices, aromatic oil (peppermint, lemon)

-Artificial perfumes are cheaper, more readily available and more stable than natural products.

Classification of Solutions According to Vehicle

(a)

Aqueous solutions

(b) Non-aqueous solutions Aqueous Solutions

Aqueous solutions are homogeneous mixtures that are prepared by dissolving a solid, liquid or gas in an aqueous medium (vehicle). Vehicle: This may be water, aromatic water or extracts.

WATER
Water is used both as vehicle and as a solvent for the desired flavoring or medicinal ingredients. Advantages: Tasteless, odourless, lack of pharmacological activity, neutral and very cheap
Tap Water It is not permitted to use tap water for the dispensing of pharmaceutical dosage forms due to its possible bacterial contamination and the presence of dissolved salts that destroy the active ingredients or enhance their decomposition. Freshly Boiled and Cooled Water Boiling is seldom used to destroy vegetative bacteria. But, on storage for long time spores may yield vegetative microorganism.

Purified Water -Must be used for most pharmaceutical operations and in all the tests and assays. -Such water is prepared by distillation, deionization or reverse osmosis. -Hard" waters are those that contain the Ca and Mg cations. -Alkaline" waters are those that contain bicarbonates as the major impurity. -Ultraviolet energy, heat or filtration (Millipore filtration) can be used to remove or kill the microorganisms present in the water. Water for injection Must be used for the formulation of parental solutions. It is obtained by sterilizing pyrogen-free distilled water.

Aromatic Waters

--Aromatic waters (medicated waters) are clear, saturated aqueous solution of volatile oils or other aromatic or volatile substances.
--They are used principally as flavored or perfumed vehicles. --Volatile oils solutions represent an incompatibility problem of -- salting out. This occurs after the incorporation of a very soluble salt in their solution.

Aromatic water will deteriorate with time therefore:

- should be made in small quantities - protected from intense light and excessive heat by storing in air tight, light resistant containers. --If they become cloudy or otherwise deteriorate; they should be discarded. --Deterioration may be due to volatilization, decomposition or mould growth.

Pharmaceutical Solutions Aqueous

1. Douches 2. Enemas 3. Gargles 4. Mouthwashes 5. Nasal washes 6. Juices 7. Sprays 8. Otic solutions 9. Inhalations

Sweet &/or Viscid Nonaqueous

1. Syrups 2. Honeys 3. Mucilages 4. Jellies 1. Elixirs 2. Spirits 3. Collodions 4. Glycerins 5. Liniments 6. Oleo Vitamin

Douches
--Douche is an aqueous solution, which is directed against a part or into a cavity of the body. --It functions as a cleansing or antiseptic agent. --Eye douches are used to remove foreign particles and discharges from the eyes. It is directed gently at an oblique angle and is allowed to run from the inner to the outer corner of the eye. --Pharyngeal douches are used to prepare the interior of the throat for an operation and to cleanse it in supportive conditions. --Similarly, there are nasal and vaginal douches. --Douches most frequently dispensed in the form of a powder with directions for dissolving in a specified quantity of water.

Enemas
--These preparations are rectal injections employed to: -evacuate the bowel (evacuation enemas),

-influence the general system by absorption (retention enemas) e.g. nutritive, sedative or stimulating properties
-affect locally the site of disease (e.g. anthelmintic property)

--Retention enemas are used in small quantities (about 30ml) and are thus called retention microenema.
--Starch enema may be used either by itself or as a vehicle for other forms of medication

Gargles
--Gargles are aqueous solutions frequently containing antiseptics, antibiotics and/or anesthetics used for treating the pharynx (throat) and nasopharynx by forcing air from the lungs through the gargle, which is held in the throat; subsequently, the gargle is expectorated.
--Many gargles must be diluted with water prior to use. Although mouthwashes are considered as a separate class of pharmaceuticals many are used as gargles, either as is, or diluted with water. --The product should be labeled so that it cannot be mistaken for preparations intended for internal administration.

Mouthwashes
Mouthwashes can be used for therapeutic & cosmetic purposes --Therapeutic mouthwashes can be formulated to reduce plaque, gingivitis, dental caries and stomatitis. --Cosmetic mouthwashes may be formulated to reduce bad breath through the use of antimicrobial and/or flavoring agents.

Mouthwashes are used as a dosage form for a number of specific problems in the oraI cavity

Mouthwashes generally contain four groups of excipients

AIcohols: (10-20% in MW) may function as a preservative. aids in masking the unpleasant taste of active ingredients, functions as a solubilizing agent for some flavoring agents
Humectants: such as glycerin and sorbitol (5-20% in MW) increase the viscosity of the preparation enhance the sweetness of the product improve the preservative qualities of the product. Surfactants: Non ionic and anionic surfactants aid in the solubilization of flavors and in the removal of debris by providing foaming action. Cationic surfactants such as cetylpyridinium chloride are used for their antimicrobial properties, but these tend to impart a bitter taste. Flavours: are used in conjunction with alcohol and humectants to overcome disagreeable tastes. The principle flavoring agents are peppermint, cinnamon, menthol or methyl salicylate.

CoIouring agents: also are used in these products.

Sweet &/or Viscid include Syrups, Honeys, Mucilages, and Jellies. All of these preparations are viscous liquids or semisolids. The sweetness and viscid appearance are given by sugars, polyols, or polysaccharides (gums). SYRUPS Syrups are concentrated solutions of sugar such as sucrose in water or other aqueous liquid. simple syrup: when water is used alone for making syrup. medicated syrup: when the aqueous preparation contains some added medicinal substance flavored syrup: which contains aromatic or pleasantly flavored substances and is intended to be used as a vehicle or flavor for prescriptions

Polyols (e.g. glycerin or sorbitol) may be added to - retard crystallization of sucrose or - increase the solubility of added ingredients. Alcohol often is included as - preservative - solvent for volatile oils. Syrups possess remarkable masking properties for bitter and saline drugs.

Preservation of Syrups

--The USP suggests that syrups be kept at a temperature not above 25C.
--Preservatives such as glycerin, methyl paraben, benzoic acid and sodium benzoate may be added to prevent bacterial and mold growth, particularly when the concentration of sucrose in the syrup is low. --The concentration of preservative is proportional to the free water. --The official syrups should be preserved in well dried bottles and stored in a cool dark place.

HONEYS
Are thick liquid preparations. At one time, before sugar was available, honey was used as a base, instead of syrup. There are few official preparations containing honey. e.g. Oxymel, or" acid honey "'is a mixture of acetic acid, water and honey

MUCILAGES
--The official mucilages are thick viscid, adhesive liquids, produced by dispersing gum (acacia or tragacanth) in water. --Mucilages are used as suspending agents for insoluble substances in liquids; their colloidal character and viscosity prevent immediate sedimentation.

--Synthetic agents e.g. carboxymethylcellulose (CMC) or polyvinyl alcohol are nonglycogenetic and may be used for diabetic patients.

Jellys
--Preparations having a jelly-like consistency. They are prepared also from gums. --Are used as lubricants for surgical gloves and catheters --Lidocaine HCl Jelly USP is used as a topical anaethetic.

Advantages
--If the drug is not completely soluble or unstable in aqueous medium it may be necessary to use an alternative non-aqueous solvent.

--Oily solutions of drugs are often used for depot therapy e.g. in muscles
It is essential to test: toxicity irritancy flammability cost stability and compatibility of solvents to avoid problems --Solvents such as acetone, benzene and petroleum ether are not used for internal products.

--Internal products may contain ethanol, glycerol, propylene glycol certain oils.
--For parental products the choice is very limited

non-aqueous solutions: 1. alcoholic or hydroalcoholic solutions, e.g. elixirs and spirits, 2. ethereal solutions, e.g. the collodions 3. glycerin solutions, e.g. the glycerites, 4. oleaginous soIutions e.g. the liniments, medicated oils, oleovitamins, sprays, and toothache drops.

ELIXIRS
--Are clear, pleasantly flavored, sweetened hydroalcoholic liquids intended for oral use. --They are used as flavors and vehicles e.g. Dexamethasone Elixir USP and Phenobarbital Elixir USP. --The main ingredients in elixirs are ethanol and water but glycerin, sorbitol, propylene glycol, flavoring agents, preservatives, and syrups are often used in the preparation of the final product. --EIixirs contain ethyl alcohol, however, the alcoholic content will vary greatly, from elixir containing only a small quantity to those that contain a considerable portion as a necessary aid to solubility --An elixir may contain water and alcohol soluble ingredients.

Incompatibility of elixir: --Alcohol precipitates water soluble substances e.g. tragacanth, acacia agar and many inorganic salts from aqueous solutions.

--If an aqueous solution is added to an elixir, a partial precipitation of ingredients may occur. This is due to the reduced alcoholic content of the final preparation.

SPIRITS
--Alcoholic or hydroalcoholic solutions of volatile substances. The active ingredient may be gas, liquid or solid. --Spirits may be used internally for their medicinal value, by inhalation but is mostly used as flavouring agents. --Spirits should be stored in tight, light-resistant containers and in a cool place, WHY?

--Spirits are preparation of high alcoholic strength and when diluted with aqueous solutions or liquids of low alcoholic content turbidity may occur, WHY?

COLLODIONS
--Are liquid preparations containing pyroxylin (a nitrocellulose) in a mixture of ethyl ether and ethanol. -- They are applied to the skin by means of a soft brush or other suitable applicator and, when the ether and ethanol have evaporated, leave a film of pyroxylin on the surface. --The official medicated collodion, Salicylic Acid Collodion USP, contains 10 % w/v of Salicylic Acid in Flexible Collodion USP and is used as a keratolytic agent in the treatment of corns and warts. --Collodion is made flexible by the addition of castor oil and camphor.

LINIMENTS
--Are solutions or mixtures of various substances in oil, alcoholic solutions of soaps, or emulsions.
--They are intended for external application and should be so labeled. --They are applied with rubbing to the affected area, the oil or soap base providing for ease of application and massage. -- Alcoholic liniments are used generally for their rubefaciant and counterirritant effects. Such liniments penetrate the skin more readily than do those with an oil base. --The oily liniments are milder in their action and may function solely as protective coatings. --Liniments should not be applied to skin that are bruised or broken.

RELEVANT PROCESSING EQUIPMENTS

Most equipment has heating/cooling capabilities to effect rapid dissolution of component of the system. Adequate transfer system & filtration equipment are required All equipment must be made of suitable , nonreactive , sanitary materials & be designed & constructed to facilitate easy cleaning. If interaction occurs metallic surfaces can be minimized by use of glass Or polytetraflourroethylene (teflon) liners.

The equipment must be selected according to the size of the batch & maximum Viscosity of the production.
Instruments used are Agitators High shear mixing equipment Homogenizing equipment Inprocess or final product filters Screens Pumps Filling equipment

PROCESS EVALUATION Items that should be examined include the following: Order of addition of components , including adjustments of their amounts. Mixing speed Mixing time Rate of addition of solvents , solution of drug , slurries etc. Heating & cooling rates Filter sizes (liquid)

MANUFACTURING CONSIDERATION o RAW MATERIALS:-Should free from any microbial contamination and also assure. Identity Purity Uniformity o The raw material received are thoroughly tested for specifications before they enter the manufacturing area. o Aside from active ingredient, water is most important.

Consist of Mixing tanks equipped with: Means of agitation. Measuring devices for large and small amounts of solids and liquids. Filtration system for the final polishing or sterilization of the solution. All equipment - thoroughly cleaned and sanitized before use. Disinfectants dilute solution of H2O2, Phenol derivatives. May sterilized by- Alcohol, Boiling water, Autoclaving, Steam or Dry heat.

The mixing apparatus consists of a container (tank) and a mixing device. These are assembled and used for the batch process. Mixing device is called impeller, which is mounted with the help of a shaft, which is driven by a motor.

Metal strips. Placed vertically to the internal surface. When bulk transport is important in mixing, baffles are used. Baffles facilitates intermingling of the liquids. Four baffles are sufficient, even one or two baffles provide a strong effect on mixing. The width of the baffles may be from 1/10th to 1/18th of the tank diameter.

Technically called as impeller. Mixing device are used to supply energy to the system so long as to bring about reasonably rapid mixing. Flow currents are responsible for transporting unmixed materials to the mixing zone. The impeller are classified on the basis of the shape and pitch of the blades are used.
Propellers Turbines Paddles

A propeller normally contains a number of blades.

A three bladed design is he most common for liquids. The marine type propeller is similar to the blades of a table fan or a ceiling fan.

Propellers may be either right or left handed, depending o the direction of slant of their blades. Four blade or toothed or similar design propellers are used for special purposes. These work in opposite directions to create a zone of high turbulence.

Propellers are used when high mixing capacity is needed. Effective in handling liquids having a maximum viscosity of about 2.0 Pascals second and slurries up to 10% solids of fine mesh size. They can be used up to 3500 liters. DISADVANTAGE Propellers are not normally effective with liquids of viscosity greater than 5 Pascal second, for e.g., glycerin, castor oil etc.

Consists of a circular disc number of short blades are attached. The diameter of the turbine ranges from 30-50% of the diameter of the vessel. It rotate at a lower speed than propeller (50-200 revolution per minute)

A paddle consists of a hub centrally with two long flat blades attached to it vertically. The blades are dished or hemispherical in shape and have a large surface area in relation to the tank Antacid suspension, agar & pectin related purgatives.

Size, Shape, Working capacity & construction. Adequate size & suitable mixing facilities. Heating & cooling capabilities to rapid dissolution of component. Construction material should not affect chemically/Physically stability. Portable mixer use.

Depends on the various characteristic like: Viscosity, Surface tension, Foaming quality. The methods used for the filling the liquid varies:-by four basic filling methods: Gravimetric. Volumetric. Constant level filling.

This is accomplished by a positive displacement piston action. Each filling station is equipped with a measuring piston & cylinder. It determines the accuracy of the filling. The filled amount is measured by the stroke of the piston. This device is capable of accuracy within fractions of ml.

DISADVANTAGESHighly viscous liquids can cause the piston to seize resulting in loss of fill or inaccuracy or line break down. Thin liquids may flow past the piston resulting in uncontrollable dripping from the filling spout. But if the machinery is engineered correctly these problems can be overcomed.

This uses the container as the means for controlling the fill of each unit. The fill amount is varied by adjusting the height to which the container is filled. The high speed, automated, constant level filling machines are used today with the major modification being the induced pressure differential between the liquid discharge nozzle & the constant level overflow system.

The most widely used method under this are:Vacuum filling. Gravity vacuum filling. Pressure vacuum filling.

For vacuum filling a seal is made between the filling head & the container. A vacuum is then developed within the container, this result in the flow of the liquid from the bulk liquid tank to the container. The liquid level rises until it reaches the vacuum tube, which is positioned at the desired constant level. If Excess liquid is drawn through the vacuum tube.

The principle same as vacuum filling, but in this type the bulk liquid tanks are kept at a level above the filling system, so that the driving force for the liquid flow results from both the negative pressure in the container & the force of gravity.

A positive pressure is applied to the bulk liquid. Which in combination with the vacuum is developed in the container. This results in a pressure difference. This allows for rapid filling of even highly viscous liquid.