Liquid dosage forms Excipients

Excipients used in the formulation of liquid dosage form

Excipients are the inactive ingredients in the dosage form added for pharmaceutical purposes. Excipients are also called pharmaceutical aids or additives. They are used in liquid dosage forms to improve The stability, taste, preservation, appearance, and overall performance of the liquid dosage forms.

1. Vehicle: A Vehicle is a pharmaceutical aid to carry active ingredients in the liquid dosage form. Vehicles for liquid dosage forms are divided into three categories. These are Aqueous vehicles, Non-aqueous vehicles, and Alcohol.

   • Aqueous vehicles: Water, Aromatic water, and syrup.

     • Water is the commonest vehicle to form liquid dosage forms. It is preferred because it is a natural component of the human body, easily administered into the human body, does not interfere with the metabolic activity of the human body, dissolves a large number of pharmaceuticals, and mixes easily with the large numbers of pharmaceuticals. Potable water contains dissolved inorganic impurities. Thus, purified water (Distilled water or De-mineralized water) is used for pharmaceutical purposes. Water for injection sterile water for injection or bacteriostatic water for injection is used as a vehicle to prepare liquid dosage form for parenteral applications. Water for injection is distilled water free from microorganisms and pyrogen.

     • Aromatic Water: Aromatic water is a saturated solution of essential oil or similar substances in purified water. Examples are Rose Water, Dill Water, Peppermint Water, Cinnamon Water, Chloroform Water, Camphor Water, etc. Aromatic waters are used as vehicles due to their flavoring properties. They also have mild therapeutic properties such as carminative and/or preservative.

     • Alcohol: Ethanol, Propylene Glycol, Glycerol, Sorbitol, Polyethylene Glycol, etc. Alcohol is the most commonly used vehicle in liquid dosage form after water.

     • Ethanol is available for pharmaceutical purposes as an absolute alcohol (dehydrated alcohol) and hydro alcohol. Absolute alcohol is free from water. Ethanol in the form of hydro alcoholic mixture is used as a vehicle in liquid dosage form most commonly. Hydroalcoholic mixture easily dissolves both water-soluble and alcohol-soluble ingredients in the liquid dosage forms. Ethanol also acts as a preservative and sanitizer due to its bactericidal activity.

     • Glycerol (Glycerin): Glycerin is clear, colorless, odorless, thick, very sweet in the test, and slightly warm to test. It is soluble in both water and ethanol and insoluble in ether, fixed oil (vegetable oil), etc. It is an excellent solvent for several pharmaceuticals especially to be applied on the skin and to sore. It does not evaporate nor become rancid. It is used as a humectant, and demulcent, to increase the viscosity, taste, and flavor of liquid preparations, It also acts as a cosolvent for pharmaceuticals with low solubility in water.

     • Propylene Glycol (PG): It is used as a solvent for several pharmaceuticals to be used in cosmetics, toothpaste, shampoo, and mouthwash. It contributes to the stability and effectiveness of the formulation. It is used commonly in pharmaceutical industries as a vehicle for the following reasons.

     • i. Solvent: Propylene glycol (PG) is colorless and odorless with characteristic test liquid with excellent solvent properties.

     • ii. Stability: PG is stable and does not react with several pharmaceuticals. It is a very effective preservative and stabilizer that helps to maintain the integrity of the dosage forms for a longer duration.

     • iii. Hygroscopic: Its hygroscopic property makes PG very effective humectants. It retains moisture and prevents drying of the formulation. It also maintains moisture at the site of its application.

     • iv. Viscosity: PG helps to adjust the viscosity of the formulation. It ensures easy pouring and accurate dispensing of the medicines.

     • v. Low toxicity: It is safe for oral, topical, and parenteral application if used in appropriate concentration. However, its use in children is discouraged due to its CNS adverse effects, especially in neonates.

   • Non-Aqueous Vehicle: Lipids. Glycerol and propylene glycol are also considered non-aqueous vehicles.

     • Lipids: Several drugs have low solubility in water. For them, lipid-based formulations are used. These formulations have the following advantages

       • i. Solubility enhancement: Lipids improve the solubility of poorly water-soluble drugs.

       • ii. Bioavailability: Lipid-based formulation increases the bioavailability of drugs. Lipid-based formulation increases the absorption of the drug from the gastrointestinal tract. It is useful for the drug with low oral bioavailability.

       • iii. Taste masking: Lipids mask the unpleasant test of the drug in the liquid dosage form.

       • iv. Protection: The lipid in the formulation protects the drug molecules from light, heat, and air. This helps to maintain the stability of the drug

Commonly used lipid-based vehicles are lipid emulsions, Liposomes, Solid lipid nanoparticles, self-emulsifying drug delivery systems, etc.

Preservatives

Preservatives are added in the pharmaceutical formulation to prevent or stop the growth of microorganisms throughout the shelf life of the preparation. Normally liquid dosage form contains water and emulsifying agent or suspending agent. Most of the emulsifying agents and suspending agents are carbohydrates. Both water and carbohydrates support the microorganism's growth. Thus these formulations require preservatives.

Parenteral preparation in a unit dose container does not require preservatives but multi-dose containers require preservatives. Microorganisms may enter into multi-dose containers during the withdrawal of the drug. Preservatives in ophthalmic solution must be gentle and well tolerated because eye tissues are very delicate.

Preservatives are essential in the formulation for the following purposes

• i. Microbial control

• ii. Prolong the shelf life of the formulation

• iii. Patient safety.

The most common preservatives are Benzalkonium chloride, Chlorhexidine, Methyl paraben, Propyl paraben, Sodium benzoate, Phenol, Chlorocresol, Ascorbic acid, salicylic acid, etc.

Choice of preservatives: Preservatives should be carefully selected and used in appropriate concentration. This ensures the effectiveness of preservatives and minimizes adverse effects of the preservatives on the human body. The preservatives should have the following characteristics:

• i. Non-toxic

• ii. Free from odor and taste

• iii. Remain stable during the shelf life of the drug,

• iv. Effective against a wide range of microorganisms,

• v. Compatible with other ingredients of the formulation

• vi. Soluble in the aqueous phase of the emulsion formulation.

Stabilizer

Stabilizer maintains the physical and chemical stability of the formulation during its shelf life period. They perform the following functions to improve stability of the liquid formulation.

• i. Prevent Chemical Degradation: Chemical reactions take place in the formulation during their shelf life such as oxidation, dehydration, photolysis, hydrolysis, etc. Among them, oxidation and decomposition under light are the most common.

  Some liquid formulations containing unsaturated fatty acids undergo rancidity. Rancidity is an auto-oxidation of unsaturated fatty acids. Rancidity makes the product rancid and develops a characteristic rancid odor in the liquid formulation.

  Stabilizers act as antioxidants or chelating agents. Antioxidants have a great affinity with oxygen. They compete with formulation ingredients to combine with oxygen. All oxygen will be utilized by the antioxidant. This action of antioxidants protects formulation ingredients from oxidation.

  Stabilizers should be colorless, non-toxic, non-irritant, thermostable, compatible with ingredients and packaging materials, and effective against a wide range of pH and temperature.

  Some of the commonly used antioxidants are ascorbic acid, tocopherol, sodium metabisulfite, sodium bisulfate, sodium thiosulphate, etc. Sometimes combination of chelating agents and antioxidants is used as a stabilizer. This combination has a synergistic effect to protect the formulation from degradation. These properties inhibit chemical reactions and protect against formulation degradation.

• ii. Protection against microbial growth: Some stabilizers act as antimicrobial agents. But this is not the primary function of a stabilizer.

• iii. Phase Separation: The separation of components in liquid dosage form is called phase separation. It is most common in emulsion and suspension. Stabilizers prevent this separation to maintain the homogeneity of the product formulation throughout its shelf life.

• iv. Reduction of Particle Agglomeration: Solid particles in suspension settle down in the bottom of the container during storage. This causes uneven dosing. Stabilizers keep these solid particles evenly distributed. This prevents particle agglomeration and ensures accurate dosing.

• v. Emulsion Stability: Stabilizers form a protective layer around dispersed droplets in the emulsion. This prevents dispersed droplet coalescence and separation. This ensures the physical stability of the emulsion.

• vi. Improve texture and mouth feel: Some stabilizers enhance the texture and mouth feel of the product such as improvement of the creaminess of the suspension or smoothness of the syrup. They make the product more palatable.

Common examples of stabilizers are polysorbate 80, carboxymethylcellulose, sodium alginate, sorbitol, bentonite, etc.

organoleptic agents

organoleptic agents are Flavoring agents, Coloring agents, and Sweetening agents.

 Flavoring agents

Flavor is not just only about taste. It is a combination of pleasant taste, aroma, temperature, texture, and visual sensation. Flavoring agents are volatile in nature with a prominent pleasant odor. Flavoring agents are used for the following purposes:

• i. Imparting pleasant odor

• ii. Masking unpleasant taste

• iii. Enhancing palatability

• iv. Improving user experience

Both natural and synthetic flavoring agents are available for pharmaceutical purposes. Generally, liquid dosage forms for oral administration are flavored with fruity or spicy flavoring agents. Liquid dosage forms for external application are flavored with a flowery flavoring agent. Examples of flavoring agents are coffee, vanilla, chocolate, tolu balsam, malt extract, pineapple, cardamom, cinnamon, peppermint, menthol, volatile oil from clove, dill, lemon, orange, rose, etc. Synthetic chemicals such as certain alcohols, aldehydes, esters, fatty acids ketones, and lactones are also used as flavoring agents. They are preferred over natural flavoring agents due to the following reasons readily available, Economic, More stable, constant composition, and easy prediction of their incompatibility. Normally, a blend of flavoring agents is used to mask the odor and taste of liquid dosage forms.

Selection of flavoring agents:

• i. Cinnamon flavor followed by orange syrup, coca syrup, cherry syrup, and raspberry are suitable for the salty liquid dosage forms,

• ii. Coca syrup, raspberry syrup, and cherry syrup are used for bitter taste liquid dosage forms,

• iii. Raspberry and other fruit syrup are preferred to mask the sour taste of liquid dosage forms,.

• iv. The oily taste of liquid dosage forms is masked by peppermint oil, wintergreen oil, malt extract, etc

  Flavoring agents are dissolved in a suitable solvent. Then it is added into preparation. Water is used to dissolve water-soluble flavoring agents. Poorly water-soluble flavoring agents are dissolved in alcohol or hydro-alcoholic solvent.

Sweetening agents

Sweetening agents are used in liquid dosage forms for oral administration. Sweetening agents perform the following functions

• i. Mask the unpleasant tastes such as bitter, sour, and other disagreeable tastes.

• ii. Enhance patient acceptance

• iii. Improve palatability

The commonly used sweetening agents for liquid dosage forms are sucrose, sorbitol, honey, maple syrup, and artificial sweeteners such as saccharine, aspartame, cyclamate, etc. Sorbitol, saccharine, and aspartame are sugar-free sweetening agents. Sweetening agents and their concentration are selected carefully to product stability while providing a pleasant taste. Patients suffering from diabetes or on a restricted diet to control weight prefer sugar-free sweetening agents.

Coloring agent (Colorants)

Coloring agents are used to increase the organoleptic properties of the liquid dosage forms. In liquid dosage forms, colorants serve the following purposes:

• i. Aesthetic appeal: Coloring agents are used as sensory adjuvant. It helps to increase product patient acceptability. It is especially helpful for pediatric patients and geriatric patients.

• ii. Masking unwanted color: Unwanted color develops in the preparation during their manufacturing or storage. This unwanted color is masked by using a flavoring agent. This improves the patient's confidence regarding preparation quality.

• iii. Identification: Colorants help to distinguish the formulation of different strengths of the same API.

• iv. Brand recognition: Sometimes colorants help to recognize a specific brand or specific manufacturer.

Types of colorants: The following are commonly used colorants for the liquid dosage forms

• i. Natural colorants: Sources of natural colorants are plants, animals, and minerals. Colorants obtained from minerals are also called pigments. They were used in cosmetics and preparations meant for external applications. But now they have been replaced by synthetic colorants. Examples are ferric oxide, titanium dioxide, carbon black, etc. Colorants from plants are chlorophyll, indigo, carotenoids, flavons, etc. Very colorants are from animal sources. Examples are carminic acid from the insect Coccus cacti cochineal. Natural colorants are not in use due to the easy availability of synthetic colorants.

• ii. Synthetic colorants: Coal tar is used to prepare synthetic colorants such as nitro-dyes, nitroso-dye, azo-dye, rosanilines, etc. Only colorants mentioned in the Drugs and Cosmetics Act-1940 are used in the pharmaceutical industry. Coloring agents should be used in appropriate concentration. Most of the colorants in liquid dosage forms for internal administration retard the absorption of API inside GIT.

Surfactants (Surface active agents)

Surfactants lower the interfacial tension between two phases to make them miscible. They are mainly used to make two immiscible liquids miscible and to make insoluble solids miscible in water. They are used in almost liquid dosage forms, semisolid dosage forms, and solid dosage forms. They are used as excipients such as emulsifying agents, solubilizing agents, wetting agents, foaming agents, antifoaming agents, flocculating agents, deflocculating agents, and detergents.

Surfactant molecules have two parts. These are polar and nonpolar parts. In liquid dosage forms containing immiscible liquids or insoluble solids, polar parts move towards ingredients with high polarity and nonpolar parts move towards ingredients with low polarity. They are absorbed in between both phases. The layer between both phases is called interphase. Interphase becomes saturated with surfactant as the concentration of surfactant is increased in the formulation.

Surfactant molecules move towards the bulk of the preparation after a further increase in their concentration. Surfactant molecules aggregate to form micelles. One micelle consists of 50 to 150 surfactants. The concentration of surfactants that form micelles is called critical micelle concentration (CMC). Visible effects of surfactants in formulation start at CMC and their effects increase with further increase in concentration of surfactants.

Classification of Surfactants: The most accepted classification of surfactants is based on their ionic behavior.

• i. Anionic surfactants: They ionize inside water. Its anionic portions act as surfactants such as soap of monovalent metals, soap of divalent metals, sulfated compounds, sulfonated compounds, etc. Examples of sulfated compounds are sodium lauryl sulfate, sodium cetyl sulfate, etc. An example of a sulfonated compound is dioctyl sodium sulfosuccinate. (Sulphated compounds have sulfate group SO4—and sulfonated compounds have sulfonate group SO3-). They are normally used as emulsifying agents.

• ii. Cationic surfactants: They ionize inside water and their cationic portions act as surfactants. Examples are benzalkonium chloride, cetyl trimethyl ammonium bromide, etc. They are normally used as emulsifying agents.

• iii. Non-ionic surfactants: They are not ionized in the water. They are stable over a wide range of pH. They are the most commonly used surfactants in pharmaceutical industries.

Hydrocolloids

 They are high molecular weight substances used to increase the viscosity of the solution, suspension, and gel. Gum is a commonly used hydrocolloid in pharmaceutical industries. Gums consist of polysaccharides and proteins. They are more soluble in hot water. They precipitate or form gel on cooling. Examples are agar and gelatin. Some polymers are also hydrocolloids such as methyl cellulose, hydroxypropyl cellulose, etc. They are soluble in cold water. Their solubility in water decreases with an increase in temperature.

Classification of hydrocolloids: Hydrocolloids are classified into the following three classes

• i. Natural hydrocolloids: They are obtained from plants, animals, and minerals. Hydrocolloids from plants such as gum are most commonly used. Chemically they are polysaccharides. Examples are acacia, tragacanth, agar, etc.

• ii. Semi-synthetic Hydrocolloids: Chemical modification of cellulose from plant source of semi-synthetic hydrocolloids. Examples are methyl-cellulose, sodium carboxymethyl cellulose, hydroxyl ethyl cellulose, etc.

• iii. Synthetic hydrocolloids: Carbopols, polyox, etc.