Unit 7 Module 11: Liquid Dosage Forms - Pharmaceutical Solutions
Introduction to Liquid Dosage Forms
Liquid Dosage Forms (LDFs) are pourable pharmaceutical formulations that contain active drug components and non-drug components (excipients) dissolved or suspended in a suitable solvent or solvent mixture.
They are designed to provide maximum therapeutic response, particularly for target populations who have difficulty swallowing solid dosage forms, and to produce rapid therapeutic effects.
LDFs are prepared by:
Dissolving the active drug substance in an aqueous or non-aqueous solvent (e.g., alcohol, ether, glycerin).
Suspending the drug in an appropriate medium.
Incorporating the drug substance into an oil or water phase.
LDFs are classified into:
Monophasic LDFs
Biphasic LDFs
Solutions
In physicochemical terms, solutions can be prepared from any combination of solid, liquid, or gas, which are the three states of matter.
They are liquid preparations comprising one or more soluble chemical substances dissolved in a suitable solvent or a mixture of mutually miscible solvents.
Solutions are homogeneous mixtures formed by dissolving a solid, liquid, or gas in another liquid, where the molecules of the solute (dissolved substance) are dispersed.
Types of Solutions
Solid Solution – The solvent is solid.
Solid in solid: Example: Cu + gold = 12 karat yellow gold.
Liquid in solid: Example: Hg dissolved in Ag = amalgam.
Gas in solid: Example: air dissolved in soap = floating soap.
Liquid Solution – The solvent is liquid.
Solid in liquid: Example: salt in water.
Liquid in liquid: Example: alcohol and water.
Gases in liquid: Example: carbonated beverages.
Gaseous Solutions – The solvent is gas.
Solid in gas: Example: sulfur in air.
Liquid in gas: Example: water vapor in air.
Gas in gas: Example: oxygenated air.
Solubility
Solubility is expressed as grams of solute dissolving in milliliters of solvent.
USP Descriptive Terms of Solubility (Relative Terms):
Very soluble: <1 part of solvent required for 1 part of solute.
Freely soluble: 1 - 10 parts of solvent required for 1 part of solute.
Soluble: 10 - 30 parts of solvent required for 1 part of solute.
Sparingly soluble: 30 - 100 parts of solvent required for 1 part of solute.
Slightly soluble: 100 - 1,000 parts of solvent required for 1 part of solute.
Very slightly soluble: 1,000 - 10,000 parts of solvent required for 1 part of solute.
Practically insoluble or insoluble: >10,000 parts of solvent required for 1 part of solute.
Factors Affecting the Rate of Solubility
Particle size: An increase in surface area (achieved by comminution) will increase the rate of solution.
Agitation: Increases the rate of solution by continually removing more concentrated solution from the surface of the solute, allowing less concentrated solvent to interact.
Temperature: Heating a liquid generally causes solution to occur more rapidly by increasing the frequency with which solvent molecules collide with the surface of the dissolving mixture.
Factors Affecting Solubility of Solute
Temperature:
Endothermic reaction: Heat is absorbed; an increase in temperature will cause more of the solute to go into solution.
Exothermic reaction: Solute gives off heat; solubility is decreased with an increase in temperature. Examples: methyl cellulose and calcium salts like {\rm Ca}({{\rm OH})_2} are more soluble in cold than hot water.
Molecular Structure: The general rule is "like dissolves like."
Effects of other substances: Example: Iodine is very slightly soluble in water, but when added to a concentrated solution of KI, it dissolves immediately.
pH: The aqueous solubility of many organic substances used medicinally, particularly weak acids or weak bases, depends on the pH of the solvent.
Examples of Weak Bases: Alkaloids (atropine, codeine, morphine), antihistamines (diphenhydramine, tripelennamine), local anesthetics (cocaine, procaine, tetracaine).
Examples of Weak Acids: Barbiturates (phenobarbital, pentobarbital), sulfonamides (sulfadiazine, sulfacetamide).
Solubility of Inorganic Molecules
Monovalent cations and anions of an ionic compound are generally water soluble (e.g., NaCl, LiBr, KI, {\rm NH4}{\rm NO3}).
Compounds where only one of the two ions is monovalent are typically water soluble (e.g., {\rm BaCl2}, {\rm MgI2}, {\rm Na2}{\rm SO4}, {\rm Na3}{\rm PO4}).
Compounds with both ions being multivalent often have poor water solubility (e.g., {\rm CaSO4}, {\rm BaSO4}, {\rm BiPO4}). Exceptions include {\rm ZnSO4} and {\rm FeSO_4}.
Common salts of alkali metals are usually water soluble, with {\rm Li2}{\rm CO3} as an exception.
{\rm NH4} and quaternary {\rm NH4} salts are water soluble.
Nitrates, nitrites, acetates, chlorates, and lactates are generally water soluble, with exceptions for silver and mercurous acetate.
Sulfates, sulfites, and thiosulfates are generally water soluble, with exceptions for Calcium and Barium salts.
Chlorides, bromides, and iodides are water soluble, with exceptions for salts of silver and mercurous ions.
Acid salts corresponding to an insoluble salt will be more water soluble than organic salts.
Hydroxides and oxides of compounds other than alkali metal cations and the ammonium ion are generally water insoluble.
Sulfides are water insoluble, except for their alkali metal salts.
Phosphates, carbonates, silicates, borates, and hypochlorites are water insoluble, except for their alkali metal salts and ammonium salts.
Solubility of Organic Molecules
Molecules with 1 polar functional group are soluble up to a total carbon chain length of 5 carbons.
Molecules with branched chains are more soluble than their corresponding straight-chain compounds.
Water solubility decreases with an increase in molecular weight (MW).
Increased structural similarity between solute and solvent is accompanied by increased solubility.
Solvents for Liquid Preparations
Water: Widest range of usefulness, good solvent for most inorganic and organic substances.
Alcohol USP (Ethyl Alcohol, Ethanol): Good solvent for many organic substances (natural and synthetic). It is 94.9 to 96.0\% alcohol at 15.56^ extrm{o}{
m C}. Limits: 0.5\% for 6 to 12 years, 5\% for over 12, 10\% for adults.Dehydrated Alcohol: 99.5\% absolute alcohol, partially free from water.
Diluted Alcohol NF: Prepared by mixing equal volumes of Alcohol USP and purified water.
Alcohol, Rubbing: Contains about 70\% ethyl alcohol by volume, remainder is water, denaturants, and optional additives.
Glycerin USP (Glycerol): Clear, syrupy liquid with a sweet taste. Miscible with both water and alcohol. Excellent solvent for tannins, phenol, and boric acid. Possesses preservative qualities.
Propylene Glycol: Miscible in water, acetone, alcohol, and chloroform.
Polyethylene Glycol 400: Miscible in water, acetone, alcohol, and other glycols.
Chloroform: Miscible with alcohol, ether, benzene, hexane, and both fixed and volatile oils.
Acetone: Miscible with water, alcohol, ether, chloroform, and most volatile oils.
Methods of Preparing Solutions
Simple Solution: Prepared by dissolving the solute in the solvent. Examples: Calcium hydroxide solution USP (lime water), Sodium Phosphate solution, Strong Iodine solution USP (Lugol’s).
Solution by Chemical Reaction: Prepared by reacting two or more solutes with each other in a suitable solvent. Examples: Aluminum subacetate (reacting aluminum sulfate with calcium carbonate and acetic acid), Magnesium Citrate (reacting magnesium carbonate with citric acid), Sodium Citrate and Citric acid oral solution (Systemic alkalinizer).
Solution by Extraction: Vegetable or animal origins are often extracted with a suitable solvent. These preparations are often classified as extractives.
Common Methods of Expressing the Strengths of Pharmaceutical Preparations
Percent weight in volume (w/v): Number of grams of a constituent in 100\,\textrm{mL} of preparation. (1\%\ \textrm{w/v} = 1\,\textrm{g} of constituent in 100\,\textrm{mL} of preparation).
Percent volume in volume (v/v): Number of mL of constituent in 100\,\textrm{mL} of preparation. (1\%\ \textrm{v/v} = 1\,\textrm{mL} of constituent in 100\,\textrm{mL} of preparation).
Percent weight in weight (w/w): Number of grams of a constituent in 100\,\textrm{g} of preparation. (1\%\ \textrm{w/w} = 1\,\textrm{g} of constituent in 100\,\textrm{g} of preparation).
Ratio strength: weight in volume (w/v): Number of grams of constituent in stated number of mL of preparation. (1:1000\ \textrm{w/v} = 1\,\textrm{g} of constituent in 1000\,\textrm{mL} of preparation).
Ratio strength: volume in volume (v/v): Number of mL of constituent in stated number of mL of preparation. (1:1000\ \textrm{v/v} = 1\,\textrm{mL} of constituent in 1000\,\textrm{mL} of preparation).
Ratio strength: weight in weight (w/w): Number of grams of constituent in stated number of grams of preparation. (1:1000\ \textrm{w/w} = 1\,\textrm{g} of constituent in 1000\,\textrm{g} of preparation).
Examples of Oral Solution by Category (Ansel’s)
Antidepressants: Nortriptyline HCl (Pamelor Oral Solution), Fluoxetine HCl (Prozac Liquid).
Antiperistaltic: Diphenoxylate HCl and Atropine Sulfate (Lomotil Liquid), Loperamide HCl (Imodium A-D Liquid).
Bronchodilator: Theophylline (Theophylline Oral Solution).
Antipsychotics: Haloperidol (Haldol Concentrate), Perphenazine (Trilafon Concentrate), Thiothixene HCl (Navane Concentrate).
Cathartics: Magnesium citrate, Sodium Phosphate (Phospho-Soda).
Corticosteroid: Prednisolone Sodium Phosphate (Pediapred Oral Solution).
Dental Care Protectant: Sodium Fluoride (Pediaflor Drops).
Electrolyte Replenisher: Potassium Chloride (KaoChlor 10% Liquid).
Fecal Softener: Docusate Sodium (Colace syrup).
Hematinic: Ferrous Sulfate (Fer-in-sol Drops).
Histamine {\rm H_2} Antagonist: Cimetidine HCl liquid (Tagamet HCl Liquid).
Narcotic Agonist Analgesic: Methadone HCl (Methadone HCl).
Vitamin D source: Ergocalciferol (Calciferol drops).
Aqueous Solutions
Defined as solutions where water is the major ingredient, serving as a vehicle and solvent.
Characteristics of Water: Tasteless, freedom from irritating qualities, lack of pharmacologic activity.
Disadvantages: Favorable medium for many chemical reactions, supports growth of microorganisms when contaminated, adding pure form increases production cost.
Preparation:
Distillation.
Demineralization or Deionization: Known as the Zeolite process for softening high mineral content water, utilizing acid/cation or base/anion exchangers. While Zeolite acts as a catalyst, deionization alone may not meet USPHS requirements for drinking water and typically requires prior purification for pharmaceutical use.
Reverse Osmosis (RO): A separation process where solvent passes through a semipermeable membrane from a less concentrated to a more concentrated solution. Also called "crossflow or tangential flow" membrane filtration.
Pore Sizes in Filtration:
Microfiltration: 0.1 to 2 microns (removes bacteria).
Ultrafiltration: 0.01 to 0.1 microns (removes viruses).
Nanofiltration: 0.001 to 0.01 microns (removes organic compounds with MW 300 to 1000).
Reverse Osmosis: Smaller than 0.001 microns.
Aromatic Waters (Aqua Aromatica)
Defined by USP as more or less saturated clear or almost clear aqueous or weak alcoholic solutions of volatile oils or other aromatic/odoriferous volatile substances.
Description:
Odor and taste similar to their source substances.
Should be colorless, clear, and free from fibers, particles, and sediment.
Should not be used after a few weeks of storage.
Must be free from foreign odors (e.g., smoke-like).
Components: Volatile oil, Water.
Uses:
Provide pleasantly flavored mediums for water-soluble medicinals.
Mask undesirable tastes in suspensions and emulsions.
Some are not used as oral vehicles: Rose Water (perfumery), Hamamelis Water (astringent in cosmetics), Camphor Water (eye drops/washes for refreshing effect).
Official Processes of Preparation:
Distillation:
Cohobation: Process of obtaining aromatic water by distilling delicate drugs with small quantities of volatile principles one or more times. Example: Stronger Rose (Aqua Rose Fortier, Triple Rose Water).
Solution Method:
Simple Solution Method: Example: Peppermint water (Aqua Menthae Piperitae). Uses: vehicle, carminative, flavoring diluent. Description: Clear, saturated solution.
Alternate Solution by Intervention: The volatile material is mixed thoroughly with 15\,\textrm{g} of purified talc, agitated with purified water for 10 minutes, then filtered. Disadvantage: Fineness of filter aid may pass through filter paper.
Stability: Not permanently stable preparations.
Preservation: Protect from excessive light and heat. Deterioration may occur due to volatilization, decomposition, or mold growth, leading to cloudy preparation or disagreeable odor.
Examples:
Orange Flower Water, NF: Saturated solution of odoriferous principles of Citrus Aurantium Linne flowers. Uses: flavored vehicle and perfume in solutions, syrups, and elixirs.
Cinnamon Water: Uses: flavored vehicle, antiseptic in eye lotion, carminative. Description: Clear, saturated solution.
Aqueous Acids
Inorganic and organic acids (e.g., HCl, {\rm HNO3}, HI, HBr, {\rm H2}{\rm SO_4}, HAc) are crucial in chemical and pharmaceutical manufacturing.
Division of inorganic acids:
Hydroacids (no oxygen).
Oxygen-containing acids.
Example: Diluted Acetic Acid (Acidum Aceticum Dilutum):
Uses: Bactericidal (e.g., 1\% solution for surgical dressings), 1\% spermatocidal (e.g., vaginal douche).
Description: Clear, colorless, strong characteristic odor, sharply acid taste, miscible with water.
Examples of Official Acids (not all aqueous): Acetic Acid, Diluted Acetic Acid, Glacial Acetic Acid, Diluted Hydroiodic Acid, Diluted Hydrochloric Acid, Hypophosphorous Acid, Folic Acid, Citric Acid, Phosphoric Acid, Tartaric Acid, Salicylic Acid.
Gargles
Aqueous solutions for treating the pharynx and nasopharynx by forcing air from the lungs through the liquid held in the throat.
Many require dilution with water before use.
Examples:
Phenol Gargle and Potassium Chlorate (Golden Gargle) and Phenol Gargle (B.P.C. official).
Phenol Gargle: Contains 50\,\textrm{mL} Phenol Glycerin (16% w/w phenol, 84% w/w glycerin), 10\,\textrm{mL} amaranth solution (1% w/v in chloroform water), and water to make 1\,\textrm{L}. Diluted with equal warm water before use. For external use. Uses: antiseptic and soothing effect.
Mouthwashes (Lavatio Ori)
Aqueous solutions predominantly used for their deodorant, refreshing, and antiseptic effects.
May contain alcohol, glycerin, synthetic sweeteners, surface-active agents, flavorings, and colorings.
Commercial preparations often contain local anti-infective agents like hexetidine and cetylpyridinium chloride.
Examples:
Dobell’s solution or compound Sodium Borate NF: Contains Sodium borate, Liquefied Phenol, Glycerin, and Sodium Bicarbonate. Use: antiseptic.
Compound Sodium Chloride Mouthwash: Contains Zinc sulfate and {\rm ZnCl_2}.
Special Washes
Eye washes (Collyrium): Used as anesthetic, anti-infective, diagnostic, myotic, and anti-inflammatory agents.
Mouthwash (Collutorium): Antibacterial properties.
Nasal wash (Collunarium): Antibacterial and antiseptic properties.
Juices
Formerly known as INSPISSATED JUICES.
Prepared from ripe fruit, aqueous in character, used in making syrups as vehicles.
Examples: Cherry juice and Raspberry juices (official in USP).
Sprays
Aqueous solutions delivered as coarse droplets or finely divided solids for topical application, most commonly to the nasal-pharyngeal tract or skin.
Applied to mucous membranes of nose and throat via atomizer or nebulizer.
May contain antibiotics, antihistamines, vasoconstrictors, alcohol, and suitable solubilizing/wetting agents.
"Spray-o-mizer" is a device for throat sprays.
Examples: Nasalide (Syntex), Nostrilla.
Collodions
Liquid preparations consisting of pyroxylin dissolved in a solvent mixture, usually alcohol and ether, with or without added substances.
Pyroxylin: (nitrocellulose, soluble gun cotton, collodion cotton) obtained by the action of nitric and sulfuric acids on cotton, mainly cellulose tetranitrate.
Uses:
As a protective coating to the skin.
As medication where a thin layer of medication is firmly placed against the skin.
Directions for Use: Applied to skin with a soft brush or applicator. The solvent rapidly evaporates, leaving a film residue of pyroxylin.
Examples of Official Collodions:
Protective Coating:
Collodion, USP: Clear or slightly opalescent viscous liquid, 4\% w/v pyroxylin in 3:1 ether:alcohol mixture.
Flexible Collodion, USP: Prepared by adding 2\% Camphor and 3\% castor oil to Collodion.
Medicated:
Salicylic acid Collodion, USP: 10\% solution of salicylic acid in flexible collodion. Used for keratolytic effect (softens keratin, promotes desquamation), especially for corn removal. Synonym: Corn solvent.
Spirits
Formerly called "Essences," these are alcoholic or hydroalcoholic solutions of volatile substances.
First Spirits:
Brandy (Spiritus Vini Vitis): 48 to 54\% alcohol from grapes.
Whisky (Spiritus Frumenti): 47 to 53\% alcohol from cereals.
Uses:
As flavoring agents pharmaceutically.
For therapeutic value of the aromatic solute medicinally.
Preparation of Spirits:
Simple Solution: Majority prepared by dissolving solute in alcohol with agitation. Filtration often used for clarity. Example: Aromatic Spirit (62 to 68% hydroalcoholic solution of ammonia and ammonium carbonate, flavored with lemon, lavender, myristica oil).
Solution with Maceration: Macerate vegetable materials in suitable solvent to remove undesired or extract desired constituents. Example: Peppermint Spirit (Spiritus Menthae Piperitae) – 79 to 85% hydroalcoholic solution with 10% peppermint oil. Use: digestive aid or carminative.
Solution by Chemical Reaction: Only Aromatic Spirit of Ammonia NF (involving ammonium carbonate) is prepared this way.
Distillation: No spirits are currently official by distillation, but historically Brandy and Whisky were prepared this way.
Toothache Drops and Dental Oral Solutions
Toothache Drops: Preparations for temporary relief of toothache, applied with saturated cotton into the tooth cavity (e.g., clove oil, phenol with camphor or creosote).
Dental Oral Solution: Medicinal substances employed topically in the oral cavity.
Benzocaine: Topical anesthetic for temporary relief of pain, soreness, irritation (teething).
Camphorated Parachlorophenol: Dental anti-infective. Eutectic liquid (65% camphor, 35% parachlorophenol) for sterilization of deep root canals.
Carbamide Peroxide: Dental anti-infective. Acts as chemomechanical cleansing and debriding agent by releasing bubbling oxygen. Commercial product: Gly-Oxide (10% carbamide in flavored anhydrous glycerin).
Cetylpyridinium Chloride Solution and Lozenges: Local anti-infective. Commercial: Cepacol Mouthwash/Gargles and Lozenges.
Erythrosine Sodium Solution/Tablets: Diagnostic Aid. Solution applied to teeth to reveal plaque. Tablets: same purpose, not to be swallowed.
Eugenol/Clove oil: Dental Analgesic. Applied to dental cavities and as dental protectives.
Lidocaine Oral Spray: Topical dental anesthetic, 10\,\textrm{mg} per metered spray.
Nystatin Oral Suspension: Antifungal.
Na Fluoride / Tablets: Dental caries prophylactic.
Saliva Substitutes: Contain electrolytes in a CMC base, for relief of dry mouth/throat (xerostomia).
Triamcinolone Acetonide Dental Paste: Topical anti-inflammatory.
Zinc Oxide-Eugenol Mixtures: Temporary dental filling mix.
Inhalations
Drugs or drug combinations with high vapor pressure carried by a current into the nasal passage for local effect. Administered via an inhaler.
Examples: Amyl Nitrite inhalant (anginal pain), Propylhexedrine inhalant (nasal decongestant).
Drugs or solutions of drugs administered via nasal or oral respiratory route.
Nebulizers: Widely used instrument producing fine particles for inhalation therapy.
Humidifiers/Vaporizers: Volatile medication added to water in chamber, volatilized and inhaled. Household vaporizer produces fine mist for room humidification.
Examples: Isoetharine inhalation (bronchial asthma), Isoproterenol inhalation (bronchial asthma).
Syrups
Concentrated solutions of sugar (e.g., sucrose) in water or other aqueous liquids, with or without added flavoring agents and medicinal substances.
3 Types of Syrups:
Simple syrup: Concentrated solution of sucrose in purified water alone.
Medicated syrup: Aqueous solution of sucrose containing other substances like polyols (glycerin, sorbitol) and therapeutic agents.
Non-medicated/Flavored syrup: Contains aromatic and pleasantly flavored substances, intended as a vehicle or flavorant.
Classification of Syrups:
A. Medicinal Classification:
Non-medicated/Flavoring syrups: Used as vehicles, no official formulas or detailed descriptions in compendia.
B. Pharmaceutical Classification (Based on basic formula):
Sugar-based syrups: Concentrated solutions of sugar.
Artificial sweeteners and non-nutritive syrups: Formulated with artificial sweetening agents and viscosity builders.
Examples of Flavoring Syrups:
Orange Syrup: Sucrose-based, utilizes sweet orange peel tincture, citric acid for flavor/tartness.
Ora-Sweet and Ora-Sweet SF: Commercial vehicles for extemporaneous compounding, SF is sugar-free.
Raspberry Syrup: Sucrose-based, ~48\% by volume raspberry juice.
Glycyrrhiza Syrup (Licorice syrup): Contains Glycyrrhiza fluid extract, fennel oil, anise oil.
Cocoa Syrup: Chocolate flavored.
Cherry Syrup: Cherry juice, sucrose, alcohol.
Acacia Syrup: Acacia powder, sodium benzoate, vanilla tincture.
Citric acid Syrup (Syrup lemon): Lemon tincture, citric acid.
Simple Syrup: 85\% sucrose in purified water. Basis for flavored or medicated syrups.
2. Medicated Syrups: Contain ingredients with therapeutic value. Example: Ephedrine Sulfate Syrup (for cough), Ipecac Syrup (emetic).
Some syrups are used as Cathartic, Cholinergic, Decongestant, Expectorant, Fecal Softener, Sedative.
Examples by Category:
Analgesic: Meperidine HCl Syrup (Demerol Syrup).
Anticholinergics: Dicyclomine HCl Syrup (Bentyl Syrup), Oxybutynin Chloride (Ditropan syrup).
Antiemetics: Chlorpromazine HCl Syrup (Thorazine Syrup), Dimenhydrinate Syrup (Childrens Dramamine Liquid), Prochlorperazine Edisylate (Compazine Syrup), Promethazine HCl (Phenergan Syrup).
Anticonvulsant: Sodium Valproate Syrup (Depakene Syrup).
Antipsychotic: Lithium Citrate (Lithium Citrate Syrup).
Antihistamines: Chlorpheniramine Maleate (Chlor-Trimeton), Cyproheptadine HCl (Periactin Syrup), Hydroxyzine HCl (Atarax Syrup).
Antitussives: Dextromethorphan (Benylin Syrup), Diphenhydramine (Benelyn Allergy Liquid).
Antiviral: Amantadine HCl (Symmetrel Syrup).
Bronchodilators: Albuterol Sulfate (Proventil, Ventolin Syrup), Metaproterenol Sulfate (Alupent syrup).
Cathartic: Lactulose (Chronulac Syrup).
Cholinergic: Pyridostigmine Bromide Syrup (Mestinon Syrup).
Decongestant: Pseudoephedrine Hydrochloride (Children’s Sudafed Liquid).
Expectorant: Guaifenesin Syrup (Guaifenesin Syrup).
Fecal Softener: Docusate Sodium (Colace syrup).
Gastrointestinal stimulant: Metoclopramide Syrup (Amicar Syrup).
Hemostatic: Aminocaproic Acid (Amicar Syrup).
Hypnotic/Sedative: Chloral Hydrate (Chloral Hydrate Syrup).
Examples of Non-Sugar Based Medicated Syrups:
Antihistamine (Chlorpheniramine Maleate: includes glycerin, sorbitol solution, sodium benzoate, alcohol, color, flavor, purified water).
Ferrous Sulfate (includes citric acid, sorbitol solution, glycerin, sodium benzoate, flavor, purified water).
Cough and Cold Syrup (Dextromethorphan HCL, Guaifenesin, Chlorpheniramine Maleate, Phenylephrine HCl, Sodium Benzoate, Saccharin Sodium, Citric acid, Sodium Chloride, Alcohol, Sorbitol Solution, Syrup, Liquid Glucose, Glycerin, Color/Flavor, Purified Water).
Acetaminophen Syrup (Paracetamol, Benzoic Acid, Disodium Calcium EDTA, Propylene glycol, Alcohol, Saccharin Sodium, Purified water, Flavor, Sorbitol Solution).
Components of Syrups:
Sugar: Usually sucrose, or substitutes for sweetness and viscosity.
Antimicrobial preservatives.
Flavorants.
Colorants.
Miscellaneous: Special solvents, solubilizing agents, thickeners, or stabilizers.
Pharmaceutical Classification based on basic formula:
Sugar-Based syrups: Sucrose and dextrose commonly used.
Artificial sweeteners: Sugar-free syrups for regulated sugar/calorie intake.
Preservation and Storage of Syrups:
Stored at room temperature in tightly closed, well-filled bottles.
Amount of preservative varies with water available for microbial growth.
Common Preservatives: Benzoic acid (0.1\% to 0.2\%); Sodium benzoate (0.1 to 0.2\%); Combination of methyl, propyl, butyl parabens (totaling 0.1\%).
Dextrose: Used as sucrose substitute in strong acid syrups to avoid caramelization discoloration (e.g., Hydroiodic syrup).
Problems with Dextrose:
Forms saturated solutions in water at 70\% w/v, less viscous than simple syrup.
Dissolves more slowly.
Less sweet.
Saturated solution supports microbial growth more readily, easily fermented.
Flavorants for Syrups: Synthetic flavorants or natural materials (volatile oil, vanillin) for pleasant taste. Must be sufficiently water-soluble.
Sweeteners (Non-nutritive):
Saccharin sodium: 300 - 550 times sweeter than sucrose. Used in 0.1 to 0.2\% concentration but can have bitter aftertaste.
Aspartylphenylalanine methyl ester: Potential low-calorie sweetener, 160 times sweeter than sucrose in aqueous solution.
Uses of Syrups:
Mask taste of salty and bitter drugs due to sweetness, serving as a pleasant vehicle.
Used as vehicles for pediatric use due to high viscosity, "smoothness," and mouthfeel.
Wide variety of flavors (orange, lemon, peppermint) makes them highly acceptable.
Sweeteners and Viscosity Builders – Sorbitol Based Syrup
Sorbitol: Hexahydric alcohol ({\rm C6}{\rm H{14}}{\rm O_6}) from glucose hydrogenation, mostly used as a 70\% aqueous solution (USP trademark “Sorbo”).
Characteristics of Sorbitol:
Not irritating to mouth and throat membranes.
Does not contribute to dental caries.
Metabolized and converted to glucose, but absorbed slower from GIT, preventing significant hyperglycemia.
60\% as sweet as sucrose and half as viscous as simple syrup, provides excellent "mouth feel" without acrid characteristics.
Compatible with other polyols and simple syrup.
Chemically stable and practically inert.
Inhibits sticking/locking of bottle caps seen with high sucrose concentrations, hence often combined with sucrose.
Many drugs are more stable in sorbitol solutions than sucrose solutions, potentially extending shelf-life.
Up to 10\% v/v alcohol can be added before crystallization, similar to sucrose.
Colorants for Syrup
Used to enhance appeal, correlating with the flavorant.
Should be water-soluble, non-reactive with other components, and color stable at the syrup's pH and light exposure during shelf life.
Preparation Of Syrups
Usually prepared by one of four methods, depending on ingredient characteristics:
Solution of ingredients with aid of heat:
Reasons: To prepare syrup quickly, when components are not damaged or volatilized by heat.
Procedure: Sugar added to purified water and heated until dissolved. Heat-stable components added to hot syrup. Cooled and made up to volume. Heat-labile components (e.g., alcohol, oil) added after cooling.
Caution: Avoid excessive heat to prevent sucrose inversion (hydrolysis) causing discoloration (caramelization).
Examples: Acacia syrup, NF; Cocoa Syrup, NF; Syrup USP (85% sugar, made by cold and hot process, percolation).
Solution of ingredients by agitation without aid of heat:
Purpose: To avoid heat-induced inversion of sucrose.
Procedure: Sucrose and other agents dissolved in purified water. Ingredients placed in a bottle larger than final volume. Mixture agitated.
Examples: Ferrous Sulfate Syrup, Ephedrine Sulfate, Citric acid Syrup, Glycyrrhiza Syrup.
Percolation:
Method: Purified water or aqueous solution of medication/flavoring liquid slowly passes through a column of crystalline sucrose to dissolve it. Percolate collected and recirculated until all sucrose is dissolved.
Percolator with a cotton pledget at bottom is used.
Example: Tolu Balsam syrup (flavor for cough syrup).
Addition of Sucrose to a Medicated liquid or to a Flavored liquid:
Sometimes a medicated liquid (e.g., tincture, fluidextract) is used as the medication source. Many such tinctures and fluidextracts contain alcohol-soluble constituents and are prepared with alcoholic vehicles.
Examples: Senna Syrup, NF and Cherry Syrup.
Honey (Mels)
Also called "Clarified honey" or "Strained Honey."
Formerly used as a base for thick liquid preparations known as Honeys or Mels.
Composition: Bee secretion consisting of invert sugar (62-83\%); sucrose (8\%); dextrin (0.2\%).
Examples:
Oxymel (acid honey): Contains acetic acid (150\,\textrm{mL}), purified water (150\,\textrm{mL}), honey q.s. to make 1000\,\textrm{mL}.
Squill Oxymel: Contains squill, water, acetic acid, and honey.
Mucilages
Thick, viscid, adhesive liquids produced by dispersing gum in water or by extracting mucilaginous principles from vegetable substances with water.
Primary Uses: Aid in suspending insoluble substances in liquids due to their colloidal character and viscosity, which prevents immediate sedimentation.
Examples:
Acacia Mucilage NF (Mucilago Acaciae; Mucilage of Gum Arabic): Uses: demulcent, suspending agent, excipient in pills/troches, emulsifying agent for cod liver oil.
Tragacanth Mucilage NF (Mucilago Tragacanthae): Uses: excipient for pills/troches, suspending agent for insoluble substances in internal mixtures, protective agent.
Elixirs
Clear, pleasantly flavored, sweetened hydroalcoholic liquids intended for oral use.
Less sweet and viscous than syrups due to lower sugar content, making them less effective at masking medicinal tastes.
Advantages of Elixirs:
Hydroalcoholic nature better maintains both water-soluble and alcohol-soluble components in solution.
More stable than syrups.
Easy to prepare by simple solution.
Pleasant flavor.
Characteristics of Elixir:
Main ingredients: ethanol and water. Glycerin, sorbitol, propylene glycol, flavoring agents, preservatives, and syrups are often used.
Alcohol content varies from 3 to 41\% depending on ingredient solubility.
Sweetened with sucrose, or sorbitol, glycerin, and artificial sweeteners (e.g., saccharin).
High alcoholic content elixirs usually use artificial sweeteners (like saccharin) in small quantities.
Preparation of Elixirs:
Simple solution with agitation.
Admixture of two or more liquid ingredients.
Classes of Elixirs:
Non-medicated: Used in extemporaneous compounding by adding a therapeutic agent to a pleasant vehicle or diluting an existing medicated elixir. Note: Incompatibilities should be avoided. Examples: Aromatic elixirs, Compound Benzaldehyde Elixir, Iso-alcoholic Elixir.
Medicated Elixirs: Employed for the therapeutic benefit of the medicinal agent(s).
Most contain a single therapeutic agent (exceptions: Terpene hydrate and Codeine Elixir). Advantage of single agent: easier dosage adjustments.
Examples: Phenobarbital elixir, Theophylline Elixir, Diphenhydramine Hydrochloride Elixir.
Examples by Category:
Adrenocortical steroid: Dexamethasone Elixir (Decadron Elixir).
Analgesic/Antipyretic: Acetaminophen Elixir (Children’s Tylenol Elixir).
Anticholinergic/Antispasmodic: Hyoscyamine Sulfate Elixir (Levsin Elixir).
Antiasthma: Diphenhydramine HCl (Benadryl Elixir).
Antipsychotic: Fluphenazine HCl.
Cardiotonic: Digoxin (Lanoxin Pediatric Elixir).
Sedative/Hypnotics: Butabarbital Sodium (Butisol Sodium), Phenobarbital (Phenobarbital Elixir).
Example Formulations for Non-medicated Elixirs:
Aromatic elixir: Compound Orange spirit, Syrup, Talc, Alcohol, purified water.
Compound Benzaldehyde Elixir: Benzaldehyde, Syrup, Purified water.
Iso-alcoholic elixir: Contains both low and high alcoholic concentration forms.
Low alcoholic: Compound orange spirit, Alcohol, Glycerin, Sucrose, Purified water.
High alcoholic: Compound orange spirit, Saccharin, Glycerin, Alcohol.
Glycerites
Solutions or mixtures of medicinal or pharmaceutical substances in glycerin.
Characteristics:
Generally contain a minimum of 50\% glycerin.
Highly viscous, sometimes jelly-like, due to high glycerin concentration and dissolved/undissolved substances.
Considered stable and less prone to microbial contamination due to glycerin's preservative properties.
Examples:
Starch Glycerite (Glyceratum Amyli; starch glycerin): Emollient. Starch, water, benzoic acid, glycerin.
Tannic acid Glycerite: Astringent. Tannic acid, exsiccated sodium sulfite, sodium citrate, glycerin.
Phenol Glycerite: 40\,\textrm{mL} official in BPC, diluted with glycerin.
Boroglycerin Glycerite: Antibacterial.
Iodine and Zinc Iodide Glycerite (Glyceritum Iodi et Zinci Iodi).
Tragacanth Glycerite (Glyceratum Tragacanthae).
Storage: Hygroscopic, so should be stored in tightly closed containers.
Mixtures
Aqueous liquid preparations containing suspended insoluble solid substances, intended for external use.
Characteristics:
Should have finely divided particles for better suspension and slower sedimentation, ensuring uniform dosage.
More colloidal the mixture, the better its protective and adsorbent qualities on inflamed surfaces.
Palatability associated with colloidal agents.
Labeling: "Shake well" label is essential.
Examples: Brown Mixture (Compound mixture of Glycyrrhiza), Kaolin Mixture (Ka-Pek) for diarrhea.
Extractives
Involve the separation of medicinally active portions of plant or animal tissues from inactive components using selective solvents.
Galenicals: Classes of preparations including Decoction, Infusion, Fluidextracts, Tinctures, Pilular (semi-solid) extracts, Powdered extracts.
Methods of Extraction:
Maceration: "Macerare" (Latin for to soak). Drug is comminuted and soaked in menstruum, dissolving soluble constituents. Examples (Process M): Compound Benzoin, Sweet orange Peel Tincture; Compound Cardamon; Tolu Balsam Tincture.
Percolation: "Per" (through), "Colare" (strain). Comminuted drug extracted by slow passage of suitable solvent through a drug column in a percolator. Extractive collected is the percolate.
Percolator Shapes: Cylindrical (Oldberg percolator), cylindrical with taper, conical or funnel shape.
Choice of Percolator: Depends on nature of drug, type of product, quantity of drug.
Processes and steps: Preparation of dried crude drug (powdering, moistening), packing the percolator, period of maceration, percolation and collection of percolate, adjustment of concentration.
Rates of flow: Slowly (not exceeding 1\,\textrm{mL}/minute), Moderate (1 to 3\,\textrm{mL}/minute), Rapidly (3 to 5\,\textrm{mL}/minute).
Digestion: Form of maceration with gentle heat.
Infusion: Vegetable drugs (coarsely comminuted) extracted for water-soluble constituents.
Decoction: Boiling vegetable substances with water to extract soluble principles.
Extracts
Concentrated preparations of vegetable or animal drugs, obtained by removing active constituents with a suitable menstruum, evaporating solvent, and adjusting residual mass or powders to prescribed standards.
Methods of Preparation: Prepared by percolation, then evaporation of the solvent (e.g., by distillation under pressure or using reduced heat).
3 Forms of Extract (based on solvent removal):
Semiliquid extracts: Syrupy consistency.
Pilular or solid extracts: Plastic consistency.
Powdered extracts: Dry, all solvent removed.
Packaging and Storage: Packaged in wide-mouth containers or plastic tubes, tightly closed to prevent moisture loss and hardening. Examples: Belladonna Extract NF; Cascara Sagrada Extract NF and Pure Glycyrrhiza Extract.
Tinctures
Alcoholic or hydroalcoholic solutions prepared from vegetable material or chemical substances.
Topical Solutions vs. Tinctures: Topical solutions use an aqueous vehicle, while topical tinctures use an alcoholic vehicle.
Preparation: By simple solution, and are self-preserved. Co-solvents or adjuncts may be used for stability/solubility.
Packaging: Usually glass bottles with applicator tips or plastic squeeze bottles for drops.
Labeling: Must be clearly labeled "FOR EXTERNAL USE ONLY" and kept out of reach of children.
Examples of Solutions Applied Topically:
Aluminum acetate (Burow’s Solution): Aqueous, astringent.
Aluminum Subacetate (Modified Burow’s): Aqueous, astringent.
Calcium Hydroxide (Lime Water; Liquor Calcis): Aqueous, astringent.
Coal Tar (Liquor Carbonis Detergens; Liquor Picis Carbonis; LCD): Alcoholic, antieczematic, antipsoriatic.
Hydrogen Peroxide Topical Solution (Peroxide): Aqueous, anti-infective.
Chlorhexidine Gluconate Solution: For skin wounds, general skin cleanser, surgical scrub, preoperative skin preparation. Effective against Gram-negative and Gram-positive bacteria (e.g., Pseudomonas aeruginosa).
Povidone-Iodine (Betadine Solution): Aqueous, anti-infective.
Thimerosal (Merthiolate Solution): Aqueous, antibacterial and mild fungistatic.
Examples of Tinctures Applied Topically:
Green soap Tincture: Alcoholic, detergent, contains 2% lavender oil.
Iodine Tincture: Alcohol-water, anti-infective.
Compound Benzoin Tincture: Alcohol, topical protectant.
Variations of Official Tinctures: Method of preparation, strength of active constituent, alcohol content, intended use.
Method of Preparation of Tinctures:
By simple solution: For chemical substances. Examples: Iodine, Thimerosal, Nitromersol green soap tinctures.
By extraction: By maceration or percolation. Examples: Compound Cardamon Tincture.
Strength of Active components: No set strength. Varies with preparation.
Amount of crude drugs for 100\,\textrm{mL} tincture:
Potent drugs (e.g., Belladonna leaf): 10\,\textrm{g}.
Non-potent drug (e.g., Tolu Balsam): 20\,\textrm{g}.
Undried fresh fruit peel (e.g., sweet orange peel): 50\,\textrm{g}.
Alcohol Content: Tinctures are stable preparations, alcohol protects against microbial growth.
Green soap Tincture: 28 to 32\% alcohol.
Tolu Balsam Tincture: 77 to 83\% alcohol.
Pharmaceutical Uses:
Flavoring tinctures: Vanilla, sweet orange peel, Tolu balsam tinctures.
Medicinal use: Iodine Tincture, Thimerosal, Nitromersol Tinctures (anti-infective); Compound Benzoin Tincture (topical protectant); Green soap Tincture (topical detergent); Paregoric Tincture (antiperistalsis); Belladonna Tincture (anticholinergic).
Disadvantages of Tinctures:
Unpleasant tasting.
Physicians may prefer single drugs over plant-derived preparations.
High alcohol content.
Fluidextracts
Liquid preparations of vegetable drugs containing alcohol as a solvent or preservative (or both). Each mL contains therapeutic constituents of 1\,\textrm{g} of the standard drug represented.
Characteristics:
Because of alcohol content and high concentration, sometimes called "100% tinctures."
Fluidextracts of potent drugs are 10 times as concentrated or potent as corresponding tinctures (e.g., Belladonna Tincture is 0.6\,\textrm{mL}, its fluidextract is 0.06\,\textrm{mL}, implying fluidextract is 10 times more potent per unit volume).
Disadvantages:
Highly concentrated, many are too potent for safe self-administration.
Often too bitter tasting or unpalatable.
Preparations: Percolation is preferred due to exhaustive extraction requirement. Three processes labeled A, D, or B and C or E.
Process A: Exhaustive percolation with an alcoholic or hydroalcoholic menstruum. Example: Senna Fluidextract.
Process B or D: Used for fluidextracts with boiling water as menstruum; alcohol generally added to concentrated percolate as preservative. Requires heat-resistant or metallic percolator. Example: Aromatic Cascara Sagrada.
Process C and E: Designed for total drug extraction by collecting 1000\,\textrm{mL} of percolate from each 1000\,\textrm{g} of drug, using a long narrow drug column and percolation under pressure.
Official Preparation:
Glycyrrhiza Fluidextract (Licorice root Fluidextract) - flavoring agent.
Eriodictyon Fluidextract (Yerba Santa Fluidextract) - cathartic.
Cascara Sagrada Fluidextract (Rhamnus Purshiana Fluidextract).
Aromatic Cascara Sagrada Fluidextract.
Senna Fluidextract (Fluidextratum Sennae).
Nasal Preparations
Aqueous preparations made isotonic to nasal fluids, stabilized, and preserved.
Examples:
Afrin Nasal Spray/drops – Oxymetazoline (Nasal decongestant).
Beconase AQ Nasal Spray – Beclomethasone dipropionate (synthetic corticosteroid).
Diapid Nasal Spray – Lopressin (Antidiuretic, diabetes prevention).
Nasalcrom spray – Cromolyn (allergic rhinitis).
Ocean Mist – isotonic sodium chloride (restore moisture/relieve dry inflamed nasal).
Privine HCl solution – Naphazoline HCl (nasal adrenergic).
Syntocinon Spray – Oxytocin (synthetic, preparatory to breast feeding).
Neo-Synephrine – Oxymetazoline HCl (nasal adrenergic).
Nasalide Nasal Solution – Flunisolide (perennial/seasonal rhinitis).
Otic Solutions
Also called ear or Aural preparations.
Liquid preparations frequently used in the ear, though suspensions or ointments also have applications.
Usually placed in the ear canal by drops for removal of excessive cerumen (ear wax), or treatment of ear infections, inflammation, or pain.
Examples of Commercial Otic Solutions:
Americaine – Benzocaine (Local anesthetic).
Auralgan – Antipyrine, Benzocaine (Acute Otitis Media).
Cerumenex drops – Triethanolamine (Cerumenolytic agent; removes impacted earwax).
Chloromycetin – Chloramphenicol (Anti-infective).
Cortisporin Solution – Polymyxin B sulfate (antibacterial).
Debrox Drops – Carbamide Peroxide (Ear wax removal).
PediOtic – Polymyxin B sulfate, neomycin sulfate (Antibacterial).
Metreton – Prednisolone sodium phosphate (Anti-inflammatory).
Otobiotic Solution – Polymyxin B Sulfate, hydrocortisone (Antibacterial).
VoSol Solution – Acetic acid (Antibacterial/Antifungal).
Douches
Aqueous solutions directed against a body part or into a body cavity.
Function: Cleansing or antiseptic.
Characteristics: Usually directed with a bulb syringe (e.g., vaginal syringe with 8 to 10 ounce capacity). More often dispensed as powders with directions for dissolving in water.
Kinds of Douches:
Eye Douche: Removes foreign particles and discharges, directed gently at an oblique angle from inner to outer corner of the eye.
Pharyngeal Douche: Prepares throat interior for operation, cleanses in suppurative conditions.
Nasal Douche: Cleanses nasal passage.
Vaginal Douche (Urethral douche or irrigation): For irrigative cleansing of the vagina for hygienic effects.
Examples: Dobell’s Solution Tablets (Compound Sodium Borate Solution NF) for nasal/pharyngeal douches. Benzalkonium Chloride used in various douches.
Not official as a class, but substances from USP/NF are frequently employed.
Enemas
Also known as CLYSTER, these are rectal injections.
Uses:
Evacuate the bowel.
Influence the general system by absorption.
Affect locally the seat of disease.
For diagnostic visualization of the GIT (e.g., antihelmintic, nutritive, sedative, stimulating properties, or radiopaque substances for roentgenographic examination of lower bowel).
Characteristics: Usually given at body temperature in quantities of 1 to 2 pints, injected slowly with an enema syringe. If intended for retention, quantities should not exceed 6 fluid ounces for an adult.
Examples:
Enema of soft soap: 50\,\textrm{g} soft soap dissolved in purified water to make 1000\,\textrm{mL}.
Barium Sulfate Enema (Barium Salt; Baric Sulfae): For diagnostic visualization of GIT.
2 Types of Enema:
Evacuation Enemas: Promote bowel evacuation, cleanse the colon for retention and diagnosis. Available in disposable plastic squeeze bottles with pre-measured solutions. Agents: sodium phosphate, sodium biphosphate, glycerin, docusate potassium, light mineral oil.
Retention Enemas: Administered rectally for local or systemic effects of medication. Examples: Hydrocortisone (local), aminophylline (systemic effect).
Types of Retention Enema:
Nutritive Enema: Supply nutrients.
Medicated Enema: Supply medication for systemic effect.
Diagnostic Enema: {\rm BaSO_4} and Fleet Enema.
Other Enemas: Aminophylline Enema (NLT 90\% and NMT 110\% of {\rm C6}{\rm H{24}}{\rm N{10}} \cdot {2}{\rm H2}{\rm O}), Methyl Prednisolone Acetate (NLT 90\% and NMT 110\% of {\rm C{24}}{\rm H{32}}{\rm O6}), Cortisol Enema (NLT 90\% and NMT 110\% of {\rm C{21}}{\rm H{30}}{\rm O5}).
Miscellaneous Preparations for Topical Application
Rubbing Alcohol (Alcohol Rubbing Compound):
Contains about 70\% ethyl alcohol by volume, water, denaturants, optional color/perfume/stabilizers.
Uses: rubefacient externally, soothing rub for bedridden patients, germicide for instruments, skin cleanser before injection.
Isopropyl Rubbing Alcohol:
About 70\% by volume isopropyl alcohol, water, optional additives.
Uses: rubefacient, soothing rub. 91\% isopropyl alcohol used by diabetic patients for needle/syringe preparation and skin disinfection.
Hexachlorophene Liquid Cleanser:
Antibacterial sudsing emulsion containing colloidal dispersion of hexachlorophene (3% w/w) in a stable emulsion with entsufon sodium, petrolatum, lanolin cholesterols, methylcellulose, polyethylene glycol, PG monostearate, lauryl myristyl diethanolamide, sodium benzoate, water.
Uses: bacteriostatic cleansing agent, surgical scrub.
Liniments
Alcoholic or oleaginous solutions or emulsions of medicinal substances for external application to skin, generally with rubbing. Formerly called "embrocations."
Types:
Alcoholic liniments.
Oil liniments.
Dental liniments (not official).
Different Forms: Emulsion, suspension, solution.
Components: Counterirritant, antiseptic, local anesthetics, analgesics.
Actions:
Alcoholic liniment: Rubefacient (induces mild irritation and reddening), counterirritant, mildly astringent, penetrating.
Oily liniment: Milder action, less irritating to skin, protective coating, rubefacient for muscular pain.
Methods of Preparation: Same as solutions, emulsions, or suspensions.
Labeling: Must indicate "For external use only," "Shake well" (for emulsions/suspensions), store in tight containers, and not to be applied to bruises or broken skin.
Factors for Solvents/Vehicles:
Type of action desired (rubefacient, counterirritant, massage).
Solubility of components in solvents.
For oleaginous liniments: solvents may be fixed oils (almond, peanut, sesame, cottonseed), volatile oils (wintergreen, turpentine), or combinations.
No official liniments in USP and NF currently.
Examples:
White Liniment BPC (Ammonium chloride, Diluted Ammonia Solution, Oleic acid, Turpentine oil, Water).
Calamine Liniment/Lotion. Oily BPC (Calamine, Wool fat, Oleic acid, Arachis oil, {\rm Ca}({{\rm OH})_2} solution).
Camphor Liniment (Linimentum Camphoras; Camphorated Oil) (Camphor, Cottonseed oil).
Monophasic Liquid Dosage Forms Overview
Simplest form of medication for rapid and high absorption.
One-phase system (solute and solvent).
Classified into:
I. Liquids for oral use: Mixtures, linctuses, draughts, elixirs, syrups, and drops.
II. Liquids for external use: Lotions, liniments, and collodions.
III. Liquids for special use: Gargles, mouthwashes, throat paints, eye drops, eye lotions, ear drops, nasal drops and sprays, douches, enemas, inhalations, and aerosols.
IV. Parenteral solutions (injections).
Monophasic Liquid Dosage Forms for Oral Use
a. Mixtures:
* Liquid oral preparations with one or more medicaments dissolved, suspended, or diffused in an aqueous vehicle.
* Usually freshly prepared, used quickly (€$<$ ext{1 month}) for short-term therapy (cough, diarrhea, constipation).
* Further classification:
1. Simple mixtures containing soluble substances.
2. Mixtures containing diffusible solids (don't dissolve, but mix evenly by shaking).
3. Mixtures containing indiffusible solids (don't dissolve and don't remain uniformly distributed).
4. Mixtures containing precipitate-forming liquids.
5. Mixtures containing slightly soluble liquids.
* Note: 'Mixture' can also refer to a suspension.
b. Linctuses:
* Viscous oral liquids with one or more medicaments dissolved in a vehicle, usually high in sucrose or other sugars.
* Uses: Demulcent, expectorant, or sedative for cough relief.
* Manner of taking: Sipped slowly in small, undiluted doses, allowed to trickle down the throat for maximum, prolonged effect.
c. Elixirs:
* Clear, sweetened hydro-alcoholic solutions for oral use, usually flavored. Less sweet and viscous than syrups.
* Classes: Non-medicated (vehicles), Medicated (therapeutic effects).
* Advantages: Better maintain water-soluble and alcohol-soluble components, stable, easily prepared.
* Disadvantages: Less effective in masking taste, alcohol accentuates saline taste of bromides.
d. Draughts:
* Older term for liquid oral preparations containing only one or two large doses.
* Larger volume than traditional mixtures, each dose in separate bottle.
e. Syrups:
* Concentrated aqueous preparations of sugar or sugar substitute, with/without flavoring and medicinal substances. Sugar concentration is 66.7\%\ \textrm{W/W}.
* Types: Medicated (flavoring agents with drugs), Flavored (vehicles for unpleasant tasting medications).
* Advantages: Mask bad taste, thick character soothes throat, little/no alcohol, easy dose adjustment for children.
f. Drops (Pediatric drops):
* Liquid preparations of potent drugs (usually solutions) administered in small volumes via a calibrated dropper to pediatric patients.
g. Infusion:
* Dilute solution of readily soluble constituents of crude drugs (from soft plant parts).
* Fresh infusions prepared by macerating drugs for 15 min with boiling water.
h. Decoction:
* Extract of water-soluble and heat-stable constituents of crude drugs (from hard plant parts) by boiling in water for 30 min and cooling.
* Infusions and decoctions have short durations (no more than 3 days).
Fomentation
Topical application: cloth soaked in strong infusion, applied to body like a compress.
Unlike normal compresses, fomentations are kept warm (hot compress/hot pack).
Can include hot water, oils, hydrosols, vinegars, with or without herbs.
Uses: Treating strains, sprains, cramps, inflamed areas, coughs, and congestion (old-fashioned natural home remedy).
Effectiveness: Skin absorbs herbal properties, effective when teas/tinctures cannot be ingested (e.g., upset stomach). May take longer.
Preparation:
Decoctions: Tougher herbs (barks, roots, stems). 1 teaspoon dried herb per cup of water, brought to boil, simmer for 15-20 minutes.
Infusions: Leaves, stems, flowers. 1 teaspoon dried herb per cup of water, boiling water poured over herbs, covered, steep for 10-15 minutes, then strain.
Monophasic Liquid Dosage Forms for External Use
a. Lotions:
* Can be solutions, suspensions, or emulsions for external skin application.
* Rubbed onto skin without friction using absorbent material (cotton, wool, gauze).
* Alcohol-based lotions for scalp allow rapid drying (e.g., Salicylic Acid Lotion 2%). Flammability issues addressed by labeling.
b. Liniments (Embrocations):
* Medicated topical preparations for skin application, also called balms.
* Liquid preparations to be rubbed with friction and massaged onto unbroken skin for analgesic, rubefacient, or stimulating effects.
* Usually solutions of oils, alcohols, or soaps, sometimes emulsions. Similar viscosity to lotions, but applied with friction.
* Uses: Relieve pain and stiffness from sore muscles or arthritis.
c. Collodions:
* Principally solutions of pyroxylin in ether and alcohol, painted onto skin and left to dry, forming a protective film.
* Highly volatile and flammable; require appropriate labeling.
* Composed of nitrocellulose in ether or acetone, sometimes with alcohols. Dries to a celluloid-like film.
* Types: Flexible (surgical dressing, holds dressings in place, discolors over time) and non-flexible (theatrical make-up).
* Uses: Topical protectant, closing small wounds, abrasions, cuts, holding surgical dressings, keeping medications in contact with skin.
Monophasic Liquid Dosage Forms for Special Use
a. Gargles:
* Aqueous solutions with antiseptics, antibiotics, and/or anesthetics for throat infection prevention/treatment.
* Generally formulated as concentrates.
b. Mouthwashes:
* Aqueous solutions with pleasant taste/odor for local treatment of mouth/gum lining.
* Contain antibacterial agents, alcohol, glycerin, sweeteners, flavorings, colorings.
* Uses: Addressing specific oral problems (e.g., antihistamines/hydrocortisone for stomatitis, pilocarpine for xerostomia, tranexamic acid for post-oral surgery bleeding, carbenoxolone for orofacial herpes simplex).
c. Throat paints:
* Viscous liquid preparations applied with a brush to mouth or throat mucosa.
* Glycerin commonly used as base due to sweet taste and adherence to mucous membrane.
d. Eye drops:
* Sterile solutions or suspensions of drugs instilled into the eye with a dropper.
* Usually aqueous, must be isotonic with lachrymal secretions, buffered, and free from foreign particles to avoid irritation.
e. Eye lotions:
* Sterile aqueous solutions for washing the eye.
* Supplied concentrated, diluted with warm water before use.
* Generally used to remove foreign substances.
f. Ear drops:
* Medicated solutions instilled into the ear with a dropper.
* Used for cleaning, softening wax, treating mild infections.
g. Nasal drops and sprays:
* Solutions instilled into nostrils (drops via dropper, sprays via spray device).
* Intended for administration to nasal cavities for systemic or local effect.
h. Douches:
* Liquid preparations for cleansing, deodorizing, soothing, or medicating wounds, body orifices, or cavities.
i. Enemas:
* Liquid preparations (solutions, emulsions, or suspensions) for rectal administration.
* Used for cleansing, therapeutic, or diagnostic purposes.
j. Inhalations:
* Preparations containing volatile substances.
* Used to relieve congestion and inflammation of respiratory tract; added to hot water, vapors inhaled.
k. Aerosols:
* Liquid preparations dissolved in a gaseous solvent.
* Delivered as a spray, mainly for asthma and migraine treatment.
Biphasic Liquid Dosage Forms
Contain two phases.
Suspensions
Biphasic liquid dosage forms containing essentially insoluble finely divided solid particles (drug(s)) suspended with a suspending agent(s) in a liquid medium.
Solid particles act as disperse phase, liquid acts as continuous phase.
Emulsions
Biphasic liquid preparation containing two immiscible liquids (usually oil and water), one dispersed as minute globules into the other, rendered homogeneous by an emulsifying agent.
Disperse phase: liquid converted into globules. Continuous phase: liquid globules are dispersed in.
Can be administered topically, orally, and intramuscularly (IM).
Two types:
Oil in water (O/W): Oil is disperse phase, water is continuous phase.
Water in oil (W/O): Water is disperse phase, oil is continuous phase.
Advantages of Liquid Dosage Forms (LDFs)
Suitable for patients with difficulty swallowing tablets/capsules (pediatric, geriatric).
Attractive appearance, beneficial psychological effects.
Bitter/unpleasant drugs can be given in sweetened, colored, flavored vehicles.
Higher flexibility in dosing; easily adjusted by measuring different volumes.
If given orally, rapidly available for absorption compared to tablets/capsules.
Hygroscopic and deliquescent medicaments, unsuitable for solid forms, can be dispensed in liquid form.
Products like adsorbents and antacids are more effective in liquid form.
Expected for certain products (e.g., cough medicaments).
Disadvantages of Liquid Dosage Forms (LDFs)
Usually more susceptible to chemical degradation.
Bulky, inconvenient for transport and storage.
Accidental container breakage results in loss of entire dosage form.
Shorter shelf-life due to lower stability.
Often suitable media for microbial growth, requiring preservatives.
Some products (e.g., vaccines) may require special storage conditions.
Unpleasant drug taste is more prominent in solution than in solid form.
Higher chance of dose variability as delivery depends on patient measuring proper volume. Significant issue for vision-impaired, arthritis patients, or those unable to read dosing marks.
Other LDFs (taken orally or applied topically)
Tincture: Liquid preparation from macerating plant material in alcohol/water mixture at room temperature, then pressed and filtered to yield a fluid with dissolved active constituents. Made by soaking plant/animal material in alcohol for ~72 hours. Common solvent is ethanol; others include vinegar, glycerin, distilled water.
Otic preparations: Products applied to or placed in the ear to treat external and middle ear conditions (dermatitis, cerumen buildup, infection).
Nasal Preparations: Liquid, semi-solid, or solid preparations for nasal administration (systemic or local effect). Must be non-irritating and not adversely affect mucosa/cilia.
Excipients used in the formulation of LDFs
LDFs combine drug substance(s) with various excipients, each serving multiple functions depending on concentration and dosage form need.
Essential to ensure all excipients are physically and chemically compatible with the drug substance and other components.
Common Excipients:
Solvents/vehicles: Liquid in which drugs/excipients are dissolved/dispersed. Examples: Purified water, alcohol, acetic acid, acetone, vegetable/mineral oils, organic oily bases, emulsified bases.
Co-solvents: Enhance drug solubility. Examples: Ethanol, glycerol, propylene glycol.
Surfactant: Enhance drug solubility. Examples: Cetrimide, sodium lauryl sulphate, triethanolamine.
Preservatives: Prevent microbial growth. Examples: Parabens, phenylmercuric nitrate, sodium benzoate, benzalkonium chloride.
Viscosity modifiers: Control formulation viscosity. Examples: Cellulose polymers, polyvinyl pyrrolidone, alginic acid, xanthan gum.
Buffers: Regulate pH. Examples: Phosphate buffers, Acetate buffers, Citric acid phosphate.
Antioxidants: Control oxidation. Examples: Sodium bisulphite, ascorbic acid, butylated hydroxytoluene.
Thickening agents: Prevent settling/sedimentation, modify viscosity. Examples: Methylcellulose, Hydroxy.
Chelating agents: Enhance drug stability. Examples: Disodium edetate, phosphoric acid.
Sweeteners: Enhance oral liquid palatability. Examples: Sucrose, saccharin, aspartame, sorbitol.
Flavoring agents: Enhance oral liquid palatability. Examples: Lemon oil, orange oil, peppermint, menthol.
Colorants: Enhance aesthetic appearance. Examples: Amaranth, Erythrosin, Eosin, Tartrazine.
Antifoaming agents: Discourage stable foam formation. Examples: Simethicone, Organic phosphates, Alcohols, Paraffin oils, Stearates and glycols.
Humectants: Retard evaporation of aqueous vehicles. Examples: Propylene glycols, Glycerol, Polyethylene glycol.
Emulsifying agents: Prevent coalescence of dispersed globules. Examples: Sodium Lauryl Sulphate, Cetrimide, Macrogol esters, Sorbitan esters.
Flocculating agents: Prevent caking. Examples: Starch, Sodium alginate, Carbomer.
Excipient used in aerosol (Propellant): Develops pressure to expel product. Examples: Trichloromonofluoromethane, Dichlorodifluoromethane.
Manufacture of Liquid Dosage Forms
Most LDFs are prepared by:
Simply dissolving solutes (API and excipients) in aqueous or nonaqueous solvent/mixture.
Suspending solutes in appropriate medium.
Incorporating solutes into an oil or water phase.
Industrial scale: Prepared in large mixing vessels with ports for mechanical stirrers, often thermostatically controlled. Order of component addition is fixed through product development and scale-up.
Packaging of Liquid Dosage Forms
Containers and packaging components vary considerably based on LDF physical/chemical properties and distribution/use.
Stability concerns: Container must not physically or chemically interact with the product to alter strength, quality, or purity beyond official requirements.
Light-sensitive ingredients: Supplied in light-resistant containers.
Volatile ingredients: Kept in tightly closed containers.
Transparency: Containers for parenteral and oral LDFs should be sufficiently transparent to permit visual inspection of contents (unless monograph specifies otherwise).
Labeling of Liquid Dosage Forms
Every pharmaceutical preparation must comply with Good Manufacturing Practice (GMP) labeling requirements.
Label should include:
Name of pharmaceutical product.
Name(s) of active ingredients (INN whenever possible).
Amount of active ingredient in suitable dose-volume.
Name and concentration of any antimicrobial preservative and any other excipient.
Batch (lot) number.
Expiry date and, if required, date of manufacture.
Any special storage conditions or handling precautions.
Directions for use, warnings, and precautions.
Name and address of manufacturer or person responsible.
For granules or powder to be constituted before use, label should specify:
That contents are granules or powder for reconstitution.
Strength: amount of active ingredient in a suitable dose-volume of the constituted preparation.
Directions for preparing liquid (nature and quantity of liquid to be used).
Storage conditions and shelf-life of constituted preparation.
Quality Assurance and Quality Control/Evaluation of Liquid Dosage Forms
LDFs have specifications for drug substance and drug products.
Manufacturers monitor specifications to ensure batch-to-batch uniformity and product stability over shelf life.
An established and validated stability-indicating assay method is crucial for quality control/assurance.
Parameters routinely monitored:
Content uniformity, viscosity, pH, color, odor.
Efficacy of preservative over shelf life.
For suspensions and emulsions, effect of storage on flow properties and particle size.