Pharmaceutical Dosage Forms PDF

01/04/1446 Pharmaceutical Dosage Forms The Need for Dosage Forms Providing the mechanism for the safe and convenient delivery of accurate dosage. To protect the drug substance from the destructive influences of atmospheric oxygen or humidity (coated tablets, sealed am...

01/04/1446 Pharmaceutical Dosage Forms The Need for Dosage Forms Providing the mechanism for the safe and convenient delivery of accurate dosage. To protect the drug substance from the destructive influences of atmospheric oxygen or humidity (coated tablets, sealed ampules) To protect the drug substance from the destructive influence of gastric acid after oral administration (enteric-coated tablets) To conceal the bitter, salty, or offensive taste or odor of a drug substance (capsules, coated tablets, flavored syrups) To provide rate-controlled drug action (various controlled-release tablets, capsules, and suspensions) 1  01/04/1446 The Need for Dosage Forms To provide optimal drug action from topical administration sites (ointments, creams, transdermal patches, and ophthalmic, ear, and nasal preparations) To provide for insertion of a drug into one of the body’s orifices (rectal or vaginal suppositories) To provide for placement of drugs directly in the bloodstream or body tissues (injections) To provide for optimal drug action through inhalation therapy (inhalation aerosols) Liquid Dosage Forms Solutions 2  01/04/1446 Objectives After reading this chapter, the student will be able to: 1) Define the various types of liquid dosage forms. 2) List the advantages and disadvantages of using liquid dosage forms. 3) Compare liquid dosage forms to solid oral dosage forms. 4) Evaluate and select a proper solvent and delivery system for a given solute, purpose, and/or patient population. Pharmaceutical solution In pharmaceutical terms, solutions are “liquid preparations that contain one or more chemical substances dissolved in a suitable solvent or mixture of mutually miscible solvents They are administered by many different routes; they are often therefore classified by the intended route (e.g., oral, otic (ear), parenteral). Solutions are also classified by the nature of the formulation, or by the traditional name which relates to the solvent system used, such as syrups, elixirs, spirits and tinctures. 3  01/04/1446 Advantages of pharmaceutical solutions 1) The drug is already dissolved in the solvent system, hence drug action can be rapid, allowing their use in emergencies, e.g., the use of adrenaline solution, as an injection, for the treatment of anaphylaxis 2) When drug absorption is required prior to drug action, for example, following oral administration, the drug in a solution is already in a molecular form and thus, available for absorption. 3) Solutions provide dose uniformity, and specific volumes of the liquid solutions that can be measured accurately. 4) Oral solutions are easily swallowed and are beneficial for patients whom swallowing may be difficult, e.g., children and geriatric 5) Solutions are easier to manufacture compared to other dosage forms. Disadvantages of solutions 1) Many drugs are unstable, and instability is increased when a drug is present in solution. 2) Many drugs are poorly soluble in water. Their formulation as a solution is challenging. 3) liquids are bulky and less easy for the patient to carry, for example, the daily dose, compared to solid dosage forms. 4) Liquids are also more expensive to transport, which increases the medicine’s cost. 5) Solutions often provide suitable media for the growth of microorganisms and may therefore require the incorporation of a preservative. 6) Less stable than solid dosage forms (precipitation, gas formation, color changes are major signs of solution instability). Shorter shelf life than solid forms 4  01/04/1446 Ingredients of Pharmaceutical Solutions: 1- Vehicles Commonly, vehicles are solvents in which the active and inactive ingredients are dissolved. The choice of vehicles depends on the intended use of the preparation and on the nature and physicochemical properties of the active ingredients. Although water is the most commonly used solvent, different non-aqueous vehicles can be used. Vehicles of both types will be studied in detail. 5  01/04/1446 2- The drug The drug could be a small molecule like aspirin, or a large biotherapeutic molecule, such as insulin. The drug is present as molecules or ions throughout the solvent. It is usual to ensure that the drug concentration in a pharmaceutical solution is well below its saturation solubility in order to avoid the possibility of drug precipitating out of the solvent as a result of subsequent temperature changes during storage and use. 11 3- The excipients (Formulation additives) Excipients – substances other than the drug which are included in pharmaceutical solutions – are used for a number of reasons, such as To enhance product stability, bioavailability or patient acceptability, aid in product manufacture. The excipient must be non-toxic, non-sensitizing, nonirritating, as well as compatible with all the other components of the formulation. The route of administration is important; many excipients are acceptable by certain, but not all, routes. For example, the preservative benzalkonium chloride is used in oral, but not nebulizer solutions, as it causes bronchoconstriction. 12 6  01/04/1446 Examples of formulation additives (1) Buffers Buffers are compounds (solution) that resist changes in pH upon the addition of limited amounts of acids or bases. Changes in pH may arise due to interactions between an ingredient in the formulation and the container, or from changes in storage temperature. The physiological pH of plasma and extracellular fluid is 7.4; therefore, ideally all solution products should be formulated to this pH value. However, there is likely to be an optimum pH value at which the drug substance is most stable. The solubility of the drug in the vehicle may also be dependent on pH. Therefore, the pH chosen for a product is likely to be a compromise between the requirements for stability, solubility and physiological compatibility. 13 2- Flavoring Agents and perfume Flavoring Agents used to mask the taste of drugs, many of which have a very unpleasant taste. This is particularly useful in pediatric formulation to ensure patient compliance. 1- Naturally occurring flavorings such as fruit juices (raspberry), aromatic oils (orange and lemon oil), herbs and spices are used for oral solutions. 2- Synthetic or artificial flavor are cheaper, readily available, less variable in composition and more stable than natural 14 flavor. 7  01/04/1446 Certain flavors appeal to certain patient populations; this must be borne in mind by the formulator. For example, fruit and bubble gum flavors are acceptable to children, whilst mint flavor is not. In some cases, there are a strong association between the use of a product and its flavor content, for example products intended for indigestion are mint flavored as mint used for its carminative effect. Flavors such as menthol, peppermint oil, and chloroform may act as desensitizing agents by exertion of a mild anaesthetics effect on the sensory taste receptor. 3- Coloring Agents A coloring agent should correlate with the flavoring agent, e.g., green with mint, red with cherry flavor to improve the attractiveness of the product. Natural coloring agents are more acceptable than synthetic ones. However ,they exhibit the usual problem associated with natural product, namely variation in availability and chemical composition. Synthetic dyes tend to give brighter colors and are more stable. 16 8  01/04/1446 4- Preservatives There are two strategies for preparation of microbiologically accepted pharmaceutical product. 1) Minimize the access of M.O. From the sources 2) Formulate the product with inclusion of preservative * Sources of contamination 1) Equipment: Should be as simple as possible to allow cleaning in place. 2) Raw material: Raw material , particularly of natural origin and water are a rich source of M.O. Treatment applied to remove the microbial load such as ionizing radiation , heat without affecting the material adversely. 3) Personnel: Appropriate clothing must be available to protect the product from body surfaces such as hood, mask, gloves and boots. 17 A preservative is included to inhibit the growth of any microorganisms that may be accidentally introduced into the product during repeated use by the patient. Ideal Preservatives should be 1) Effective against wide spectrum of microorganisms. 2) Stable over its shelf life. 3) Nontoxic, non-sensitizing. 4) Free of taste and odor. 5) Compatible with other ingredients. Examples: of the preservatives used in aqueous solutions Alcohols: Ethanol used in concentration > 10 %. Propylene glycol used in 15–30 %. Phenolics Chlorocresol 18 9  01/04/1446 Examples: of the preservatives used in aqueous solutions Acids Benzoic acid, effective at pH < 4.5 as non-ionized form, in conc. 0.1- 0.5%. Sorbic acid; effective in acidic pH in conc. 0.05 - 2%. Esters Methyl, ethyl, propyl and butyl parabens (Para-hydroxy benzoic acid ester). Effective and stable over a wide pH range (4-8). Used in 0.2% conc. Quaternary ammonium compound Benzalkonium chloride. Used externally in low conc. (0.002-0.02%). Active over wide pH range (4 -10). It is cationic so incompatible with anionic compounds. 19 5- Antioxidants The oxidation reaction can be catalyzed by heat, light, and presence of heavy metals (Cu and Fe in waters). e.g., Vitamins, essential oils and fats can be oxidized. Methods used to slow the rate of oxidation: 1) Antioxidants are chemicals that have a lower oxidation potential than the drug substance and thus will react with any oxygen present in preference to the drug. Used to reduce the rate of drug degradation by oxidation and thus improve the shelf-life or expiry date. In case of non aqueous solutions: e.g., Propyl gallate (PG), butylated hydroxyl anisole (BHA), butylated hydroxyl toluene (BHT) and tocopherols (vitamin E). In case of aqueous solutions: e.g., Sodium bisulphate and ascorbic acid (vitamin C) 2) Sequestering or chelating agents e.g., EDTA minimize the effect of trace elements. 3) Keep in cool place 4) Use of light resistant containers 20 10  01/04/1446 6- Sweeteners Sweetening agents are added to improve the palatability of oral solutions, for example: Low MWT carbohydrates, particularly Sucrose, is the most widely used sweetening agent. Sucrose has advantages of being colorless, very soluble in water and stable over a pH range of about 4-8. Polyhydric alcohols such as sorbitol, mannitol and glycerol also have sweetening power and can be used in preparation for diabetic. Artificial sweeteners such as saccharin sodium and aspartame are suitable for diabetic patients. They are sweeter than sucrose, exhibiting high water solubility, stable over wide rang of pH. 21 7- Isotonicity Adjusters Solution for injection, for application to mucous membrane and large volume ophthalmic must made isotonic to avoid pain and irritation. Examples: Sodium chloride, potassium chloride, mannitol, dextrose, glycerol. 22 11  01/04/1446 8- Viscosity enhancement agents It may be difficult for aqueous-based topical solutions to remain in place on the skin or in the eyes for any significant time because of their low viscosities. To counteract this effect, low concentrations of gelling agents can be used to increase the apparent viscosity of the product. Hydroxyethyl cellulose, polyvinyl alcohol, carbomer 940. 23 12  01/04/1446 Liquid Dosage Forms Solutions Types of solutions 1  01/04/1446 Solutions can be classified according to the type of solvent in which the active ingredients are dissolved into 1- Aqueous solution 2- Non-Aqueous solution Types of 1- Aqueous solution: 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. A- Water Water is the most commonly used solvent due to its many advantages, such as a) Its lack of toxicity and low cost. b) Odorless and colorless c) Physiological compatibility (Palatable, Non-irritant for topical use) d) Ability to dissolve wide range of material (Have High dielectric constant) Disadvantage of water as a solvent a) Hydrolysable drugs (e.g., glycosides and some esters e.g., aspirin) form unstable solution when dissolved in water 2  01/04/1446 Types of water 1- Naturally occurring water Containing varying amounts of dissolved inorganic salts, usually sodium, potassium, and iron; chlorides; and sulfates; along with organic matter and microorganisms. 2- Drinking water (tap or potable water) Water found in most cities, where water is purified for drinking usually contains less than 0.1% of total solids. Acceptable drinking water should be Clear, colorless, odorless, and neutral or only slightly acidic or alkaline. Must meet the Public Health Service regulations with respect to bacteriologic purity. Tap water is not acceptable for the manufacture of most aqueous pharmaceutical preparations or for the extemporaneous compounding of prescriptions because of the possible chemical incompatibilities between dissolved solids and the medicinal agents being added. 3- Purified Water, USP, Purified Water, USP, has fewer solid impurities than ordinary drinking water. When evaporated to dryness, it must not yield more than 0.001% of residue (1 mg of solids per 100 mL of water). Is obtained by distillation, ion exchange, reverse osmosis. Purified Water, USP, is intended for use in the preparation of aqueous dosage forms except those intended for parenteral administration (injections). Water for Injection, USP; Bacteriostatic Water for Injection, USP; or Sterile Water for Injection, USP, is used for injections. 3  01/04/1446 Preparation of purified water 1- Distillation Method Many of the contaminants found in water are inorganic minerals, metals etc. Those types of contaminants have very high melting points, much higher than the boiling point of water. So, as the water (with its contaminants) is boiled, the pure water turns into steam and is captured and cooled and thus becomes purified water. Generally, the first portion of aqueous distillate (about the first 10% to 20%) must be discarded because it contains many foreign volatile substances usually found in drinking water. Also, the last portion of water (about 10% of the original volume of water) remaining in the distillation apparatus must be discarded and not subjected to further distillation because distillation to dryness would result in decomposition of the remaining solid impurities to volatile substances that would distill and contaminate the previously collected distillate. 8 4  01/04/1446 2- Ion Exchange Method The ion exchange equipment generally passes water through a column of cation and anion exchangers consisting of water-insoluble synthetic polymerized resins of high molecular weight. These resins are mainly of two types: (a) The cations, or acid exchangers, which permit the exchange of the cations in solution (in the tap water) with hydrogen ion from the resin, and (b) The anions, or base exchange resins, which permit the removal of anions. The processes are indicated as follows, with Cation exchange M+ indicating the metal or cation (as Na+) X− indicating the anion (as Cl−). Water purified in this manner, referred to Anion exchange as demineralized or deionized water. Advantages of Ion Exchange over distillation a) The requirement of heat is eliminated b) Simpler equipment and ease of operation, c) Minimal and low-cost maintenance, and a more mobile facility. 5  01/04/1446 Reverse Osmosis Osmosis is defined as the spontaneous diffusion of solvent from a solution of low solute concentration (or a pure solvent) into a more concentrated one, through a semipermeable membrane. The flow of the water (as the solvent) can be stopped by applying pressure, equal to the osmotic pressure, to the concentrated solution. Reverse Osmosis Principle: The flow of the water can be reversed by applying a pressure greater than the osmotic pressure of the concentrated solution (e.g., tap water), and the pure water could be obtained. The filtered portion is called the permeate because it has permeated the membrane. The retained water which contains the concentrated contaminants that did not pass through the semipermeable membrane is called the reject or concentrate. Reverse osmosis removes virtually all viruses, bacteria, pyrogens, and organic molecules and 90% to 99% of ions. In large scale production: a pressurized stream of water is passed parallel to the inner side of a filter membrane core. A portion of the feed water, or influent, permeates the membrane as filtrate, while the rest of the water exit the system without being filtered. 6  01/04/1446 3- Aromatic Waters Aromatic waters is defined as clear, saturated aqueous solutions of volatile oils or other aromatic or volatile substances. Used mainly for their flavoring properties, although they might be used for their medicinal effect. Examples include peppermint water, Rose water and anise water, which also have carminative properties, and chloroform water, which also acts as a preservative. Aromatic waters suffer from deterioration (cloudy appearance) with time due to volatilization, decomposition or mold growth, so they should be freshly prepared in small suitable quantity and protected from light and heat. Aromatic waters are no longer in widespread use. Preparations of Aromatic Waters Aromatic water can be prepared by two methods: distillation and solution 1- Distillation method The odoriferous drug is distilled in a suitable still (distillation unit), with a sufficient quantity of water, until the specified volume of aromatic water has been collected. The aromatic water is set aside for 12 hours, then filtered if necessary. If the volatile oil in distillate is present in small quantities, the distillate is returned several times to be redistilled with more fresh drug. Thus, giving rise to the commercial terms double distilled, triple distilled, or quadruple distilled, according to the number of re-distillations. This process is called “Cohobation” = redistillation) 7  01/04/1446 Old distillation method Distillation method 8  01/04/1446 2- Solution method Triturate about 1 part or the specified amounts of the odoriferous substance with 15 parts of talc powder (Increases the "surface; area of volatile substance to ensure saturation of water (distributing agent). Then gradually add of recently boiled and cooled distilled water, in successive small portions, and agitate the mixture frequently for 15 minutes. Set aside for 12 hours, filter and pass sufficient amount of the water through the filter to produce 1000 parts of almost clear filtrate. Types of aqueous solutions 1- Simple & Effervescent Mixtures: Douches Enemas Gargles Mouthwashes Ophthalmic solutions Nasal solutions Otic solutions Irrigation solutions 2- Sweet or viscid aqueous solution: Syrups- Linctuses- Mucilage- Jellies 9  01/04/1446 1- Douches A douche is an aqueous solution directed against a part or into a cavity of the body. It functions as a cleansing or antiseptic agent. An eye douche, used to remove foreign particles and discharges from the eyes. Pharyngeal douches are used to prepare the interior of the throat for an operation and cleanse it in suppurative conditions. Similarly, there are nasal douches and vaginal douches. Douches most frequently are dispensed in the form of a powder with directions for dissolving in a specified quantity of water (usually warm). 1-Vaginal Solutions Vaginal Douches Solutions may be prepared from powders or from liquid solutions or liquid concentrates. In using liquid concentrates, the patient is instructed to add the prescribed amount of concentrate (usually a teaspoonful or capful) to a certain amount of warm water (frequently a quart). Powders are used to prepare solutions for vaginal douche, that is, for irrigation cleansing of the vagina. The powders themselves may be prepared and packaged in bulk or as unit packages. The user simply adds the prescribed amount of powder to the appropriate volume of warm water and stirs until dissolved. 10  01/04/1446 ◦ Among the components of douche powders are the following: 1) Astringents, for example, zinc sulfate 2) Antimicrobials, for example, oxyquinoline sulfate, Quaternary ammonium compounds and povidone iodine 3) Detergents, for example, sodium lauryl sulfate 4) Salts, for example, sodium citrate and sodium chloride 5) Aromatics, for example, menthol, thymol, eucalyptol, methyl salicylate 6) Anesthetics or antipruritics (menthol, phenol) 2- Enemas They are aqueous solution for rectal administration of drug for cleansing (evacuating), diagnostic or therapeutic reasons. Enema has two types: 1- Retention enema: They may be used to affect the general system by absorption (systemic action for therapeutic reasons) e.g., aminophylline, nutritive, sedative, or they may also be used to affect a local disease or retained in the intestine without absorption (local effects e.g., hydrocortisone) or diagnosis e.g., barium Sulphate. In the case of aminophylline, rectal administration minimizes the undesirable gastrointestinal reactions associated with oral therapy. Clinically effective blood levels of the agents are usually obtained within 30 minutes following rectal instillation. Corticosteroids are administered as retention enemas as adjunctive treatment of some patients with ulcerative colitis. 11  01/04/1446 2- Evacuation Enemas Rectal enemas are used to cleanse and evacuate the bowel from its contents. Commercially, many enemas are available in disposable plastic squeeze bottles containing a premeasured amount of enema solution. The agents are solutions of sodium phosphate and sodium biphosphate, glycerin and docusate potassium, and light mineral oil. Instruction from a pharmacist is advantageous to ensure that the patient correctly uses these products. The patient should be advised to gently insert the tip of the product with steady pressure and be told that it is not absolutely necessary to squeeze all of the contents out of the disposable plastic bottle. The patient should be told that the product will most probably work within 5 to 10 minutes. 3-Topical Oral (Dental) Solutions A variety of medicinal substances are employed topically in the mouth for a number of purposes. Some of these products, such as teething lotions and toothache drops, are medicated, whereas others are used for hygienic purposes, such as dentifrices, and many of the mouthwashes. Examples: ▪ Benzocaine: Indicated for temporary relief of pain and irritation in the mouth associated with teething, and canker sores. Eugenol: Dental analgesic. Applied topically to dental cavities and having an aromatic odor of clove. 12  01/04/1446 4. Gargles Gargles are aqueous solutions frequently containing antiseptics, antibiotics, and/or anesthetics Used for treating the pharynx and nasopharynx by forcing air From the lungs through the gargle that is held in the throat. Many gargles must be diluted with water prior to use. 5. Mouthwashes Mouthwashes are aqueous solutions (may be concentrated form) containing one or more active ingredients intended to act in the mouth. Mouthwashes can be used for two purposes, therapeutic and cosmetic. Therapeutic washes 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. 13  01/04/1446 Ingredients in Mouthwashes Mouth washes generally contain the following D- Surfactants: excipients Non-ionic and anionic surfactants aid in the A- Alcohols: (10-20% in MW) solubilization of flavors and in the removal of debris by providing foaming action. May function as a preservative or as a solubilizing agent for some flavoring agents. Cationic surfactants such as cetylpyridinium chloride are used for their antimicrobial properties, B- Humectants: such as glycerin and sorbitol (5-20%) but these tend to impart a bitter taste. Increase the viscosity of the preparation. E- Flavors Enhance the sweetness of the product. Used in conjunction with alcohol and humectants Improve the preservative qualities of the product. to overcome disagreeable tastes. C- Coloring agents: The principle flavoring agents are peppermint, Used in these products to impart attractiveness. cinnamon, menthol or methyl Salicylate. 5. Ophthalmic solutions Eye drops are fluid preparations which are applied by dropping into the conjunctival sac. Eye drops are usually dispensed in bottles equipped with a dropper device. Eye lotions are fluid preparations intended for bathing or rinsing the eye. Both should be clear, sterile, isotonic with lachrymal fluid and possess physiological pH (7.4). 14  01/04/1446 6. Nasal solutions Nasal solutions are usually aqueous solutions designed to be administered to the nasal passages in drops or sprays. Although many of the drugs are administered for their local sympathomimetic effect (ephedrine sulfate or naphazoline hydrochloride) to reduce nasal congestion, a few other official preparations are administered in spray form for their systemic effect. Lypressin Nasal Solution USP for its systemic effect for the treatment of diabetes insipidus. Intranasal drug administration offers rapid absorption to the systemic circulation. This route is safe and acceptable alternative to the parental administration. 7. Otic solutions These solutions occasionally are referred to as aural preparations and intended to be administered to the ear. The main classes of drugs used for topical administration to the ear include analgesics, antibiotics and anti-inflammatory drugs. The main solvents used in these preparations include glycerin or water. The viscous glycerin vehicle permits the drug to remain in the ear for a long time. This is of very important use in some preparations especially those intended to remove ear wax. 15  01/04/1446 8. Irrigation solutions Irrigation solutions are used to wash or bathe surgical incision, wound, or body tissues. 16 LIQUID DOSAGE FORMS SOLUTIONS Types of aqueous solutions 1- Simple & Effervescent Mixtures: Douches Enemas Gargles Mouthwashes Ophthalmic solutions Nasal solutions Otic solutions Irrigation solutions 2- Sweet or viscid aqueous solution: Syrups- Linctuses- Mucilage- Jellies 1  Syrups Definition: Syrups are concentrated aqueous preparations of a sugar or sugar substitute with or without flavoring agents and medicinal substances. 1-Non-medicated Syrups: R/ EP USP and BP a) Simple syrup, which contains only sugar with (W/W) (W/V) water. b) Flavored syrup: if flavoring agents is added to Sucrose 667 gm 850 gm syrup but not medicinal substances. Purified Water ad 1000 gm 1000 ml These syrups are intended to serve as pleasant- tasting vehicles for medicinal substances to be added in the extemporaneous compounding of prescriptions. 2- Medicated syrups Are commercially prepared from the starting materials, such as sucrose, purified water, flavoring agents, coloring agents, the therapeutic agent, and other necessary and desirable ingredients. Medicated syrups are employed in therapeutics for the value of the medicinal agent present in the syrup such as antitussive and anti-histaminic syrup. 4 2  Components of Syrups Most syrups contain the following components in addition to the purified water and any medicinal agents present: a) The sugar usually sucrose, or sugar substitute used to provide sweetness and viscosity; b) Antimicrobial preservatives; c) Flavoring agent; such as orange oil or vanillin and d) Coloring agent (green with mint, brown with chocolate) 5 Sucrose- and Non-sucrose Based Syrups Sucrose is the sugar most frequently employed in syrups. Polyhydric alcohols (polyols) such as glycerol, propylene glycol or sorbitol may be added to retard crystallization of sucrose or to increase solubility of other drugs. They give both viscosity and sweetness to the preparation, but they are glycogenetic material (materials converted to glucose in the body) which are not suitable for use by the diabetic patients. For diabetic patients, Non-glycogenetic substance as methylcellulose, hydroxyethyl cellulose are used to give the required viscosity to the preparation. 6 3  Sucrose- and Non-sucrose Based Syrups So, to add the required sweetness, artificial sweeteners as saccharin sodium, cyclamate sodium, aspartame must be added. Saccharin sodium is 300 to 550 times as sweet as sucrose, but it has bitter aftertaste. Cyclamate sodium is 30 to 40 times as sweet as sucrose and has less bitter aftertaste. Aspartame is 200 times as sweet as sucrose without bitter aftertaste. 7 Preservation of syrups As syrups are nearly saturated solutions of sucrose, if properly stored, they do not need any preservatives. This is because these solutions do not contain free water, so they are anhydrous medium with respect to growth of microorganisms. A problem arises, however, when pharmacists must add other ingredients to syrups that can result in a Preservative In Use Concentration decrease in the sucrose concentration. (%w/v) This may cause a loss of the preservative effectiveness Benzoic acid 0.1% of the sucrose (sucrose in lower concentrations Sorbic acid 0.2% provides an excellent nutrient media for molds). Ethanol 15-20% Methylparabens, 0.1%. This can be overcome, by calculating the quantity of a preservative to add to the formula to maintain the propylparabens, and preservative effectiveness of the final product. butylparabens 8 4 Preparation of Syrups Syrups are prepared by one of four general methods, depending on the physical and chemical characteristics of the ingredients. 1 Solution of the ingredients with the aid of heat Solution of the ingredients by agitation without 2 the use of heat Preparation of Syrups Addition of sucrose to a prepared medicated 3 liquid or to a flavored liquid Percolation of either the source of the medicating 4 substance or the sucrose. 5 1- Solution with the Aid of Heat Syrups are prepared by this method when 1) It is desired to prepare the syrup as quickly as possible and 2) The syrup’s components are not damaged or volatilized by heat. In this method, The sugar is generally added to the purified water, and heat is applied until the sugar is dissolved. Then, other heat-stable components are added to the hot syrup, the mixture is allowed to cool, and volume is adjusted to the proper level by the addition of purified water. If heat labile agents or volatile substances, such as volatile flavoring oils and alcohol, are to be added, they are generally added to the syrup after the solution is cooled to room temperature. Caution must be exercised against using excessive heat. Sucrose, a disaccharide, may be hydrolyzed into monosaccharides, dextrose (glucose), and fructose (levulose). This hydrolytic reaction is inversion, and the combination of the two monosaccharide products is invert sugar. The sweetness of the syrup is altered because invert sugar is sweeter than sucrose, and the colorless syrup darkens because of the effect of heat on the levulose portion of the invert sugar. When the syrup is greatly overheated, it becomes amber colored as the sucrose caramelizes. Syrups so decomposed are more susceptible to fermentation and to microbial growth than the stable, undecomposed syrups. Because of the decomposition by heat, syrups cannot be sterilized by autoclaving. 6  2- Solution by Agitation Without the Aid of Heat To avoid heat-induced inversion of sucrose, a syrup may be prepared without heat by agitation. On a small scale, sucrose and other ingredients are dissolved in purified water by placing the ingredients in a vessel larger than the volume of syrup to be prepared, permitting thorough agitation of the mixture. This process is more time consuming than the use of heat, but the product has maximum stability. Huge glass-lined or stainless-steel tanks with mechanical stirrers or agitators are employed in large- scale preparation. When solid agents are to be added to a syrup, it is best to dissolve them in minimal amount of purified water and incorporate the resulting solution into the syrup. When solid substances are added directly to a syrup, they dissolve slowly because the viscous nature of the syrup does not permit the solid substance to distribute readily throughout the syrup and because a limited amount of available water is present in concentrated syrups. 3- Addition of Sucrose to a Medicated Liquid or to a Flavored Liquid Occasionally, a medicated liquid, such as a tincture or fluidextract, is employed as the source of medication in the preparation of a syrup. Many tinctures and fluidextracts contain alcohol- soluble constituents and prepared with alcoholic or hydroalcoholic vehicles. If the alcohol-soluble components are desired medicinal agents, some means of rendering them water soluble is employed. However, if the alcohol-soluble components are unnecessary components of the corresponding syrup, they are generally removed by mixing the tincture or fluidextract with water, allowing the mixture to stand until separation of the water- insoluble agents is complete, and filtering them from the mixture. The filtrate is the medicated liquid to which the sucrose is added in preparation of the syrup. If the tincture or fluidextract is miscible with aqueous preparations, it may be added directly to simple syrup or to a flavored syrup. 7  4-Percolation In the percolation method, either sucrose may be percolated to prepare the syrup, or the source of the medicinal component may be percolated to form an extractive to which sucrose or syrup may be added. This latter method really is two separate procedures: first the preparation of the extractive of the drug and then the preparation of the syrup. When preparing percolated sucrose, purified water is allowed to pass through a bed of crystalline sucrose, where a cotton is placed in its neck, thus dissolving sucrose and forming syrup. An example is ipecac syrup, which is prepared by adding glycerin and syrup to an extractive of powdered ipecac obtained by percolation. This syrup is commonly used in the management of poisoning in children when evacuation of the stomach contents is desirable. 2. Linctuses Linctus is a viscous preparation usually prescribed for the relief of cough and sore throat. It usually consists of a simple solution of the active agent in a high concentration of sucrose often with other sweetening agents such as glycerol. The syrup content has a demulcent and sedative action on the mucous membranes of the throat. The dose volume is small (5 ml), and to prolong the demulcent action they should be taken undiluted sipped and swallowed slowly. Examples are Codeine Linctus in sucrose syrup. 8 3. Mucilage The official mucilages are thick, viscid, adhesive liquids, produced by dispersing gum in water, or by extracting the mucilaginous principles from vegetable substances with water. The mucilages all are prone to decomposition, showing appreciable decrease in viscosity on storage, they should never be made in quantities larger than can be used immediately, unless a preservative is added. They are used in herbal medicine chiefly for suspending more active medicinal substances, for soothing irritated internal or external surfaces and for their local action as palliatives. 4. Jellies Jellies are a class of gels in which the structural coherent matrix contains a high portion of liquid, usually water. They are similar to mucilages, in that they may be prepared from similar gums, but they differ from the latter in having a jelly-like consistency. These preparations also may be formulated with water from acacia, gelatin, carboxymethylcellulose, hydroxyethyl cellulose, and similar substances. 9  The need for non-aqueous solvents appeared to 1) Ensure complete solubility of all ingredients at all storage temperatures. 2) They are also important if the drug is unstable in the aqueous medium. 3) In addition, because body fluids are aqueous, the use of oily vehicle provides a depot action for injections, as the oily injections releases drugs into the surrounding tissues in a rate slower than that if the drug II- Non-Aqueous in aqueous medium. This section is, therefore devoted to groups of non-aqueous solutions: Solutions 1) Alcoholic or hydroalcoholic solutions (elixirs, tinctures and spirits), 2) Ethereal solutions (collodions), 3) Glycerin solutions (glycerites), 4) Oleaginous solutions (liniments and oleo-vitamins). Examples of commonly used organic liquids 1- Alcohols, including polyhydric ones (i.e., those containing more than one hydroxyl group per molecule) Ethanol is the most common organic solvent used in pharmaceutical solutions. It is often used as a co-solvent in oral, topical and parenteral solutions. Propylene glycol (CH3CH(OH)CH2OH) contains 2 hydroxyl groups per molecule. It is often used as a co-solvent in oral, topical, parenteral and otic solutions. Glycerol contains 3 hydroxyl groups per molecule. It is widely used as a solvent or co-solvent with water, in oral and parenteral solutions. Low molecular weight polyethylene glycols (PEGs) with the general formula HOCH2(CH2CH2O)nCH2OH. These are used as solvents or co-solvents with water or ethanol. Used in parenteral solutions. 10 2- Fixed vegetable oils They are non-volatile oils and are mainly triglycerides of fatty acids. Examples include corn oil, sesame oil, arachis oil, almond oil, soya oil, cottonseed oil, castor oil. Historically, they have been used for intramuscular administration. They are used to a lesser extent now due to their irritancy and the possibility of allergic reactions to certain oils. They are being replaced by synthetic alternatives such as ethyl oleate. 3- Ethyl ether: Used as a co-solvent with ethanol in collodions. 4- Dimethyl sulfoxide Used as a carrier for idoxuridine (anti- herpesvirus) for topical application to the skin. 5- Esters Such as ethyl oleate, benzyl benzoate, ethyl ethanoate: These are used as a vehicle in certain intramuscular injections. 11  Elixirs Elixirs are clear, sweetened hydroalcoholic solutions intended for oral use and are usually flavored to enhance their palatability. Compared with syrups, elixirs are usually less sweet and less viscous because they contain a lower proportion of sugar and consequently are less effective than syrups in masking the taste of medicinal substances. However, because of their hydroalcoholic character, elixirs are better able than aqueous syrups to maintain both water-soluble and alcohol-soluble components in solution. Also, because of their stable characteristics and the ease with which they are prepared (by simple solution), from a manufacturing standpoint, elixirs are preferred to syrups. A disadvantage of elixirs for children and for adults who choose to avoid alcohol is their alcoholic content. In addition to alcohol and water, other solvents, such as glycerin and propylene glycol, are frequently employed in elixirs as adjunctive solvents. Although many elixirs are sweetened with sucrose or with a sucrose syrup, some use sorbitol, glycerin, and/or artificial sweeteners. Elixirs having a high alcoholic content usually use an artificial sweetener, such as saccharin, which is required only in small amounts, rather than sucrose, which is only slightly soluble in alcohol and requires greater quantities for equivalent sweetness. Elixirs containing more than 10% to 12% of alcohol are usually self-preserving and do not require the addition of an antimicrobial agent. Example of medicated elixirs are Phenobarbital Elixir, Theophylline Elixir, Bronchicum Elixir, and Bisolvon Elixir. 12  Preparation of Elixirs Elixirs are usually prepared by simple solution with agitation Alcohol soluble and water-soluble components are generally dissolved separately in alcohol and in purified water, respectively. Then the aqueous solution is added to the alcoholic solution, rather than the reverse, to maintain the highest possible alcoholic strength at all times so that minimal separation of the alcohol-soluble components occurs. Frequently, the final mixture will be cloudy, principally because of separation of some of the flavoring oils by the reduced alcoholic concentration. If this occurs, the elixir is usually permitted to stand for a prescribed number of hours to ensure saturation of the hydroalcoholic solvent and to permit the oil globules to coalesce so that they may be more easily removed by filtration. Talc, a frequent filter aid in the preparation of elixirs, absorbs the excessive amounts of oils and therefore assists in their removal from the solution. Tinctures Tinctures are alcoholic or hydroalcoholic solutions prepared from vegetable materials or from chemical substances. When they are prepared from chemical substances (e.g., iodine), tinctures are prepared by simple solution of the chemical agent in the solvent. Depending on the preparation, tinctures contain alcohol in amounts ranging from approximately 15% to 80%. The alcohol content protects against microbial growth and keeps the alcohol-soluble extractives in solution. Because of the alcoholic content, tinctures must be tightly stoppered and not exposed to excessive temperatures. Example of Medicated tinctures taken orally is Opium Tincture. 13 27 14 II- Non-Aqueous Solutions Presented by Islam Kamal Abdallah 1  Spirits Spirits, sometimes known as essences, are alcoholic or hydroalcoholic solutions of volatile substances. The concentration of the alcohol is usually more than 60%. Due to the greater solubility of volatile substance in alcohol than in water, spirits contain greater concentration of volatile substances than aromatic water. Some spirits are used internally for their medicinal value, some applied externally and a few by inhalation, while a large number as flavoring agents. The latter group provides a convenient and ready means of obtaining the volatile oil in the proper quantity. For example, a spirit may be used in the formulation of aromatic waters or other pharmaceuticals that require a distinctive flavor. Spirits When taken orally, they are generally mixed with a portion of water to reduce the pungency of the spirit. Spirits must be stored in tight, light resistant containers, and in a cool place. Examples: 1. Aromatic ammonia spirit (a respiratory stimulant to prevent or treat fainting), 2. Camphor spirit (For the temporary relief of minor aches, muscle and joint pain associated with arthritis, strains, brusies and simple backache.), 3. Compound orange spirit (as a carminative, flavored spirit, and a diluent for aqueous internal preparation. 4. Peppermint spirit (stomach/intestinal disorders such as upset stomach, cramps, irritable bowel syndrome-IBS) 2  Preparation of Spirits a- Simple solution This is the method by which the majority of spirits are prepared. Aqueous ingredients are dissolved in water; oils are then dissolved in alcohol. The aqueous solution is added gradually to the alcoholic one. Set aside for 24 hours, then filter. b- Solution with maceration In maceration process, the plant material is placed in pieces or powder, depending on convenience, in a container full of menstruum and let stand for three or more days, shake frequently until complete extraction of plant material. After this, the material is strained and the remaining solid is squeezed to remove all the remaining liquid. The obtained liquid is clarified by decantation or filtration. The maceration is performed at room temperature. Methods for extraction Maceration, percolation, infusion and decoction are the most important methods for extraction. In infusion, cold or boiling water is used as menstruum (extracting solvent). This extraction technique is used for plant with soft structure as leaves. Drug constituents could be volatile. In decoction the drug is boiled in water, and this is used for plant with hard structure such as roots. Drug constituents must be non-volatile. 3  Collodions (Ethereal solutions) Collodions are liquid preparations containing pyroxylin (a nitrocellulose) in a mixture of ethyl ether and ethanol with or without added medicinal substances. They are applied to the skin by means of a soft brush or other suitable applicator. When the ether and ethanol have evaporated, leave a film of pyroxylin on the surface. This provide as occlusive protective film to the skin and when the collodion is medicated, it leaves a thin layer of that medication firmly placed against the skin. Collodions, is highly flammable and must be stored away from flame in well-closed containers, protected from light. Collodion is applied to the skin for the protection of small cuts and abrasions. ℞/ Pyroxylin 4g Ether 75 ml Alcohol 25 ml Fiat: Collod., Mitte i Preparation Dissolve pyroxylin in ether and alcohol using a suitable beaker and glass rod. Transfer to well-stoppered bottle equipped with either an applicator or a brush. Store at temperature not exceeding 30° C in airtight container. N.B.: The film is useful in holding the edges of an incised wound together. However, its presence on the skin is uncomfortable because of its inflexible nature. The following product, which is flexible, has a greater appeal where a pliable film isobtained 4  Examples of the official collodions 1- Flexible Collodion Flexible collodion is prepared by adding 2% camphor and 3% castor oil to collodion. The castor oil renders the product flexible, permitting its comfortable use over skin areas that are normally moving, such as joints, fingers, and toes. The camphor makes the product waterproof. Physicians frequently apply the coating over bandages or stitched incisions to make them waterproof and to protect them from external stress. 2- Salicylic Acid Collodion Salicylic acid collodion is a 10% solution of salicylic acid in flexible collodion. It is used for its Keratolytic effects, especially in the removal of corns from the toes. Glycerites Glycerins or glycerites are solutions or mixtures of medicinal substances in not less than 50% by weight of glycerin. Most of the glycerins are extremely viscous and some are of a jelly-like consistency. Because of the high percentage of glycerin, they are viscous, hygroscopic and heavy preparations. Being hygroscopic, they should be stored and dispensed in tightly closed containers. The advantages of using glycerin in these preparations: 1) It has a wide range of solvent power, allowing solutions of greater strength to be made than are possible with water or alcohol. 2) It is of good sweet taste. 3) It is used as a preservative and does not become rancid. 4) The liquid glycerites are readily miscible with water and for this reason serve as stock solutions, which may be diluted readily with water or alcohol. 5  Examples of the official glycerites: 1- Glycerin of Starch ℞/ Starch 10 gm Benzoic acid 0.2 gm Distilled Water 20 ml Glycerin ad 100 gm It should be freshly prepared. It is translucent, jelly-like mass, composed chiefly of starch paste in glycerin. This preparation is used as emollient and demulcent and is used directly for these effects or as a vehicle for other substances to be employed locally. 2. Glycerol of Boric Acid It is used as antibacterial and when diluted with glycerin can be used for its antiseptic effect as throat paint. 3. Glycerol of tannic acid It is used for its astringent action in treatment of sore throat. When diluted with water can be used in stomatitis, pharyngitis, and tonsillitis. 4. Glycerol of Phenol It contains 10% of phenol in glycerin. It is used for antiseptic action as ear drops. 6  Liniments Liniments are solutions of various substances in oil, alcoholic solutions of soap. These preparations are intended for external application and should be so labeled. Liniments usually are applied with friction and rubbing of the skin, the oil or soap base providing for ease of application and massage. Alcoholic liniments are used generally for their rubefacient, counterirritant, mildly astringent, and penetrating effect. Such liniments penetrate the skin more readily than do those with an oil base. The oily liniments, therefore, are milder in their action but are more useful when massage is required. The vehicle for a liniment should therefore be selected for the type of action desired (rubefacient, counterirritant, or massage) and also on the solubility of the desired components in the various solvents. For oleaginous liniments, the solvent may be a fixed oil such as almond oil, peanut oil, sesame oil, or cottonseed oil or a volatile substance such as wintergreen oil or turpentine, or it may be a combination of fixed and volatile oils. Liniments Liniments are not applied to skin areas that are broken or bruised because excessive irritation might result Liniments are one of the least desirable forms of externally applied liquids from the patient's view-point because 1. Its application must be repeated over a period of time 2. The patient is required to extent effort on application 3. May leave a noticeable film on the surface or may stain clothing. 4. Its removal from the surface may be difficult. 5. Its appearance and odor may not be pleasing. Examples of official liniments: 1) Liniment of Calamine: It is used as protective in dermatitis. 2) White Liniment: It is used as rubefacient 7 Oleovitamins They are preparations using fish liver oil (or fish liver oil diluted with vegetable oil) or a solution of vitamin concentrate (usually vitamin A & D) in fish liver oil. Vitamin A, D and E preparations are official in National Formulary. It should be stored in tight containers and protected from light. 8