Pharmaceutical Technology PDF

# Pharmaceutical Technology ## Pharmaceutical Dosage Forms Drug substances are usually administered as part of a formulation in combination with one or more nonmedicinal agents. Selective use of these nonmedicinal agents, referred to as pharmaceutical ingredients or excipients, produce dosage form...

# Pharmaceutical Technology ## Pharmaceutical Dosage Forms Drug substances are usually administered as part of a formulation in combination with one or more nonmedicinal agents. Selective use of these nonmedicinal agents, referred to as pharmaceutical ingredients or excipients, produce dosage forms of various types. The pharmaceutical ingredients solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, give color or flavor, and fashion medicinal agents into efficacious and appealing dosage forms. Each type of dosage form is unique in its physical and pharmaceutical characteristics. ## Types of Dosage Forms | Classification Based on Route/Method of Administration | Classification Based on the Physical Form of the Dosage Form | |---|---| | Topical Dosage Forms | Solid Dosage Forms | | Parenteral Dosage Forms | Semi-solid Dosage Forms | | Vaginal Dosage Forms | Liquid Dosage Forms | | Nasal Dosage Forms | Gaseous Dosage Forms | | Oral Dosage Forms | | Rectal Dosage Forms | | Respiratory/Inhaled Dosage Forms | | Ophthalmic Dosage Forms | | Otic Dosage Forms | ### Liquid 1. Monophasic - Solution - Syrup 2. Biphasic - Suspension - Emulsion ### Solid 1. One Unit - Tablets - Capsules ### Semisolid - Gel - Paste - Cream - Ointment ### Gas - Inhaler - Aerosols ## Terms - **Drug:** (active pharmaceutical ingredient - API) chemical compound intended for used in diagnosis, treatment or prevention of diseases. - **Excipients:** (inactive pharmaceutical ingredients) Technological, biopharmaceutical and/or stability reasons. Diluents/fillers, binders, lubricants, desintegrants, coatings, preservants and stabilizers, colorants and flavourings - **Dosage form:** Drug + excipients ## Why drugs are formulated as Dosage Forms Dosage forms are needed for the following: 1. Providing the mechanism for the safe and convenient delivery of accurate dosage. 2. Protecting the drug substance from the destructive influences of atmospheric oxygen or humidity (coated tablets, sealed ampules). 3. Protecting the drug substance from the destructive influence of gastric acid after oral administration (enteric-coated tablets). 4. Concealing the bitter, salty, or offensive taste or odor of a drug substance (capsules, coated tablets, flavored syrups). 5. Providing liquid preparations of substances that are either insoluble or unstable in the desired vehicle (suspensions). 6. Providing clear liquid dosage forms of substances (syrups, solutions). 7. Offering a rate-controlled drug action (various controlled-release tablets, capsules, and suspensions). 8. Providing optimal drug action from topical administration sites (ointments, creams, transdermal patches, and ophthalmic, ear, and nasal preparations). 9. Insertion a drug substance into one of the body's orifices (rectal or vaginal sup-positories). 10. Placement of drugs directly in the bloodstream or body tissues (injections). 11. Providing an optimal drug action through inhalation therapy (inhalants and inhalation aerosols). ## Solubility Attractive forces between atoms lead to the formation of molecules and ions. When molecules interact, attractive and repulsive forces are in effect. The attractive forces cause the molecules to cohere, whereas the repulsive forces prevent molecular inter-penetration. When the attractive and repulsive forces are equal, the potential energy between two molecules is minimum and the system is most stable. Large groups of molecules may be associated through weak attractions, known as dipole-dipole or Van der Waals forces. Other attractions also occur between polar and nonpolar molecules and ions. These include ion-dipole forces and hydrogen bonding. When a solute dissolves, the substance's intermolecular forces of attraction must be overcome by forces of attraction between the solute and solvent molecules. The solubility of an agent in a particular solvent indicates the maximum concentration to which a solution may be prepared with that agent and that solvent. When a solvent at a given temperature has dissolved all of the solute, it is said to be saturated. **Example** Two official aqueous saturated solutions are given as examples, Calcium hydroxide topical solution, USP, and Potassium iodide oral solution, USP. The first prepared by agitating an excess amount of calcium hydroxide with purified water, contains only about 140 mg of dissolved solute per 100 mL of solution at 25°C, whereas potassium iodide solution contains about 100 g per 100 mL of solution, more than 700 times much solute as in the calcium hydroxide topical solution. When excess of solid (solute) is shaken with solvent for a period of time a maximum amount of it will be dissolved (saturated solubility). If excess amount of solute is added to saturated solution and the temperature is increased, more of solute will be dissolved (super saturated solution). ## Solubility vs Dissolution Solubility is the capacity of a solute to dissolve in a pure solvent while dissolution rate is a kinetic process. Dissolution is a process of a solute dispersing or dissociating in a solvent forming solution in contrast to solubility which is an endpoint. **Solute + Solvent --> dissolution --> Solution** ## Factors affecting solubility The solubility can be affected by: 1. **Selection of a different solubilzing agent or using a different chemical salt form of the drug.** Substitution in part or in whole of the solvent. For example, iodine is soluble in water only to the 1 g in about 3000 mL and the maximum concentration possible would be approximately 0.03% of iodine. However, through the use of an aqueous solution of potassium iodide or sodium iodide as the solvent, much larger amounts of iodine may be dissolved as the result of the formation of a water-soluble complex with the iodide salt. This reaction is taken advantage of, for example, in iodine topical solution, USP, prepared to contain about 2% iodine and 2.4% sodium iodide. 2. **Temperature** is an important factor in determining the solubility of a drug and in preparing its solution. Most chemicals absorb heat when they are dissolved and are said to have a positive heat of solution, resulting in increased solubility with an increase in temperature. A few chemicals have a negative heat of solution and exhibit a decrease in solubility with a rise in temperature. 3. **Other factors** in addition to temperature like the various chemical and physical properties of both the solute and the solvent, and the pressure. The solubility of a pure chemical substance at a given temperature and pressure is constant; however, its rate of solution (the speed at which it dissolves) depends on the particle size of the substance and the extent of agitation. The finer the powder, the greater the surface area that comes in contact with the solvent and the more rapid the dissolving process. 4. **The agitation applied to the solution**, the greater the agitation, the more unsaturated solvent passes over the drug, and the faster the formation of the solution. 5. **pH of the solution.** Many of the important organic medicinal agents are either weak acids or weak bases, and their solubility mostly depends on the pH of the solvent. These drugs react either with strong acids or strong bases to form water-soluble salts. For instance, the weak bases, including many of the alkaloids (atropine, codeine, and morphine), antihistamines (diphenhydramine), local anesthetics (cocaine, procaine, and tetracaine), are not very water soluble, but they are soluble in dilute solutions of acids. However, if the pH of this solution is increased, the free base may precipitate. Organic medicines that are weak acids including the barbiturates (e.g., phenobarbital) and the sulfonamides (e.g., sulfadiazine and sulfacetamide), form water-soluble salts in basic solution and may separate from solution by lowering of the pH. The solubility of a substance in a given solution may be determined by preparing a saturated solution of it at a specific temperature using chemical analysis. The amount of solvent required to dissolve the amount of solute can be determined by simple calculation. The solubility may then be expressed as grams of solute dissolving in milliliters of solvent; for example, "1 gram of sodium chloride dissolves in 2.8 mL of water." ## General rules of solubility ### Inorganic Molecules 1. If both the cation and anion are monovalent, the solute-solute attractive forces are usually easily overcome, therefore, these compounds are generally water soluble (e.g., NaCl, KI, NH4NO3). 2. If only one of the two ions is monovalent, the solute-solute interactions are also usually easily overcome and the compounds are water soluble (e.g., BaCl2, Na2SO4, Na3PO4). 3. If both the cation and anion are multivalent, the solute-solute interaction may be too great to be overcome by the solute-solvent interaction, and the compound may have poor water solubility (e.g., CaSO4, BaSO4; exceptions: ZnSO4, FeSO4). 4. Common salts of alkali metals (Na, K, Li, Cs, Rb) are usually water soluble (exception: Li2CO3). 5. Ammonium and quaternary ammonium salts are water soluble. 6. Nitrates, nitrites, acetates, chlorates, and lactates are generally water soluble (exceptions: silver and mercurous acetate). 7. Sulfates, sulfites, and thiosulfates are generally water soluble (exceptions: calcium and barium salts). 8. Chlorides, bromides, and iodides are water soluble (exceptions: salts of silver and mercurous ions). 9. Acid salts corresponding to an insoluble salt will be more water soluble than the original salt. 10. Hydroxides and oxides of compounds other than alkali metal cations and the ammonium ion are generally water insoluble. 11. Sulfides are water insoluble except for their alkali metal salts. 12. Phosphates, carbonates, silicates, borates, and hypochlorites are water insoluble except for their alkali metal salts and ammonium salts. ### Organic Molecules 1. Molecules having one polar functional group are usually soluble to a total chain length of five carbons. 2. Molecules having branched chains are more soluble than the corresponding straight-chain compounds. 3. Water solubility decreases with an increase in molecular weight. 4. Increased structural similarity between solute and solvent is accompanied by increased solubility. In addition to the factors of solubility, the selection of the solvent should have additional characteristics such as low toxicity, compatibility with other formulative ingredients, palatability, suitable viscosity, odor, color, and economy. In most instances, especially for solutions to be taken orally, ophthalmically, or parenterally, water is the preferred solvent, as it comes closer to meeting these criteria than other solvents. Alcohol, glycerin, and propylene glycol, the most widely used auxiliary solvents, have been quite effective due to the desired characteristics of pharmaceutical solutions and in maintaining their stability. Other solvents, such as acetone, ethyl oxide, and isopropyl alcohol, are too toxic to be permitted in pharmaceutical preparations to be taken internally. A number of fixed oils, such as corn oil, cottonseed oil, peanut oil, and sesame oil, are useful solvents, particularly in the preparation of oleaginous injections. ## Official solvents 1. **Alcohol, USP: Ethyl Alcohol, Ethanol, C2H5OH** It is used as a primary solvent for many organic compounds. Together with water it forms a hydroalcoholic mixture that dissolves both alcohol-soluble and water-soluble substances. 2. **Diluted Alcohol, NF** It is prepared by mixing equal volumes of alcohol, USP, and purified water USP. 3. **Alcohol, Rubbing** It contains about 70% ethyl alcohol by volume. The product is volatile and flammable and is mostly employed as a rubefacient externally. 4. **Glycerin, USP (Glycerol), CH2OH-CHOH-CH2OH** It is a clear syrupy viscous liquid with a sweet taste. Glycerin has preservative qualities and is often used as a stabilizer and as an auxiliary solvent in conjunction with water or alcohol. 5. **Propylene Glycol, USP, CH3CH(OH)CH2OH** It is a viscous liquid, frequently substituted for glycerin. 6. **Isopropyl Rubbing Alcohol** It is used externally as a rubefacient and soothing. 7. **Purified Water, USP, H2O** Naturally occurring water exerts its solvent effect on most substances, it is impure, containing varying amounts of dissolved inorganic salts, along with dissolved and undissolved organic materials and microorganisms. Ordinary drinking water from the tap is not acceptable for the manufacture of pharmaceutical preparations or for compounding of prescriptions because of possible chemical incompatibilities between dissolved solids and the medicinal agents. Purified Water, USP, has 1% as much dissolved solids as tap water. Purified Water, USP, is intended for use in 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, are used for injections. The main methods used in the preparation of Purified Water are: a) **Distillation method:** This method is performed using distillation apparatus of different sizes, styles, and capacities. b) **Ion Exchange method:** the ion exchange equipment passes water through a column of cation and anion exchangers consisting of water-insoluble synthetic resins of high molecular weight. These resins are mainly of two types: (a) the cation, or acid exchangers which permit the exchange of the cations in solution; (b) the anion, or base exchange resins, which permit the removal of anions. Water purified in this manner, referred to as demineralized or deionized water or distilled water. c) **Reverse osmosis (RO):** in this process, a pressurized stream of water is passed into a filter membrane. A portion of the water, passes the membrane as filtrate, while some sweeps along the membrane without being filtered. Reverse osmosis removes virtually all viruses, bacteria, pyrogens, and organic molecules and 90 to 99% of ions. ## 8- Solvents and vehicles for Injections a) **Water for Injection, USP.** It is the most frequently used solvent in the large-scale manufacturer of injections. This water is purified by distillation or by reverse osmosis and meets the same standards for the presence of total solids as does Purified Water, USP, that is, not more than 1 mg/100 mL. It may not contain added substances. Although water for injection is not required to be sterile, it must be pyrogen free. The water is intended to be used in the manufacture of injectable products to be sterilized after preparation. b) **Sterile Water for Injection, USP.** It is packaged in single-dose containers not larger than 1 L. As with water for injection, it must be pyrogen free. This water is intended to be used as a solvent, vehicle, or diluent for already sterilized and packaged injectable medications. c) **Bacteriostatic Water for Injection, USP.** It is sterile water for injection containing one or more suitable antimicrobial agents. It is packaged in prefilled syringes or in vials containing not more than 30 mL of the water. The water is employed as a sterile vehicle in the preparation of small volumes of injectable preparations. ## Preparation of Solution Most pharmaceutical solutions are unsaturated with solute. Thus, the amounts of solute to be dissolved are usually well below the capacity of the volume of solvent employed. The strengths of pharmaceutical preparations are usually expressed in terms of percent strength, although for very dilute preparations, expressions of ratio strength may be used. The symbol % used without qualification (as with "/, /, or "/w) means percent weight in volume for solutions or suspensions of solids in liquids; percent weight in volume for solutions of gases in liquids; percent volume in volume for solutions of liquids in liquids; and weight in weight for mixtures of solids and semisolids. Some chemical agents in a solvent require an extended time for dissolving, or applying heat, reducing the particle size of the solute, using a solubilizing agent, or subjecting the ingredients to vigorous agitation. Pharmacists do not prefer to use heat to facilitate solution, and when they do, they are careful not to exceed the minimally required temperature, to avoid medicinal agents destruction and drug deterioration. If volatile solutes are to be dissolved or if the solvent is volatile (as is alcohol), the heat would encourage the loss of these agents to the atmosphere and must therefore be avoided. Pharmacists are aware that certain chemical agents, particularly calcium salts, undergo exothermic reactions as they dissolve and give off heat. In addition to or instead of raising the temperature of the solvent to increase the rate of solution, a pharmacist may choose to decrease the particle size of the solute. This may be accomplished by comminution with a mortar and pestle on a small scale or industrial micronizer on a large scale. The reduced particle size increases the surface area of the solute. If the powder is placed in a suitable vessel with a portion of the solvent and is stirred or shaken, the rate of solution may be increased by the continued circulation of fresh solvent to the drug's surface. Most solutions are prepared by simple mixing of the solutes with the solvent. On an industrial scale, solutions are prepared in large mixing vessels with ports for mechanical stirrers. When heat is desired, thermostatically controlled mixing tanks may be used. **Note:** Pharmaceutical preparations are stable if they show no loss in therapeutic activity and no undesirable chemical and physical changes over extended periods of time. Drug expiration dates reflect the time period during which the product is known to remain stable, which means it retains its strength, quality, and purity when it is stored according to its labeled storage conditions. Shelf life may be defined as the time required for the drug level in a product stored at room temperature (normally 25°C) to degrade to 90 percent of its labeled potency. ## Oral Solutions Most solutions intended for oral administration contain flavorants and colorants to make the medication more attractive and palatable. They may also contain stabilizers to maintain the chemical and physical stability of the medicinal agents and preservatives to prevent the growth of microorganisms in the solution. The pharmacist must be wary of chemical interactions between the various components of a solution that may alter the preparation's stability and/or potency. Liquid pharmaceuticals for oral administration are usually formulated such that the patient receives the usual dose of the medication in a small volume, as 5 mL (one teaspoonful), 10 mL, or 15 mL (one tablespoonful). ## Properties of oral solutions Oral solution should have the following properties: a) **Palatable:** means that the preparations must be acceptable by patient regarding taste, appearance and odor to a reasonable degree, and this is affected by many factors like age of patients, pharmaceutical dosage form, the taste we need to improve and color of the drug. Adjuvant or additives are used to improve the drug and make it more palatable. b) **Stability:** the drug should be stable enough to ensure that the patient will receive the stated amount on the label and should be stable for such a period of time (stored at room temperature) to ensure that the patient will take the precise dose. c) **Effective:** the drug should be effective when taken by the patient like absorption, distribution and other properties. ## Dry Mixtures for Solution Number of medicinal agents, particularly certain antibiotics, has insufficient stability in aqueous solution to meet extended shelf life periods. Thus, commercial manufacturers of these products provide them to the pharmacist dry powder or granule form for reconstitution with a prescribed amount of purified water immediately before dispensing to the patient. The dry powder mixture contains all of the formulative components, including drug, flavorant, colorant, buffers, and others, except for the solvent. Once reconstituted, the solution remains stable when stored in the refrigerator for the labeled period, usually 7 to 14 days, depending on the preparation. This is a sufficient period for the patient to complete the regimen usually prescribed. However, in case medication remains after the patient complete the course of therapy, the patient should instructed to discard the remaining portion. ## Oral Solutions The pharmacist may dispense a commercially prepared oral solution; dilute the concentration of a solution, as in the preparation of a pediatric form of an adult product; prepare a solution by reconstituting a dry powder mixture; or compounding an oral solution from bulk components. In each instance, the pharmacist should be aware about the dispensed product to advise the patient of the proper use, dosage, method of administration, and storage of the product. Knowledge of the solubility and stability characteristics of the medicinal agents and the solvents employed is useful to the pharmacist for informing the patient of the advisability of mixing the solution with juice, milk, or other. ## Oral Rehydration Solutions Rapid fluid loss associated with diarrhea can lead to dehydration and ultimately death in some patients, particularly infants. Diarrhea is characterized by an increased frequency of loose, watery stools, and because of the rapid fluid loss, dehydration can be an outcome. The loss of fluid during diarrhea is accompanied by depletion of sodium, potassium, and bicarbonate ions; if severe, the loss can result in acidosis, hyperpnea, and vomiting as well as hypovolemic shock. If continuous, vomiting and diarrhea can cause malnutrition as well. Consequently, the goal is to replace lost fecal water with an oral rehydration solution and use nutritional foods, such as soybean formula and bran. Oral rehydration salts solutions (ORS) are usually effective in treatment of patients with mild volume depletion, 5 to 10% of body weight. These are available OTC and are relatively inexpensive, and their use has diminished the incidence of complications associated with parenterally administered electrolyte solutions. A liter of typical oral rehydration solution contains 45 mEq Na⁺, 20 mEq K⁺, 35 mEq CI⁻, 30 mEq citrate, and 25 g dextrose. These formulations are available in liquid or powder packet form for reconstitution. It is important that the user add the specific amount of water needed to prepare the powder forms. Furthermore, these products should not be mixed with or given with other electrolyte-containing liquids, such as milk or fruit juices. ## Oral Colonic Lavage Solution Traditionally, preparation of the bowel for procedures such as a colonoscopy consisted of administration of a clear liquid diet for 24 hours preceding the procedure, administration of an oral laxative such as magnesium citrate or bisacodyl the night before, and a cleansing enema administered 2 to 4 hours prior to the procedure. However, while the results have been satisfactory, that is, the bowel is cleared for the procedure, poor compliance with and acceptance of this regimen can cause problems during the procedure. Also, additive effects of malnutrition and poor oral intake prior to the procedure can cause more patient problems. Consequently, an alternative method has been devised. This procedure requires less time and dietary restriction and obviates cleansing enemas. This method entails oral administration of a balanced solution of electrolytes with polyethylene glycol (PEG-3350). Before dispensing it to the patient, the pharmacist reconstitutes this powder with water, creating an iso-osmotic solution having a mild salty taste. The PEG acts as an osmotic agent in the gastrointestinal tract, and the balanced electrolyte concentration results in virtually no net absorption or secretion of ions. Thus, a large volume of this solution can be administered without a significant change in water or electrolyte balance. The formulation of this oral colonic lavage solution is as follows: | Component | Quantity | |---|---| | PEG-3350 | 236.00 g | | Sodium sulfate | 22.74 g | | Sodium bicarbonate | 6.74g | | Sodium chloride | 5.86 g | | Potassium chloride | 2.97 g | | | In 4800 mL disposable container | The recommended adult dose of this product is 4 L of solution before the gastrointestinal procedure. The patient is instructed to drink 240mL of solution every 10 minutes until about 4 L is consumed. The patient is advised to drink each portion quickly rather than sipping it continuously. Usually, the first bowel movement will occur within 1 hour. Several regions are used, and one method is to schedule patients for a midmorning procedure, allowing the patient 3 hours for drinking and a 1 hour waiting period to complete bowel evacuation. ## Magnesium Citrate Oral Solution Magnesium citrate oral solution is a colorless to slightly yellow clear effervescent liquid having a sweet, acidulous taste and a lemon flavor. It is commonly referred to as citrate or as citrate of magnesia. It is required to contain an amount of magnesium citrate equivalent to 1.55 to 1.9 g of magnesium oxide in each 100 mL. The solution is prepared by reacting official magnesium carbonate with an excess of citric acid, flavoring and sweetening the solution with lemon oil and syrup, filtering with talc, and then carbonating it by the addition of either potassium or sodium bicarbonate. (MgCO3)4 Mg(OH)2 + 5H3C6H5O7 --> 5MgHC6H5O7 + 4CO2 + 6H2O The solution is employed as a saline cathartic, with the citric acid, lemon oil, syrup, carbonation, and the low temperature of the refrigerated solution all contributing to the patient's acceptance of the large volume of medication. For many patients it is a pleasant way of taking an otherwise bitter saline cathartic. ## Sodium Citrate and Citric Acid Oral Solution This official solution contains sodium citrate 100 mg and citric acid 67 mg in each milliliter of aqueous solution. The solution is administered orally in doses of 10 to 30 mL as frequently as four times daily as a systemic alkalinizer. Systemic alkalinization is useful for patients for whom long-term maintenance of an alkaline urine is desirable, such as those with uric acid and cystine calculi of the urinary tract. It is also a useful adjuvant when administered with uricosuric agents in gout therapy, since urates tend to crystallize out of an acidic urine. ## Miscellaneous Solutions ### Aromatic Waters Aromatic waters are clear, aqueous solutions saturated with volatile oils or other aromatic or volatile substances. - Aromatic waters provide a pleasantly flavored medium for the administration of water-soluble drugs and for the liquid phase of emulsion and suspensions. - Aromatic waters are not therapeutically potent because of the very small proportion of active ingredient present in them. - Aromatic waters were prepared from a number of volatile substances, including orange flower oil, peppermint oil, rose oil, anise oil, spearmint oil, wintergreen oil, camphor, and chloroform. 1. They are prepared Examples of aromatic water uses: 2. Chloroform water: was used in expectorant preparations (dose 5-15ml). 3. Several aromatic waters are not used as vehicles for oral medication. These include: - Rose water used as perfume. - Hamamelis water is employed commonly as a rub and also as an astringent and perfume in cosmetic products. - Camphor water: is frequently used as soothing in eye and cough preparations for its refreshing properties, and it is also used as rubefacient,. ### Diluted acids Diluted acids are aqueous solutions prepared by diluting the concentrated acids with purified water. The strength of a diluted acid is generally expressed on a percent weight-to-volume (% w/v) basis, whereas the strength of a concentrated acid is generally expressed in terms of percent weight to weight (% w/w). There is very little use of diluted acids in medicine today. However, because of its anti-bacterial effects, acetic acid finds application as a 1% solution in surgical dressings. # Clarification Most pharmaceutical liquid preparations such as aromatic waters, syrups, liquid extracts, elixirs and others should be clear and free from foreign solid or liquid materials. So usually the final step in the preparation of these liquid preparations is the process of clarification or removing of the suspended (unwanted) materials which might come from row materials, equipment, vehicles or others. There are many methods of clarification and choosing of the suitable method depends on many factors like: a) **Particle size of the unwanted suspended material.** Some of the particles are so large that it could be seen by eye and can easily be removed while some other may be so small to be seen and removed only by special devices. b) **Physical properties of the unwanted suspended material.** Like for example the removal of excess volatile oils from liquid preparations. c) **Quantity of the unwanted suspended material.** The choice of method will depend on the amount of foreign particles, for example small quantities of such particles can use filtration but if there is a large quantity of suspended materials which are called slurry, then filtration cannot be used and other method should be used. d) **The characteristics of fluid media.** We should consider the liquid viscosity, weather we can use high temperatures or not or it is effected by exposure to air and light. e) **The speed of method.** Faster methods are more preferred than slow methods. ## Methods of clarification ### a) Settling method It is simple and primitive method by which the product is allowed to standstill until it is separated or settled. Settling is of two types either upward settling or downward settling depending on the specific gravity or density of both the suspended materials and the liquid media. If the specific gravity or density the suspended materials are less than the liquid media it will settle upward and the reverse is true. The factors affecting the settling are determined by Stokes equation as follow: **V = dx/dt = d²(p-p)g/18η** Where dx/dt is the rate of settling, d is the diameter of particles, pi is the density of particle, pe is the density of medium, g is the gravitational constant and η is the viscosity of medium. As the diameter of particles increase, the velocity increase, also increase in the difference between the density of particles and medium will lead to increase in the velocity, while increase in the viscosity of medium will lead to decrease in velocity. Gravitational constant can be changed by centrifuge to facilitate the settling which is called centrifuge clarification. ### b) Filtration and percolation method Percolation is very simple method that involve filtration through a piece of cotton or cloth while the more advanced technique, filtration, involves the passing through a filter media like filter paper. The rate of filtration is affected by many factors like the viscosity of liquid medium, size and shape of suspended particles, and the aim of filtration whether is to get clear liquid or to get the filtering media which is called cake. Other factors that are affecting the rate of filtration can be summarized by Darcy's equation **dv/dt = K×A× ΔΡ/ η×1** Where dv/dt is the rate of filtration, K is constant, A is the surface area, AP is the difference in pressure, η is the viscosity of medium and I is the thickness of cake layer. The more the surface area exposed to liquid, the faster filtration rate, also change in pressure can be used to accelerate the process by a supplying the filtration equipment with increased pressure from the up or section pump from the down. There are different types of filters and equipment depending on size and quantity of the suspended materials and on the filter media which are of many types like: - Sheets of woven materials, where these sheets are made of cotton, wool or other materials like filter papers. - Porous plates which can be made from different substances like stones, ceramic, and glass which are made as plates with different pore size. - Membrane filter, which are made from cellulose or its derivatives. These filters form channel like pores of different sizes. - Unwoven fibrous materials are used for simple clarification or filtration. - Granular or powdered materials, like small granules, sand, charcoal or any other inert material. - Ultrafilter and microsieve: by which separate micro organisms and very small particles. ## Elixirs Elixirs are clear, sweetened hydroalcoholic solutions intended for oral use and are usually flavored to enhance their palatability. Non-medicated elixirs are employed as vehicles, and medicated elixirs are used for the therapeutic effect of the medicinal substances. Compared to 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 than aqueous syrups in maintaining both water-soluble and alcohol-soluble components in solution. Also because they are easily prepared (by simple solution). The proportion of alcohol in elixirs varies widely, since the individual components of the elixirs have different water and alcohol solubility characteristics. Each elixir requires a specific blend of alcohol and water to maintain all of the components in solution. Naturally, for elixirs containing agents with poor water solubility, the proportion of alcohol required is greater than that for elixirs prepared from components having good water solubility. 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. All elixirs contain flavorings to increase their palatability, and most elixirs have coloring agents to enhance their appearance. * Elixirs containing more than 10% of alcohol are usually self-preserving and do not require the addition of an antimicrobial agent. * Medicated elixirs are formulated so that a patient receives the usual adult dose of the drug in a convenient measure of elixir. For most elixirs, one or two teaspoonfuls (5 or 10 mL) provide the usual adult dose of the drug. * One advantage of elixirs over their counterpart drugs in solid dosage forms is the flexibility and ease of dosage administration to patients who have difficulty swallowing solid forms. * A disadvantage of elixirs for children and for adults who choose to avoid alcohol is their alcoholic content. * Because of their usual content of volatile oils and alcohol, elixirs should be stored in tight, light-resistant containers and protected from excessive heat. ## Preparation of Elixirs Elixirs are usually prepared by simple solution with agitation and/or by admixture of two or more liquid ingredients. Alcohol-soluble materials are dissolved separately in alcohol and water-soluble components are dissolved separately in purified water. Then the aqueous solution is added to the alcoholic solution, not the reverse, to maintain the highest possible alcoholic strength at all times so that minimal separation of the alcohol-soluble components occurs. When the two solutions are completely mixed, the mixture is made to volume with the specified solvent or vehicle. 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 number of hours to permit the oil globules to separate so that they are 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. ## Nonmedicated Elixirs They may be useful to the pharmacist in prescriptions involving: (a) the addition of a therapeutic agent to a pleasant-tasting vehicle and (b) dilution of an existing medicated elixir. In selecting a liquid vehicle for a drug substance, the pharmacist should concern the solubility and stability of the drug substance in water and alcohol. When a pharmacist is called on to dilute an existing medicated elixir, the nonmedicated is selected as a diluent and should have approximately the same alcoholic concentration as the elixir being diluted. Also, the flavor and color characteristics of the diluent should not be in conflict with those of the medicated elixir, and all components should be chemically and physically compatible. The three most commonly used nonmedicated elixirs were Aromatic elixir, Compound benzaldehyde elixir, and Isoalcoholic elixir. ## Medicated Elixirs Medicated elixirs are employed for the therapeutic benefit of the medicinal agent. ### Antihistamine Elixir Antihistamines are useful primarily in the symptomatic relief of certain allergic disorders. They suppress symptoms caused by histamine, one of the chemical agents released during the antigen-antibody reaction of the allergic response. The most common unwanted effect is sedation, and patients taking antihistamines should be warned against engaging in activities requiring mental alertness, such as driving an automobile or operating machinery. Other common adverse effects include dryness of the nose, throat, and mouth; dizziness; and disturbed concentration. ## Barbiturate Sedative and Hypnotic Elixirs The barbiturates are sedative and hypnotic agents that are used to produce various degrees of central nervous system depression. As the dose of these drugs is increased, the effects go from sedation to hypnosis to respiratory depression that may lead to death in fatal barbiturate overdose. Barbiturates are administered in small doses in the daytime as sedatives to reduce restlessness and emotional tension. Greater doses of the barbiturates may be given before bedtime as hypnotics to relieve insomnia. Barbiturates are classified according to the duration of their hypnotic effects: * **Long-acting agents** like phenobarbital, are considered most useful in maintaining daytime sedation. * **Intermediate-acting agents and short-acting agents:** they are used primarily for short-term daytime sedation and are effective in treating insomnia. * **Ultra-short-acting agents** like thiopental, are given IV to induce anesthesia. The most common untoward effects are drowsiness and lethargy. Prolonged use of barbiturates may lead to psychic or physical dependence. Ex. Butisol Sodium Elixir (Butabarbital sodium) 30 mg/5 mL ## Digoxin Elixir Digoxin Elixir, USP contains about 0.25 mg/ 5 mL teaspoonful. Digoxin is a cardiotonic glycoside, a white crystalline powder insoluble in water but soluble in dilute alcohol solutions. The official elixir contains about 10% alcohol. Digoxin is poisonous, and its dose must be carefully determined and administered to each individual patient. Adults generally take digoxin tablets rather than the elixir. The elixir is generally employed for children, and the commercial product available for this purpose is packaged with a calibrated dropper to facilitate accurate dosing. Digoxin is one of many drugs available in more than a single dosage form (solid dosage form like tablet or capsule or a liquid), but it is important to point out again