Lec1 Pharm.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, produces dosage fo...

# 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, produces 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 | Classifications Based on Route/Method of Administration | Classifications 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 - Monophasic - Solution - Syrup - Biphasic - Suspension - Emulsion ### Solid - One Unit - Tablets - Capsules - Bulk - Powder - Granules - Dusting powder ### Semisolid - Gel - Paste - Cream - Ointment ### Gas - Inhaler - Aerosols ## Terms: - **Drug:** (active pharmaceutical ingredient - API) chemical compound intended for use in diagnosis, treatment or prevention of diseases. - **Excipients:** (inactive pharmaceutical ingredients) Technological, biopharmaceutical and/or stability reasons. Diluents/fillers, binders, lubricants, desintegrants, coatings, preservatives and stabilizers, colorants and flavorings - **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 suppositories). 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 interpenetration. 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 of 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 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.