Pharmaceutical Dosage Form I Liquid Dosage Forms Lecture Notes PDF

1 PHARMACEUTICAL DOSAGE FORM “I“ LIQUID DOSAGE FORMS 10/17/2020 Department of pharmaceutics  MARKS DISTRIBUTION 2  Periodical Quizzes 15.00 %  Oral Examination 10.00 %  Practical Examination...

1 PHARMACEUTICAL DOSAGE FORM “I“ LIQUID DOSAGE FORMS 10/17/2020 Department of pharmaceutics  MARKS DISTRIBUTION 2  Periodical Quizzes 15.00 %  Oral Examination 10.00 %  Practical Examination 25.00 %  Final-term Examination 50.00 % The curriculum will be distributed on about 12 lectures (2 hour weekly ) 10/17/2020  Course specification 3 Pharmaceutical dosage form I This course will cover: *Pharmaceutical solutions, * Coarse dispersions, *Suspensions, colloids and emulsions. 10/17/2020  Dosage forms classification Dosage forms classification Liquid Dosage Semisolid D.F. Solid Dosage forms Ointment Molded D.F. Sterile D.F. form Solution Cream Suppositories Injection Tablets Suspension Paste Pessaries Ophthalmics capsules Emulsion gel 5 10/17/2020 6 Solutions 10/17/2020  Introduction 7 An understanding of the properties of solutions, the factors that affect solubility and the process of dissolution is essential because of the importance of solutions in so many areas of pharmaceutical formulation. Solution is a homogenous one-phase system consisting of two or more components. The solvent, or mixture of solvents, is phase in which the dispersion occurs, and the solute is the component which is dispersed as molecules or ions in the solvent. In general the solvent is present in the greater amount, but there are several exceptions. For example, Syrup BP contains 66.7% w/w of sucrose as the solute in 33.3% w/w of water as the solvent. For most pharmaceutical solutions the solvent system is likely to be liquid, and the solute will be either a liquid or a solid. Solid dispersions, in which both solute and solvent are solids, are used for the improvement of the bioavailability of poorly soluble drugs. 10/17/2020  Introduction 8 Solutions of gases in liquids are characteristic of aerosols, in which the propellant gas is dispersed or dissolved in the solvent under pressure. On actuation of the valve mechanism the propellant ejects the product from the container. The propellant immediately evaporates, leaving the active agent in the form of tiny droplets or particles or within a foam structure. Type of Solution: Example Solute Solvent Gas dissolved in gas: dry air oxygen nitrogen Gas dissolved in liquid: carbonated water carbon dioxide Water Gas dissolved in solid: floating soap air soap Liquid dissolved in gas: moist air water air Liquid dissolved in liquid: vinegar acetic acid water Liquid dissolved in solid: amalgum mercury silver Solid dissolved in gas: Mothballs in Air Moyhball Air Solid dissolved in liquid: sweet tea sugar Tea Solid dissolved in solid: bronze Tin Copper 10/17/2020 12 kerat gold copper gold  Introduction 9 Based on their composition, solutions classified as: 1- Syrups; aqueous solutions containing a sugar. 2-Elixirs; sweetened hydroalcoholic (combinations of water and ethanol) solutions. 3-Aromatic waters; aromatic materials dissolved in aqueous. 4-Spirits; aromatic materials dissolved in alcohol 5-Tinctures or fluidextracts; Solutions prepared by extracting active constituents from crude drugs. Tinctures may also be solutions of chemical substances dissolved in alcohol or in a hydroalcoholic solvent. 10/17/2020  Classification: 10 Based on route of administration and pharmaceutical use, solution classified as: I-Solutions for Internal Use:- 1- Oral solutions, syrups, elixirs, spirits, and tinctures are prepared and used for the specific effects of the medicinal agents they carry. In these preparations, the medicinal agents are intended to provide systemic effects. The fact that they are administered in solution form usually means that they are soluble in aqueous systems and their absorption from the gastrointestinal tract into the systemic circulation may be expected to occur more rapidly than from suspension or solid dosage forms of the same medicinal agent. II-Solutions for External use:- 1- Injection solutions; sterile and pyrogen free and intended for parenteral administration. 2- Topical solution; preparation intended for topical application such as paints, otics, lotions and liniments 10/17/2020  Advantages and disadvantages of solution 11 Advantages of solution as dosage form: 1-Therapeutic agents can easily be administered orally to individuals who have difficulty in swallowing, e.g. elderly, patients, infants. 2- A drugs in the form of solutions are immediately available for absorption with fast therapeutic response. 3- Reduce the irritation of the gastric mucosa caused by some drugs. 4- A dose uniformity is obtained. 5-Taste-masking of bitter therapeutic agents may be readily achieved. Disadvantages of solution as dosage form: 1- Liquids are bulk and not easy to transported and storage. 2- Require the addition of sweeteners and flavors to mask the unpleasant taste of some drugs. 3- Enhance growth of microorganisms , therefore it require the incorporation of preservatives. 4-Low ingredients stability. 5-Dose inaccuracy. 6-The poor solubility of certain therapeutic agents may prohibit their formulation as pharmaceutical solutions. 10/17/2020  Solvents for aqueous solution 12 Definition of aqueous solution: It is a homogenous mixture that is prepared by dissolving a solid, liquid or gases (dissolved substance) in water (solvent). It includes those pharmaceutical forms that are designed with water, aromatic waters, aqueous acids, as solutions, douches, enemas, gargles, mouthwashes, juices, nasal solutions, otic solutions, and irrigation solutions. I-Water: Water is the solvent most widely used as a vehicle for pharmaceutical products, because of its physiological compatibility and lack of toxicity. It possesses a high dielectric constant, which is essential for ensuring the dissolution of a wide range of ionizable materials. In some cases this property may be an advantage, but the lack of selectivity can be responsible for aqueous solutions containing unwanted substances such as inorganic salts and organic impurities. This is one reason why water is rarely used for the extraction of active constituents from vegetable sources. Naturally occurring water contains dissolved minerals indigenous to the region, such as calcium, magnesium, iron+3, sodium and potassium ions. Hard water contains calcium and magnesium cations. 10/17/2020  I- Waters 13 Water Water for Sterile water for injection free Bacteriostatic Potable water Purified water from dissolved water injection gasses Ion-exchange or Distillation de-ionized water Reverse osmosis Acid or cation Base or anion exchange step exchange step 10/17/2020  Solvents for aqueous solution 14 a- Potable water (Tap water): For many preparations potable water can be used. This is water freshly drawn from the mains system and suitable for drinking. Potable water is unsuitable for certain pharmaceutical purposes due to its possible bacterial contamination. b-Purified water (BP): Purified water must used in all occasions where the presence of salts and microorganisms (often dissolved in potable water) is undesirable. Purified water is normally prepared by: 1- Distillation: which has been freshly boiled and cooled immediately before use to destroy any vegetative microorganisms that might be present. It is a widely used method for separating mixtures based on differences in the conditions required to change the phase of components of the mixture. 10/17/2020  Solvents for aqueous solution 15 To separate a mixture of liquids, the liquid can be heated to force components, which have different boiling points, into the gas phase. The gas is then condensed back into liquid form and collected. Repeating the process on the collected liquid to improve the purity of the product, the process which is called double distillation. 2- Deionization (ion exchange): The process includes remove of the major impurities in water using cations (acid) exchanger (the replacement of cations in solution with hydrogen ion) and anion ( base) exchanger (the replacement of anions in solution with hydroxyl group). CaSO4 + H2R CaR + H2SO4 (cationic) H2SO4 + 2AOH A2SO4 + 2 H2O (anionic) 10/17/2020  Solvents for aqueous solution 16 3- Reverse osmosis: It is a membrane separation process in which feed water flows along the membrane surface under pressure. Purified water permeates the membrane and is collected, while the concentrated water, containing dissolved and undissolved material that does not flow through the membrane, is discharged to the drain. The key requirements of Reverse Osmosis process are a membrane and water under a pressure. Other requirements include pre-filtration to remove suspended impurities and carbon to remove chlorine (damages the membrane). Most membranes remove 90-99% of the dissolved impurities depending on the impurity and the composition of water. Reverse osmosis systems remove salts, microorganisms and many high molecular weight organics. System capacity depends on the water temperature, total dissolved solids in feed water, operating pressure and the overall recovery of the system. 10/17/2020  Solvents for aqueous solution 17 c)Water for injection: must be used for the formulation of parenteral solutions and is obtained by sterilizing pyrogen-free distilled water immediately after its collection. d)Water for injection free from dissolved gases: water free from CO2 or O2 are used to dissolve special drugs that are sensitive to these gases. It is obtained by boiling pyrogen-free distilled water for 10 min and immediately sealing in its final container and then sterilized. e)Bacteriostatic water for injection: It is a sterile pyrogen-free water contains one or more suitable antimicrobial agents. f) Sterile water for irrigation: Water for injection that has been sterilized and packaged. It contains no antimicrobial agent or other added substance. II- Aromatic water (Hydrolata): Known also as medicated water, which is clear, saturated with volatile or other aromatic substances ( peppermint, chloroform and rose), has a pleasant taste and odor. 10/17/2020  Solvents for aqueous solution 18 Due to its deterioration by time, it must be protected from direct sun light, excess heat and stored in air-tight container. It is prepared by one of the following methods: a) Distillation method (EP): In this method, the plant portions of interest are placed with the sufficient amounts of purified water in a still, and the produced distillate is the required aromatic water. b) Solution method (EP): The aromatics are agitated with the purified water for 15 min, and the mixture set aside for 12 h and then filtered through a wet filter paper. c) Alternate solution method (EP): In which the volatile material is mixed with purified talc powder, and then agitated with purified water for 15 min. Talc acts as distributing agent that increase surface area of volatile oil exposed to the solvent leading to enhance dissolution and aids filtration. d) Dilution method (EP): It is used to prepare a concentrated alcoholic solution of volatile oils which diluted with purified water when needed. 10/17/2020  Solvents for aqueous solution 19 Example of this, the preparation of peppermint, caraway and cinnamon concentrates as follow: 2 ml of the essential oil is dissolved in 60 ml of 90% ethyl alcohol, a successive small portions of purified water are added with shaking to produce 100 ml total volume. Then after, 5 g of sterilized purified talc is added with occasional shaking for several hours and filter. Upon uses, one volume of concentrate is diluted with 39 volume of purified water. The produced solution contain less than 1.5% alcohol. Preservation of Aromatic Waters Aromatic waters should be freshly prepared and should not be made in larger quantities than can used within a reasonable time as they deteriorate when kept too long, usually through the development of microorganisms, all traces of their agreeable odour disappearing. No preservative should be added to aromatic waters. If they become cloudy or otherwise deteriorate, they should be discarded. 10/17/2020  Solvents for aqueous solution 20 Stability of Aromatic Waters *Many of the aroma bearing solutes are oxidized by exposure to light. *High temperature cause aromatic waters to loss some of their desirable characteristics. *Since aromatic waters are saturated solutions, lowering the temperature caused separation of the aromatic component producing cloudiness. *The aromatic substances may be salted out when the water is used as a vehicle for drugs which are electrolytes and the insoluble materials collect on the top of the liquid, imparting a burning taste to the first dose.. Incompatibility of Aromatic Waters In the presence of very soluble salts, they will salt out the insoluble portion of the volatile principle in aromatic water. This difficulty can be overcomes by replacing part of the aromatic water with purified water. 10/17/2020  Solvents for aqueous solution 21 Uses of aromatic waters 1- They provide pleasantly flavoured medium for the administration of water- soluble medicinals. Flavoured waters certainly added to the elegance of prescriptions, whether simple or complex. 2- They also mask the undesirable tastes in suspensions and emulsions. 3- Several aromatic waters are not used as vehicles for oral medication, e.g., Rose water, Hammemlis water, and camphor water. Rose water is a perfume, Hammemlis water is used as astringent in after shave lotions and other cosmetic products, Camphor water is frequently prescribed in eye drops and eye washes for its slight refreshing and stimulating effects. 10/17/2020  Solvents for aqueous solution 22 III- Aqueous acids: The official undiluted organic and inorganic acids (e.g. have some pharmaceutical applications. They provide in the form of concentrated solutions with varied strength expressed in the form of percent by weight (W/W).example of the aqueous acid is 1% acetic acid used as a solvent for many ingredient as chitosan 10/17/2020  Solvents for non-aqueous solution 23 The non-aqueous solvents are used when the active ingredients not insure complete solubility or unstable in aqueous solvents. Also, the non-aqueous solvents over an advantage over the aqueous in that it can be used for depot therapy (releasing the drugs slowly). It is essential that in choosing a suitable solvent, its toxicity, irritancy and sensitizing potential are taken into account, as well as its flammability, cost, stability and compatibility with other excipients. A far wider range of solvents are available for use as part of the manufacture of pharmaceuticals. In these instances the solvent is removed before packaging and is therefore not present in the final products ( such as acetone, light petroleum and chloroform) 10/17/2020  Solvents for non-aqueous solution 24 I- ALCOHOL, USP: ETHYL ALCOHOL, ETHANOL, C2H5OH Next to water, alcohol is the most useful solvent in pharmacy. 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. By varying the proportion of the two agents, the active constituents may be selectively dissolved and extracted. Alcohol, USP, is 94.9% to 96.0% C2H5OH by volume (i.e., v/v) when determined at 15.56°C. Dehydrated Alcohol, USP, contains not less than 99.5% C2H5OH by volume and is used when an essentially water-free alcohol is desired. 10/17/2020  Solvents for non-aqueous solution 25 Alcohol is often preferred because of its miscibility with water and its ability to dissolve many water-insoluble ingredients, including drug substances, flavorants, and antimicrobial preservatives. It is also used in liquid products as an antimicrobial preservative alone or with parabens, benzoates, sorbates, and other agents. For OTC oral products intended for children under 6 years of age, the recommended alcohol content limit is 0.5%; for products intended for children 6 to 12 years of age, the recommended limit is 5%; and for products recommended for children over 12 years of age and for adults, the recommended limit is 10%. 10/17/2020  Solvents for non-aqueous solution 26 II- DILUTED ALCOHOL, NF Diluted Alcohol, NF, is prepared by mixing equal volumes of Alcohol, USP, and Purified Water, USP. The final volume of such mixtures is not the sum of the individual volumes of the two components because the liquids contract upon mixing; the final volume is generally about 3% less than what would otherwise be expected. Thus, when 50 mL of each component is combined, the resulting product measures approximately 97 mL. It is for this reason that the strength of Diluted Alcohol, NF, is not exactly half that of the more concentrated alcohol but slightly greater, approximately 49%. Diluted alcohol is a useful hydroalcoholic solvent in various pharmaceutical processes and preparations. 10/17/2020  Solvents for non-aqueous solution 27 III- RUBBING ALCOHOL Rubbing alcohol contains about 70% ethyl alcohol by volume, the remainder consisting of water, denaturants with or without color additives and perfume oils, and stabilizers. Each 100 mL must contain not less than 355 mg of sucrose octaacetate or 1.4 mg of denatonium benzoate, bitter substances that discourage accidental or abusive oral ingestion. The use of this denaturant mixture makes the separation of ethyl alcohol from the denaturants virtually impossible with ordinary distillation apparatus. This discourages the illegal removal for use as a beverage of the alcoholic content of rubbing alcohol. The product is volatile and flammable and should be stored in a tight container remote from fire. It is employed as a rubefacient externally and as a soothing rub for bedridden patients, a germicide for instruments, and a skin cleanser prior to injection. It is also used as a vehicle for topical preparations. 10/17/2020