pharmaceutical solutions, pharmacy solutions

pharmacy

1. Pharmaceutical solutions Mr.Vijaykumar Meti

2. LESSON OUTCOMES At the end of this lecture, students should be able to : Define different types of Monophasic Liquid Dosage forms. Recognize the significance of different types of one phase liquid pharmaceutical preparations. Describe Liquids used for internal use. Describe Liquids used for external use. Excipients used

3. Liquid dosage forms One of the oldest dosage forms used in treatment. Rapid & High absorption of soluble medicinal products Particular use for individuals having difficulty in swallowing solid dosage form (SDF) . Solutions are homogeneous liquid preparation containing one or more completely dissolved components (One-phase system ). Active ingredients dissolved within vehicles to obtain uniform solutions. In general, water u sed as vehicle in medicaments dissolved, water is Non-toxic, Non-irritant, Tasteless, Relatively cheap , and many drugs are water soluble (Aqueous sol .) Some drugs not water soluble so mixed with other solvents ( Non-Aqueous) 3

4. Solutions: Definition Solutions may be broadly defined as one phase system consisting of two or more substances . Pharmaceutical solutions are homogeneous, i.e. the therapeutic agent(s) and excipients are dissolved in the vehicle. Pharmaceutical solutions for oral administration are in non-sterile dosage forms. 4

5. 5 Classification of Liquid Dosage Forms Internal Administration External Administration Solutions Elixir Syrup Oral drops Linctuses Liniment Lotion Gargles Mouth Wash Throat Paint Douche Ear / Nasal Drops Nasal Spray Application on the Skin Used in Oral Cavity Instilled into Body Cavities Q?

6. Advantages of pharmaceutical solutions The drug immediately available for absorption. By providing drug in a solution, the dissolution phase absorption can bypassed → quicker absorption. Flexible dosing is possible. The active ingredient within sol. present in a certain Conc. per unit volume. Solutions are designed for any route of absorption: the oral route of administration , via Parenteral preparations (injections), enemas for rectal use, Topical (for use on skin) & ophthalmic preparations are all sols. No need to shake the container. Unlike suspensions as the active ingredient is dissolved within the vehicle. Facilitate swallowing in difficult cases (e.g. infants or the eld erly ). It is mor e eas i er for pati e nts to take so l ution 6

7. Disadvantages of solutions Drug stability is reduced in Sol ution by hydrolysis or oxidation. I t i s di f fic ul t to ma s k un p le a s ant ta s te s . T hey are much larger & more bulky, difficult to transport. Liquids packed in glass bottles are obviously prone to breakage and cause loss of the preparation. Technical accuracy is needed to measure the dose on admin. patient accuracy in measuring a dose is required Some drugs are poorly soluble so it is necessary to alter vehicle or drug form in order to formulate a convenient prep aration . A measuring device is needed for admin. so need to be supplied to the patient to be able to measure an accurate dose 7

8. Factors Affecting Solubility P hysicochemical properties : The solubility of drug molecules in a solvent are dependent on several physicochemical properties, including molecular weight, volume, density, and number of hydrogen bonds. Particle size: Reduction of particle size increase the rate of solubility. The solubility of a chemically related series of drugs is inversely related to their melting points; so as the melting point of drug increased, the solubility decrease. The solubility of a drug is directly affected by the type of chemical substituent groups. The solubility of drugs containing hydrophilic groups (e.g. OH, COO, ammonium ion) will accordingly be greater than those containing lipophilic substituent groups, e.g. methyl, ethyl, or chlorine groups. 8

9. Temperature : Most compounds are more soluble in higher temperature. pH : The vast majority of drug subs tances are either acids or bases . The solubility of therapeutic agents are pH-dependent. The solubility of acids & ba s es increases as the degree of ionization increases . Polarity : Polar comp ounds more soluble in Polar solvents as water & ethanol . Non polar comp ounds more soluble in non polar solvents as chloroform . Conc entration acid or alkali added to form water- soluble salts. The organic bases more soluble in organic solvents than the corresponding salt forms. 9

10. Methods to enhance/optimize the solubility Appropriate selection of drug salt: The majority of therapeutic agents are available in a salt form, each form a different aqueous solubility. Select the drug salt provide the required solubility in the dosage form. 2 . Optimization of the pH of the formulation: The solubility of ionized therapeutic agent is a function of both the pKa and the pH of the formulation. The acceptable pH range for oral sols is large, ranging from 5 to 8 pH units. The s e le ct io n of a pH value for formulat i on to opt imi z e the ionization and solubility of the therapeutic agent is important. The Control of pH in formulation is achieved by using a buffer 10

11. 3. Use of co-solvents : Co-solvents are liquid components incorporated into a formulation to enhance the solubility of poorly soluble drugs. The Commonly employed co solvents include , glycerol, propylene glycol, ethanol and polyethylene glycol. The final choice of the co-solvent system for a particular formulation involves consideration of the solubility of the therapeutic agent in the vehicle, the toxicity of the vehicle and the cost of formulation. The range of concentrations of each co-solvent used in oral formulations is primarily limited by concerns regarding toxicity. 11

12. Excipients used in pharmaceutical solutions for oral administration Excipients are pharmacolog ica lly inert compounds that are included in the pharmaceutical formulations. To facilitate the administration of the dosage form, e.g. pourability, and palatability , To protect the formulation from issues regarding physical and chemical stability. To enhance the solubility of the therapeutic agent. Pharmaceutical sols contain a wide range of excipients. l- The vehicle : The preferred & most commonly used vehicle in sols for oral administration is Purified Water USP, due to the low cost and low toxicity . 14 12

13. Vehicles (Solvents) for Liquid Dosage Forms A vehicle is the medium containing the ingredients of a drug. In s ol ut i on s , th e vehi c l e i s the s ol vent. The choice of a vehicle depends on: The intended use of the preparation The nature & physicochemical properties of active ingredients. Water as a vehicle Water used as the primary solvent; widely available, relatively inexpensive, palatable and non-toxic for oral use, non-irritant for external use. Water is also a good solvent for many ionizable drugs. Salts of organic compounds are more soluble in water water is the preferred solvent. for solutions to be taken orally, used ophthalmic ally, or injected. 13

14. Types of water Potable water : drinking water, should be palatable & safe for drinking, Its chemical composition may include mineral impurities which could react with drugs, e.g. the presence of calcium carbonate in hard water. Purif i e d w ater USP , obta i ned f r om potab l e w a ter by distillation , ion exchange treatment , or reverse osmosis. Distilled water is purified water prepared by distillation. Compared with ordinary drinking water: Purified Water, more free of solid impurities. When evaporated to dryness, not yield greater than 0.001% of residue (1 mg of total solids /100 mL of sample evaporated ). Purified Water is intended for use in preparation of aq u eo u s D F , e x cept those intended for P a renter al administration (injections ). 14

15. Water as a vehicle Water for preparations : potable or freshly boiled and cooled water , used in oral or external LDF not intended to be sterile. Water for injections: is pyrogen-free distilled water, sterilized immediately after collection and used for Parenteral preparations. Chloroform water : used as antimicrobial preservative and also adds sweetness to preparations. chloroform available as: Chl o rof o rm BP = 1 00% v/v Aromatic water : saturated solution of volatile oils in water and are used to provide a pleasant flavor or aroma, e.g. Peppermint Water, USP. Used as a vehicle in oral sol. Some have mild carminative action For example diluted Aromatic waters are usually prepared from a conc. ethanolic sol. in a dilution of 1 part to 39 parts with water. 15

16. II. Co-solvents Empl o yed to i n crease the so l ub i l i ty of therapeutic agent within the formulation. Co-solvents used in the formulation of oral solutions are : Glycerol (also termed glycerin) Glycerol is a clear odorless, viscous liquid, with a sweet taste , and miscible with both water and alcohol. Its co-solvency properties due to the presence of three hydroxyl gps;oH. It has similar co-solvency properties to ethanol Alcohol USP ( CH3CH2OH) Contain between 94.9 and 96.0% v/v ethyl alcohol(ethanol). Commonly used as a co-solvent, both as a single and with other co-solvents, e.g. glycerol. The known pharmacological & toxicological effects of alcohol have compromised its use in pharmaceutical preparations. 16

17. Propylene Glycol USP : Propylene Glycol is an odourless , colourless , viscous liquid that contains two hydroxyl groups; oH . Used in pharmaceutical preparations as a co-solvent, generally as a replacement for glycerin. III. Miscellaneous agents used to enhance solubility of therapeutic agents. These include the use of surface-active agents & Complexation . A. Surface-active agents These are chemicals that possess both hydrophilic (water-liking) and hydrophobic (water-disliking) regions. At dilute conc. surface-active agents will orient at the interface between two phases (e.g. water/oil), with the hydrophilic and hydrophobic regions of the molecule being positioned to the hydrophilic and hydrophobic phases, respectively. 17

18. B: Complexation : Complexation refers to the interaction of a poorly soluble therapeutic agent with an organic molecule, Eg : surface - active ag e nts, h y drop h i l ic pol y mers to generate a soluble intermolecular complex . One particular concern regarding the use of solution of drug complexes is the ability of the complex to dissociate following administration . This is particularly important in situations where the complexing agent is a hydrophilic polymer, as the high molecular weight of the drug–polymer complex would prevent drug absorption across biological membranes. 21 18

19. IV. Common Excipients in Pharmaceutical Sol ution Excipients that are commonly employed in formulation of pharmaceutical solutions are: (1) buffers; (2) sweetening agents; & (3) viscosity-enhancing agents. (1) Buffers: Buffers employed within pharmaceutical sols to control pH of the formulated product and, to optimize the physicochemical performance of the product. Typically pH control is performed: To maintain the solubility of therapeutic agent in formulated prod uct The solubility of drugs is pH-dependent , therefore, solubility of therapeutic agent compromised by small changes in pH To enhance the stability of the products in which the chemical stability of the active agent is pH-dependent. 19

20. 23 The conc. of buffer salts employed in the oral solutions should be selected to offer sufficient control of the pH of the formulation but yet should be overcome by biological fluids following administration. Examples of buffer salts used in pharmaceutical solutions include: Acetates (acetic acid and sodium acetate): about 1–2% Citrates (citric acid and sodium citrate): about 1–5% Phosphates (sodium phosphate and disodium phosphate ): about 0.8–2%. the buffer system used in solution formulations should not adversely affect the solubility of the therapeutic agent, e.g. the solubility of drugs may be affected in the presence of phosphate salts. 20

21. Sweetening Agents Sweetening agents are employed in liquid formulations designed for oral administration specifically to increase the palatability of the therapeutic agent. T h e main s w e e teni ng a ge n ts emp l oy e d in oral preparations are su c ros e , l i quid gluco s e, gl y cerol , sorbitol, saccharin sodium and aspartame . The use of artificial sweetening agents in formulations is increasing and, in many formulations, saccharin sodium is used either as the sole sweetening agent or in combination with sugars or sorbitol to reduce the sugar concentration in the formulation. The use of sugars in oral formulations for children and patients with diabetes mellitus is to be avoided. 21

22. Viscosity – enhancing a gents The admi n i s trat io n of ora l s o lu ti o ns to pat ie nts by u s in g a syringe , a small-metered cup or a traditional 5-ml spoon. The viscosity of formulation must be controlled to ensure the accurate measurement of the dispensed volume. increasing the viscosity of → increase the palatability. Certain liquid formulations do not require the addition of VEA, e.g. syrups, due to their inherent viscosity. The vis c o s ity of ph armace ut i c a l s o lu ti o ns in cr ea s ed by the addition of non-ionic or ionic hydrophilic polymers . 22

23. Antioxidants Antioxidants included in pharm. Sol. to enhance the stability of drugs that susceptible to chemical degradation by oxidation. Ant i oxida nts are c o mpoun ds tha t inhi bi t free rad i c a l - in duced drug decomposition. Both water-soluble & water-insoluble antioxidants are available . Antioxidants for aqueous formulations eg; Sodium sulphite, sod. metabisulphite, sod. formaldehyde sulphoxylate and ascorbic acid. 23

24. Preservatives Preservatives are included in pharmaceutical solutions to reduce or prevent the microbial growth of the formulation. Ideally, preservatives should exhibit the following properties: P ossess a broad spectrum of antimicrobial activity includes Gram- positive,Gram -negative bacteria & fungi ; B e chemically and physically stable over the shelf-life of the product. ; H ave low toxicity. Preservatives for use in oral pharmaceutical solutions : benzoic acid and salts (0.1–0.3 %) , sorbic acid and its salts (0.05–0.2 %) , Alkyl esters of parahydroxybenzoic acid (0.001-0.2%). A combination of two preservatives employed in solutions to enhance the antimicrobial spectrum. Methyl & propyl parahydroxybenzoates (in a ratio 9:1 ). 24

25. Flavours and colourants The vast majority of drugs in solution are unpalatable, → so the addition of flavors to mask the taste of drug subs. Flavours added to make a medicine more acceptable to take. Four basic taste sensations are salty, sweet, bitter & sour Flavours used to mask a salty taste include: butterscotch , apricot , peach , vanilla , wintergreen mint. Flavours used to mask a bitter taste include: cherry , mint , anise . Flavours used to mask a sweet taste include: vanilla , fruit and berry. Flavours used to mask a sour taste include: citrus flavours , raspberry . A combin a tion of flavo u rs is used to ach i eve the optimal taste-masking property. 25

26. Flavour Adjuncts Certain excipients added to oral solution formulations, referred to as flavour adjuncts (e.g. menthol, chloroform). flavour adjuncts add flavor to formulation and in addition, act to desensitise the taste receptors. These agents augment the taste-masking properties . Colourants : Colours are pharmaceutical ingredients that impart the preferred colour to the formulation. When used in combination with flavours, the selected colour should ‘match’ the flavour of the formulation, e.g . green with mint- flavoured solutions, red for strawberry-flavoured formulations. Although colours is not a prerequisite for all pharmaceutical sol., certain categories of solution (e.g. mouthwashes/gargles) are normally coloured. 26

27. Types of pharmaceutical solutions Pharmaceutical sols for oral administration: 3 principal types of sol utions . formulations administered orally: oral drops , oral syrups and oral elixir Other sol ution formulations employed for a local effect, e.g. mouthwashes/gargles , ear drops, ophthalmic, Nasal Drops and Inhalations . 27

28. Oral drops Drops: These are formulated for infants especially Oil soluble vitamins are solubilized and presented as aqueous ‘solutions’. Similar requirements of formulation as solutions and elixirs. Contains concentrated drug preparations 28

29. Oral syrups Syrups : Sweet viscous aqueous preparations. Either flavoring (orange or tolu ) or medicated syrups. Used in preparation of antibiotics, antitussives, antihistamines, vitamins. Syrups prepared with artificial sweetening agent and viscosity builders are also in market now days. Due to viscosity if certain components are not soluble, surfactants or another solubility enhancing agent or techniques are utilized . 29

30. Medicated Sugar-free Syrup All Medicinal products designed for administration to children & diabetic patients must be sugar-free. Syrup Substitutes must provide an equivalent sweetness, viscosity and preservation to the original syrup. Artificial sweeteners: Artificial sweeteners include Saccharin sodium, and Aspartame. Non-glycogenetic viscosity modifiers (e.g.methylcellulose, and hydroxy ethyl cellulose) . Preservatives(e.g. sodium benzoate, benzoic acid &parahydroxy benz oate ester ) are in c lud ed in medic ated su g a r - free syrup. 30

31. Oral elixirs Elixirs: Sweet and pleasantly flavored hydroalcoholic liquids for oral administration. Nowadays several official elixirs do not contain sugar or any sweetening agent. Prepared with artificial sweetening agent and viscosity builders are also in market now days. Due to viscosity of certain components are not soluble, surfactants or another solubility enhancing agent or techniques are utilized. New elixirs content alcohol is now replaced by glycerin and propylene glycol. Alcohol content varies from 4 to 40% 31

32. Linctuses A Liquid oral preparation used for a demulscent expectorant or sedative effect in treatment of cough. Linctuses are viscous preparations that contain the therapeutic agent dissolved in a vehicle composed of a high percentage of sucrose and, if required, other sweetening agents. These formulations are administered orally. Primarily employed for treatment of cough, due to their soothing actions on the inflamed mucous membranes. Linctuses also be formulated as sugar-free alternatives in which sucrose is replaced by sorbitol and the required Conc. of sweetening agent. 32

33. Mouthwashes /gargles Mouth washes/gargles are designed for the treatment of infections and inflammation of the oral cavity. Formulations designed for this purpose employ water as the vehicle, although a co-solvent, e.g. alcohol, may be employed to solubilise the active agent. The use of alcohol as a co-solvent act to enhance the antimicrobial properties of the therapeutic agent. Gargles are aqueous solutions carrying medicaments for effect on pharynx and nasophyranx , Usually concentrated forms which need specific dilution. Glycerin, Thymol gargles. Gargles should have acceptable organoleptic properties and should act fasts once they are in contact period is short Same time they should not be irritant to mucous membrane 33

34. 41 41 These preparation needs to meet rigid requirements such as sterility, irritability, tonicity, Lotions must be prepared hygienically Should posses partition of the drug from the vehicle to the tissues of the ophthalmic cavity. Posses viscosity or retain longer contact period of time when applied. Expensive manufacturing facility because of sterility requirements Need skillful experienced personnel for sterile manufacturing Liquid for ophthalmic applications 34

35. Ear drops: Also known as otologicall products Generally for formulation of ear drops propylene & propylene glycol are selected as the vehicles, glycerin Aqueous preparations are suitable for ear preparation or not ? And why? Nasal Drops: Need are as sterile preparations Vehicles used should have pH between 5.5 to 7.5, posses buffering capacity,tonicity , viscosity not exceed normal viscosity of the mucous . For viscosity adjustment liquid paraffin is suitable. 35

36. Inhalations: Solutions of medicaments administered by nasal or respiratory for local and systemic effect . Applied in the form of vapors or sprays with the help of atomizers and aerosols. Packaging commonly known as nebulizers . Designing inhalations the vehicles of preference are normal saline and other water based liquids Alcohols are rarely used, polyols like propylene glycol, glycerol etc are occasionally added to stabilize droplet size . Surfactants are added to decrease tension between the propellants and aqueous fluids Normal concentration of surfactant is 0.1 %. 36

37. References: Aulton M E., and Taylor, K.M.G. Aulton’s Pharmaceutics : The Science of dosage form design. 4 th Ed. Churchill Livingstone, London, 2013 . Remington’s Pharmaceutical Science. 22 nd ed. USA: Mack Publishing Co; 2012 . Loyd VA, Ansel HC. Ansel's pharmaceutical dosage forms and drug delivery systems. 10 th ed. Philadelphia: Wolters Kluwer Health;2013 . 37

38. THANK YOU 38