312 PHT

1. 312 PHT Nahla S. Barakat, Ph.D King Saud University Dept. of Pharmaceutics Second Term 1433-2012 1

2. Solution is a homogenousmixturecomposed of two or more substances. In such a mixture, asoluteis dissolved in another substance, known as asolvent.A common example is asolid, such assaltorsugar, dissolved inwater, aliquid. • Gasesmaydissolvein liquids, for example:carbon dioxideoroxygenin water. • Liquids may dissolve in other liquids. Gases can combine with other gases to form mixtures, rather than solutions. 2

3. Possible Types of Solutions • solid in solid e.g. brass • solid in liquid e.g. sugar in water • solid in gas e.g. mothball in air • liquid in solid e.g. dental amalgam • liquid in liquid e.g. ethanol in water • liquid in gas e.g. water in air • gas in solid e.g. hydrogen in palladium • gas in liquid e.g. O2 in water • gas in gas e.g. oxygen in nitrogen • Of the nine possible types of solutions, you are probably most familiar with those in which the solvent is a liquid, especially those in which the solvent is water. 3

4. Advantage of solutions • Liquids are easier to swallow • A drug must be in solution before it can be absorbed • A solution is an homogenous system, the drug will be uniformly distributed throughout the preparation • Some drugs can irritate the gastric mucosa if localized in one area. Irritation is reduced by administration of a solution of the drug 4

5. Problem associated with the manufacturing of solutions • Liquids are bulky and inconvenient to transport and store • The stability of ingredients in aqueous solution is often poor than in solid dosage form • Solution provide suitable media for the growth of micro-organisms and may require the addition of preservative • Accurate dose measuring depends on the ability of patient to measure the dose • The taste of a drug is always pronounced when it in solution 5

6. Aqueous solutions and non-aqueous solutions • Aqueous solutionsSolutions that contain water as the solvent are called aqueous solutions.For example, sugar in water, carbon dioxide in water, etc.  • Non-aqueous solutionsSolutions that contain a solvent other than water are called non-aqueous solutions. • Ether, benzene, petrol, carbon tetrachloride etc., are some common solvents. or example, sulphur in carbon disulphide, naphthalene in benzene, etc.  6

7. Concentrated solutions and dilute solutions Between two solutions, the solute quantity may be relatively more or less. The solution that has a greater proportion of solute is said to be more concentrated than the other that has a lesser proportion. If the proportion of solute is less, the solution is said to be dilute.  7

8. Saturated and unsaturated solutions • Saturated Solution A solution in which no more solute can be dissolved at a given temperature is called a saturated solution • Unsaturated solution A solution in which more solute can be dissolved at a given temperature is called an unsaturated solution. A given solution that is saturated at a particular temperature may become unsaturated when the temperature is increased. 8

9. Solubility and Miscibility • Different substances have different solubilities. • Solubilityrefers to the maximum amount of a solute that can be dissolved in an amount of solvent under specific temperature and pressure conditions. • A substance that cannot be dissolved in another (or does so to a very limited extent) is said to beinsoluble. 9

10. Solubility of a solute • Solubility is defined as the number of grams of a solute that dissolves in 100g of a solvent to form a saturated solution at a given temperature and pressure • Solubility is the maximum weight of a solute that can be dissolved in 100g of a solvent at a given temperature and pressure • Solubility = Wt of solute in saturated solution  100 Wt of solvent in saturated solution 10

11. Relative terms of solubility parts of solvent required for 1 part of solute • Very soluble  1 • Freely soluble 1-10 • Soluble 10-30 • Sparingly soluble 30-100 • Slightly soluble 100-1000 • Very slightly soluble 1000-10,000 • Practically insoluble  10,000

12. Miscibilityrefers to the ability of a liquid to dissolve in another in all proportions. • Alcohols like methanol and ethanol aremisciblewith water. There is no limit to the amount of these alcohols that can be dissolved in water - they dissolve in all proportions. • When a liquid does not dissolve in another to any extent, the liquids are said to beimmiscible. • Oil and water are immiscible. 12

13. Electrolytes and Non-Electrolytes • One way to distinguish between solutions that contain ions and those that contain molecules is an electrical conductivity test. 13

14. A solution that conducts electrical current is said to beelectrolyticand the solute is called anelectrolyte. The sodium chloride solution is an electrolytic solution. • The solute in a solution that does not conduct electrical current is anon-electrolyte. Examples include: sugar, urea, glycerol, andmethylsulfonylmethane (MSM. • Generally, dissociated ionic compounds are electrolytes whereas dissolved molecular compounds are non-electrolytes. 14

15. Units of Measure in Solutions • Concentrations are often given in terms of weight/volume.  For example, mg/L, or mg/100 mL (common clinical units). • AMolar Solutionis an aqueous solution consisting of one mole of a substance plus enough water to make one Liter of solution. • AMolal Solutionis an aqueous solution consisting of one mole of a substance plus 1 kg of water (usually very close to 1 L water).  The total volume may thus be more than 1 L. 15

16. Parts per million (PPM). Parts per million works like percent by mass, but is more convenient when there is only a small amount of solute present. PPM is defined as the mass of the component in solution divided by the total mass of the solution multiplied by 106one million A solution with a concentration of 1 ppm has 1 gram of substance for every million grams of solution. in general, one ppm implies one mg of solute per liter of solution.

17. Terms of expression the strength of pharmaceutical preparations • Percentage (%) • % w/v 1g in 100 mL preparation • %v/v 1mL in 100 mL preparation • % w/w 1 g in 100 g preparation • Ratio strength: • weight in volume (1:1000 w/v= 1g constituent in 1000 mL preparation) • volume in volume (1:1000 v/v = 1ml constituent in 1000 mL preparation) • weight in weight (1:1000 w/w = 1 g constituent in 1000 g preparation)

18. Factors Affecting Solubility Temperature will affect solubility. If the solution process absorbs energy then the solubility will beINCREASEDas the temperature is increased. If the solution process releases energy then the solubility willDECREASEwith increasing temperature • Mechanical stirringMechanical stirring increases solubility.For example, sugar dissolves faster on stirring with a spoon. • pH of the solvent (examples include weak acids and weak base) 18

19. Molecular Size will affect the solubility. The larger the molecule or the higher its molecular weight the less soluble the substance will be. Larger molecules are more difficult to surround with solvent molecules in order to solvate the substance. • In the case of organic compounds the amount of carbon "BRANCHING" will increase the solubility since more branching will reduce the size (or volume) of the molecule and make it easier to solvate the molecules with solvent. 19

20. Anaqueous solutionis asolutionin which thesolventis water. • As water is an excellentsolventas well as naturally abundant. • Substances that do not dissolve well in water are calledhydrophobic )'water fearing') whereas those that do are known ashydrophilic(Water-loving'). • An example of a hydrophilic substance would be thesodium chloride, ordinary table salt. 20

21. Aqueous solutions Types of pharmaceutical water Purified water, USP Water for injection Aromatic water • Physiological compatibility • Lack of toxicity • Possesses a high dielectric constant • ensuring the dissolution of a wide range of ionizable materials • Lack of selectivity 21

22. I- Some solvents for liquid preparations • Alcohol • The most useful solvent in pharmacy (orally and parenterally) • It form hydroalcoholic mixture with water that dissolves both alcohol-soluble and water-soluble substances • It is miscible with water and can dissolve many water-insoluble ingredients, including drug substances, flavorants, preservatives. • It is used as antimicrobial preservative (15%) • Toxicity of ingested alcohol particularly for children.

23. Diluted alcohol • Is prepared by mixing equal volumes of alcohol and purified water (50%) • Alcohol, Rubbing • Alcohol rubbing compound • It contains about 70% ethyl alcohol by volume • It is employed as a rubefacient externally and as soothing rub for bedridden patients, a germicide for instruments • As vehicle for topical preparation • As skin cleanser before injection

24. Glycerol • It is a clear syrup liquid with sweet taste • It is miscible with water and alcohol • As solvent it is compatible with alcohol • It is used as a stabilizer and as auxiliary solvent • It has preservative qualities • It is used in internal preparations • Isopropyl rubbing alcohol • Is about 70% by volume isopropyl alcohol, with or without colour additives, stabilizers and perfume oils • It is used externally as a rubefacient and soothing rub and for topical products • It is less likely to be abused

25. Propylene glycol • A viscous liquid, miscible with water, glycerol and alcohol • It is substituted for glycerol in modern pharmaceutical preparations • It is used for formulation of digoxin, diazepam, phenobarbital injection • As diluent for ear drops • PEG 400 • Is used as a solvent in topical solution • Used as co-solvent with alcohol and water • Can be used for extraction processes • In the formulation of veterinary solutions

26. Ethyl ether • Used for extraction of crude drugs • It is used as a co-solvent with alcohol in some collodions • It is not used for internal use • Liquid paraffin • It is unpleasant to use externally • It is used as a solvent for topical application of drugs in emulsion formulations

27. Dimethylsulfoxide • It is used as a solvent for veterinary drugs • It is used for application to human skin • Miscellaneous solvents • Isopropyl myristate, isopropyl palmitate are solvent for external use, cosmetics • Low viscous, lack of greasiness • Xylene is used in ear drops for human use to dissolve ear wax

28. II- Other formulation additives • Buffers Injection, eye drops and nasal drops should be buffered at pH 7.4 Ex: carbonates, citrates, phosphate, lactates, gluconates, tartarates, borates (external) • Density modifier Ex: dextrose • Isotonicity modifier Ex: dextrose and sodium chloride • Viscosity enhancement Low conc., of gelling agents can be used to increase the apparent viscosity of the product Ex: Povidone, Carbomer, Hydroxyethylcellulose 28

29. Preservatives Ex: parahydroxybenzoic acid esters (Parabens) • Reducing agent and antioxidants Ex: sodium metabisulphite, butylatedhydroxyanisole or butylatedhydroxytoluene • Sweetening agent Ex: sucrose, polyhydric alcohols: sorbitol, mannitol, artificial sweeteners: sodium or calcium salt of saccharin • Flavours and perfumes To mask the unpalatable taste, ex: fruit juices, aromatic oils, herps • Colours To improve the attractiveness of the product and to enable ease of identification Ex: carotenoids, chlorophyll, riboflavines, coal tar dyes

30. According to particular pharmaceutical solution’s use may be classified as: • Oral • Otic • Ophthalmic • Nasal • Topical According to the composition or use, solutions may be classified as : • Aqueous solution containing sugar are termed syrups • Sweetened hydroalcoholic solutions are termed elixirs • Solution of aromatic materials are termed spirits • Solutions prepared by extracting active constituents from crude drugs are termed tinctures

31. Oral solutions Dry mixtures for solution Certain antibiotics have insufficient stability in aqueous solution to meet extended shelf life periods They are provided in dry powders or granules for reconstitution before use Once reconstituted, the solution remain stable for 7-14 days depending on the condition of storage Examples: Penicillin V Potasium for oral solution, USP Cloxacillin Sodium for oral solution, USP 31

32. Oral rehydration solutions Are usually effective in treatment of diarrhea and mild volume depletion (5-10% of body weight). These are available OTC Oral solution contains: 45mEq Na+, 20 mEq K+, 35 mEq CL-, 30 mEq citrate, 25 g dextrose / 1 Liter These formulations are available in liquid or powder packets form for reconstitution These products should not be mixed with milk or fruit juice Oral colonic lavage solution Used for preparation of the bowel for colonoscopy Composed of oral solution of electrolytes with PEG-3350. Before dispensing it to the patient, the solution is reconstituted with water, creating an iso-osmotic solution. PEG is an osmotic agent in the GIT • The formulation is as follows: • PEG-3350; Sodium sulfate; sodium bicarbonate; sodium chloride; potassium chloride 240 ml every 10 min (total 4 L).

33. Syrup • In cooking, a syrup (from Arabic شرابsharab, beverage, viaLatinsiropus) is a thick, viscousliquid, containing a large amount of dissolvedsugars, or sugar substitute with or without flavoring agents and medicinal substances. • Syrup containing flavoring agents but not medicinal substances are called nonmedicated or flavored vehicles (syrup): • Cherry syrup • Orange syrup • Raspberry syrup 33

34. The syrup are intended to serve as pleasant-tasting vehicles for medicinal substances, consists of a concentrated or saturated solution of refined sugar in distilled water. • The "simple syrup" of the BritishPharmacopoeiais prepared by dissolving 85 g of refined sugar in purified water to make 100 mL of syrup. The specific gravityof the syrup should be 1.313. • Flavoured syrups are made by adding flavouring matter to a simple syrup. For instance, syrupusaromaticusis prepared by adding certain quantities oforange flavouringandcinnamonwater to simple syrup. Similarly, medicated syrups are prepared by adding medicaments to, or dissolving them in, the simple syrup. 34

35. As syrups can contain up to 85% of sugars, they are capable of resisting bacterial growth by virtue of their osmotic effect. • Syrup, NF, also called simple syrup. • The amount of preservative required to protect a syrup against microbial growth varies with the proportion of water available for growth • Preservative commonly used in syrups : benzoic acid 0.1-0.2%, sodium benzoate 0.1-0.2%, parabens (0.1%). • To enhance the appeal of the syrup, a coloring agent that correlates with the flavorant employed (green with mint, brown with chocolate). • Most syrups are flavored with synthetic flavorants or with naturally occurring materials, such as volatile oils (orange oil), vanilin • Colorant to enhance the appeal of the syrup may be added • Sucrose-based syrup may be substituted by a polyol, such as sorbitol solution USP, 64%

36. Examples of medicated syrup: • Analgesic • Anticholenergic • Antiemetics • Anticonvulsant • Antihistamine • Antiviral • Antitussives • Expectrorant • Bronchodilators • Fecal softener

37. Elixirs • An elixir (From Arabic,الإكسير) are clear, sweetened hydroalcoholic solutions intended for oral use and usually flavored to enhance their palatability. • Non-medicated elixirs are employed as vehicles. • Elixirs are usually less sweet and less viscous than syrup. • In addition to alcohol and water, other solvents, such as glycerol and propylene glycol are frequently employed in elixirs as adjunctive solvents. 37

38. Elixirs are sweetened with sucrose, sorbitol, glycerol, and/or artificial sweeteners (Saccharine) • Most elixirs have coloring agents to enhance their appearance • Elixirs containing more than 10-12% alcohol are usually self-preserving • Because of their usual content of volatile oils and alcohol, elixirs should be stored in tight, light-resistant containers and protected from excessive heat • Antihistamine Elixir: Diphenhydramine HCl • Analgesic Elixir: acetominophen • Cardiotonic Elixir: digoxin • Antispasmodic Elixir: hyoscyamine sulfate • Sedative Elixir: phenobarbital

39. Tinctures • In medicine, a tincture is an alcoholicextract (e.g. of leaves or other plant material) or solution of a non-volatile substance; e.g. of iodine, mercurochrome). • Tinctures contain alcohol in amounts ranging from approx. 15-80%. • The alcohol content protects against microbial growth • Other solvent, such as glycerol, may be employed • Tincture must be tightly stopered and not exposed to excessive temperature 39

40. Many tinctures must be stored in light-resistant containers and protect from sunlight. • Some examples that were formerly common in medicine include: • Tincture ofCannabis sativa • Tincture of Benzoin • Tincture ofcantharides • Tincture of greensoap ( (which also containslavender) • Tincture ofguaiac • Tincture of iodine • Tincture ofopium (laudanum) • Camphoratedopium tincture(paregoric) 40

41. Tincture of iodine is often found in emergency survival kits, used both to disinfect wounds and to sanitize surface water for drinking. • When an alcohol solution is not desirable, Lugol's iodine, an aqueous solution of iodine in potassium iodide solution, or povidone iodine (Betadine), a PVP solution, can be used. • Other names for Lugol's solution are I2KI (Iodine-Potassium Iodide); Markodine, Strong solution (Systemic); Aqueous Iodine Solution BP.

42. Linctuses • A viscous preparation, usually for the relief of cough • It consists of a simple solution of the active agent in a high concentration of sucrose • The syrup content has a demulcent action on the mucous membranes of the throat • For diabetic use, the sucrose is replaced by sorbitol or synthetic sweeteners • This type of product, should be sipped slowly and not be diluted beforehand • It is administered in multiple of 5 mL

43. Sodium Salicylate – 15 gr. Sodium Bicarbonate – 30 gr. Aromatic Spirit of Ammonia – 20 min. Camphor water, up to – 1 oz. For use in acute rheumatism and other febrile conditions Sodium Salicylate – 15 gr. Sodium Bicarbonate – 30 gr. Strong Solution of Amm. acetate – 30 min. Compound Tincture of Cinchona – 20 min. Syrup of Tolu – 1 dr. Camphor water, up to – 1 oz. Useful in Influenza.

44. Topical solutions Aluminum acetate (Burow’s solution) • Is colourless and has a faint acetous odor, • Is applied topically as an astringent wash or wet dressing after dilution with 10 to 40 parts of water. • Used in various types of dermatological lotions, cream and pastes • Commercial tablets are available for preparation of this solution Calcium hydroxide (lime water) • It is called Limewater, contain not less than 140 mg of Ca(OH)2 in each 100 mL of solution • Cool purified water is the solvent • The solution is intended to be saturated with solute • The solution should be stored in well-filled tightly stopered containers and kept in a cool place to maintain an adequate conc., of dissolved solute. • The solution is astringent and is employed in dermatological solutions and lotions

45. Hydrogen peroxide Synonym: Peroxide • It contains 2.5-3% w/v hydrogen peroxide H2O2, suitable preservative may be added (0.05%) • Is a clear, colorless liquid. • It deteriorates upon long standing also by the effect of light and heat • The solution should be preserved in tight, light-resistant containers, at temp. not exceeding 35C • It is categorized as a local anti-infective for use topically on the skin or mucous membranes (gargle). • Its germicidal activity is based on the release of nascent oxygen on contact with the tissues and its ability to cleanse wounds

46. Povidone iodine • Commercial product: Betadine Solution • It is a chemical complex of iodine with PVP • It contains approx. 10% available iodine and slowly released when applied to the skin • It is employed as surgical scrub and nonirritating antiseptic solution • Thimerosal topical • Is a water-soluble organic mercurial antibacterial agent used topically for its bacteriostatic and mild fungistatic properties • It is used to disinfect skin and as an application to wounds and abrasions • It has been also applied to the eye, nose, throat in dilution 1:5000 • It is also used as a preservative for various preparations • The solution is affected by light and must be maintained in light resistant containers

47. Topical tinctures • Iodine Tincture • It is a reddish-brown colour tincture • It is prepared from 2% iodine crystal and 2.4% sodium iodide in a vehicle alcohol/water (44-50% alcohol) • It is a popular local anti-infective agent applied to the skin in general household first aid • Compound Benzoin tincture • It is prepared from 10% benzoin and lesser amounts of aloe, storax and tolu balsam • The mixture is macerated in alcohol • It is used to protect and toughen skin in the treatment of bedsores, ulcers, cracked nipples, and fissures of the anus • Also used in treatment of venereal warts • It is also used as an inhalent for bronchitis and other respiratory conditions • It is best stored in tight, light-resistant containers 47

48. Thimerosal Tincture • The vehicle is water, acetone and 50% alcohol • It must be manufactured and stored in glass or suitably resistant containers • Ethylenediamine is used as stabilizer in the official solution and tincture • The commercial preparation is colored orange red, the colour defines the area of application • It is a commonly used household antiseptic for application to the skin abrasions and cuts and in preparation of patients for surgery • Green Soap tincture • 65% of active constituent in alcohol • Also contains 2% lavender oil as perfume • Used as detergent

49. Vaginal and rectal solutions • Vaginal douches • Solution for irrigation cleansing of the vagina, used for hygienic effect • Solutions may be prepared from powders or liquid concentrates. • The resultant solution contains the appropriate amount of chemical agents in proper strength • Boric acid – astringents - antimicrobial – quaternary ammonium compound – detergents – oxidizing agents – salts – aromatics • Evacuation Enemas • Rectal enemas are used to cleanse the bowel. • The enema solution are solutions of; sodium phosphate, sodium biphosphate, glycerin, docusate sodium, light mineral oil • The product will work within 5-10 min • They are available in disposable plastic squeeze bottles • Typical example: Soft soap 25 g / 500 mL water as an emollient 49

50. Simple Enema Soft Soap – 1 oz. Warm water, up to – 1 pint. Dissolve and mix. For use in constipation. To be given at body temperature.