2. Learning Objectives Upon completion of this lecture, you should be able to: Define, give an example of, and/or classify examples of each of the followings Solute, Solvent, Syrups, Mucilages State at least six (6) pharmaceutical uses or applications of solutions. Identify commonly used pharmaceutical solvents. Identify at least three (3) necessary criteria of pharmaceutical solvents. Define simple syrups, flavoring syrups, medicinal syrups, syrup USP, and caramelization. List three (3) methods of preparing syrups. Describe and demonstrate how to prepare a syrup by the "agitation with heat" method. Describe alternative formulations for "syrups" prepared with non- sugar sweeteners and state their advantages and limitations.

3. Advantages of Solutions (1) Easier to swallow therefore easier for: children - old age - unconscious people. (2) More quickly effective than tablets and capsules. (3) Homogenous therefore give uniform dose than suspension or emulsion which need shaking. (4) Dilute irritant action of some drugs (aspirin, Kl, KBr) minimize adverse effects in the GIT like KCl.

4. Disadvantages of Solutions (1) Difficult to mask unpleasant tastes (2) Bulky, difficult to transport and prone to container breakages (3) Technical accuracy needed to measure dose on administration (4) Measuring device needed for administration (5) Some drugs poorly soluble

5. Classification of Solutions according to route of administration Orally: Syrups, elixirs, drops In mouth and throat: Mouth washes, gargles, throat sprays. In body cavities: Douches, enemas, ear drops, nasal sprays. On body Surfaces: Collodions, lotions.

6. Classification of Solutions According to Vehicle (a) Aqueous solutions (b) Non-aqueous solutions Aqueous Solutions Aqueous solutions are homogeneous mixtures that are prepared by dissolving a solid, liquid or gas in an aqueous medium (vehicle). Vehicle: This may be water, aromatic water or extracts

7. Pharmaceutical Applications of Solutions Solutions have a wide variety of uses in the pharmaceutical industry: They are used therapeutically as vehicles for oral, parenteral, topical, otic, ophthalmic, and nasal products. They are also used as flavorings, buffers, preservatives, and suspending agents for a variety of liquid dosage forms.

8. Solutions A solution is a thermodynamically stable, one- phase system composed of 2 or more components, one of which is completely dissolved in the other. The solution is homogeneous because the solute, or dispersed phase, is dispersed throughout the solvent in molecular or ionic sized particles.

9. Solutions The solute is the component present in the smallest amount and the solvent is the larger liquid component. Water is nearly always considered the solvent. Pharmaceutical solutes may include  active drug components,  flavoring or coloring agents,  preservatives,  stabilizers or buffering salts.

10. Solutions Water is the most common solvent for pharmaceutical solutions, but ethanol, glycerin, propylene glycol, isopropyl alcohol or other liquids may be used, depending on the product requirements. To be an appropriate solvent, the liquid must dissolve the drug and other solid ingredients at the desired concentration, be nontoxic and safe for ingestion or topical application, and be aesthetically acceptable to the patient in terms of appearance, aroma, texture, and/or taste.

11. Solubility Solubility: it is the concentration of a solute in a saturated solution at a certain temperature. A saturated solution: is one in which an equilibrium is established between dissolved and undissolved solute at a definite temperature b) The USP lists the solubility of drugs as the number of ml of solvent in which 1 g of solute will dissolve. E.g. 1g of boric acid dissolves in 18 mL of water, and in 4 mL of glycerin.

12. 3. Solubility expressions c) Substances whose solubility values are not known are described by the following terms:

13. Solubility The solubility of a drug in a given solvent is largely a function of the polarity of the solvent. Polar solvents (water, glycols, methyl & ethyl alcohol), dissolve ionic solutes & other polar substances Non polar solvents can dissolve non polar solutes i.e. like dissolves like

14. Quiz 1. The statement ‘like dissolves like’ means that solutes best dissolve in solvents of similar…… pH Properties Component Polarity

15. WATER Water is used both as vehicle and as a solvent for the desired flavoring or medicinal ingredients. Advantages: Tasteless, odorless, lack of pharmacological activity, neutral and very cheap Tap Water It is not permitted to use tap water for the dispensing of pharmaceutical dosage forms due to its possible bacterial contamination and the presence of dissolved salts that destroy the active ingredients or enhance their decomposition. Freshly Boiled and Cooled Water Boiling is seldom used to destroy vegetative bacteria. But, on storage for long time spores may yield vegetative microorganism.

16. WATER Purified Water Must be used for most pharmaceutical operations and in all the tests and assays. Such water is prepared by distillation, deionization or reverse osmosis. "Hard" waters are those that contain the Ca and Mg cations. “Alkaline" waters are those that contain bicarbonates as the major impurity. Ultraviolet energy, heat or filtration (Millipore filtration) can be used to remove or kill the microorganisms present in the water. Water for injection Must be used for the formulation of parental solutions. It is obtained by sterilizing pyrogen-free distilled water.

18. Aqueous pharmaceutical solutions Syrups are concentrated, viscous, sweetened, aqueous solutions e.g. Syrup USP, Wild Cherry Syrup USP. Aromatic waters are saturated solutions of volatile oils in water and are used to provide a pleasant flavor or aroma, e.g. Peppermint Water, USP.

19. Aqueous pharmaceutical solutions Mucilages are thick, viscous macromolecular solutions produced by dispersing vegetable gums in water. They are commonly used as suspending or thickening agents, e.g. Acacia Mucilage; Tragacanth Mucilage. Aqueous acids are dilute aqueous solutions of acids (usually < 10%), e.g. Diluted HCl, USP.

20. Methods of Preparation of Solutions (a) Simple Solution (b) Solution by Chemical Reaction (c) Solution by Extraction

21. Methods of Preparation of Solutions (a) Simple Solution Solutions of this type are prepared by dissolving the solute in a suitable solvent (by stirring or heating). The solvent may contain other ingredients which stabilize or solubilize the active ingredient e.g. solubility of Iodine is 1: 2950 in water however, it dissolves in presence of KI due the formation of more soluble polyiodides (KI.I 2 KI.2I 2 KI.3.I 3 KI.4I 4 ) [ Strong Iodine Solution USP (Lugol's SoIution)].

22. Methods of Preparation of Solutions (b) Solution by Chemical Reaction These solutions are prepared by reacting two or more solutes with each other in a suitable solvent. (c) Solution by Extraction Plant or animal products are prepared by suitable extraction process. Preparations of this type may be classified as solutions but more often, are classified as extractives.

23. Additives (Excipients) Buffers A buffer is a solution that resists change in pH when a small amount of an acid or base is added or when solution is diluted. A Buffer solution consists of a mixture of weak acid and its salt or weak base and its salt. Examples: NaAc + HAc NH4Cl + NH4OH

24. Additives (Excipients) Buffers Buffers were added to adjust the pH of solutions. Why? 1. solubility Most drugs are weak acids or weak bases Ionization (dissociation) of these drugs depends on pH Dissociated form of weakly acidic or basic drug has a higher solubility than undissociated form

25. Quiz 2. The solubility of Compound A is (See the Figure) a) Compound A is 550 fold more soluble than compound B b) Compound B is 550 fold more soluble than compound A c) The two compounds have same solubility d) The two compounds were insoluble A B

26. Additives (Excipients) 1) Buffers Buffers were added to adjust the pH of solutions. Why? 2. Therapeutic response Undissociated form of weakly acidic or basic drug often has a higher therapeutic activity than that of the dissociated form. Why? Undissociated form is lipid soluble and can penetrate body membranes readily compared to ionic form

27. Additives (Excipients) 1) Buffers Buffers were added to adjust the pH of solutions. Why? 3. Stability Choose the pH of maximum stability

28. Additives (Excipients) 1) Buffers Buffers were added to adjust the pH of solutions. Why? 4. Tissue irritation  large pH difference between the solution being administered and the physiologic environment in which it is used should be minimal to reduce tissue irritation.  Eye is a delicate tissue, therefore it is important to adjust the pH of ophthalmic preparations and large parenteral solutions

29. Additives (Excipients) 2) Isotonicity modifiers  Solutions that have the same osmotic pressure as the body fluid are said to be isotonic with the body fluid.  A 0.9 percent solution of sodium chloride, or a five percent solution of dextrose, are isotonic with our body fluids solutions should be made isotonic –To avoid crenation or hemolysis of RBC's, to avoid pain and discomfort if solutions are injected or introduced into the eyes and nose. Most widely used isotonicity modifiers are: dextrose and NaCl

30. Additives (Excipients) 3) Viscosity enhancement It is difficult for aqueous-based topical solutions to remain on the skin or in the eye (why?) therefore low concentrations of jelling agents are added to increase the viscosity

31. Additives (Excipients) 4) Preservatives Solution may become contaminated for a number of reasons: Raw materials used in the manufacture of solutions are excellent growth media for bacterial substances such as gums, dispersing agents, sugars and flavors Equipment, environment and personnel contribute to product contamination. Consumer use may result in the introduction of microorganism.  a preservative should be added to the product

32. Preservatives Preservatives may be used alone or in combination to prevent the growth of microorganisms. Examples Ethanol Propylene glycol Acids Benzoic acid and asorbic acid Esters Parabens are esters (methyl, ethyl, propyl and butyl) of p-hydroxybenzoic acid. Quaternary Ammonium Compounds Benzalkonium chloride

33. Antioxidants Vitamins, essential oils & almost all fats and oils can be oxidized. Oxidation reaction can be initiated by: 1. heat: maintain oxidizable drugs in a cool place 2. light: use of light- resistant container 3. heavy metals (e.g. Fe, Cu): effect of trace metals can be minimized by using citric acid or ethylenediamine tetra­acetic acid (EDTA) i.e. sequestering agent. Antioxidants as propyl & octyl esters of gallic acid, tocopherols or vitamin E, sodium sulfite, ascorbic acid (vit. C) can be used.

34. Sweetening agents Sucrose is the most widely used sweetening agent. Advantages: Colourless, highly water soluble, stable over a wide pH range (4-8). Increase the viscosity, masks both salty and bitter taste, has soothing effect on throat. Polyhydric alcohols (sorbitol, mannitol and glycerol) possess sweetening power and can be used for diabetic preparations.

35. Flavors and perfumes Mask unpleasant taste or odour Enable the easy identification of the product. Natural products: fruit juices, aromatic oil (peppermint, lemon) Artificial perfumes are cheaper, more readily available and more stable than natural products.

36. Pharmaceutical Solutions Aqueous Douches Enemas Gargles Mouthwashes Nasal washes Juices Sprays Otic solutions Inhalations Sweet &/or Viscid Syrups Honeys Mucilages Jellies Nonaqueous Elixirs Spirits Collodions Glycerins Liniments Oleo Vitamin

38. Sweet Pharmaceutical Preparations These include Syrups, Honeys, Mucilages, and Jellies. All of these preparations are viscous liquids or semisolids. The sweetness and viscid appearance are given by sugars, polyols, or polysaccharides (gums). SYRUPS Syrups are concentrated solutions of sugar such as sucrose in water or other aqueous liquid. simple syrup: when water is used alone for making syrup. medicated syrup: when the aqueous preparation contains some added medicinal substance flavored syrup: which contains aromatic or pleasantly flavored substances and is intended to be used as a vehicle or flavor for prescriptions

43. Sweet Pharmaceutical Preparations Polyols (e.g. glycerin or sorbitol) may be added to - retard crystallization of sucrose or - increase the solubility of added ingredients. Alcohol often is included as - preservative - solvent for volatile oils. Syrups possess remarkable masking properties for bitter and saline drugs. It is important that the concentration of sucrose approaches but not quite reach the saturation point, WHY? In dilute solutions sucrose provides an excellent nutrient for molds, yeasts, and other microorganisms. In concentration of 65 % by weight or more the solution will retard the growth of such microorganisms. A saturated solution may lead to crystallization of a part of the sucrose under conditions of changing temperature.

44. Sweet Pharmaceutical Preparations Invert Syrup: It is prepared by hydrolyzing sucrose with hydrochloric acid and neutralizing the solution with Ca or Na carbonate. C 12 H 22 O 11 heat & acid 2 C 6 H 12 O 6 Sucrose Invert sugar (dextrose and levulose) The invert syrup, when mixed in suitable proportions with syrup, prevents the deposition of crystals of sucrose under most conditions of storage. The levulose formed during inversion is sweeter than sucrose; therefore the resulting syrup is sweeter than the original syrup. When syrup is overheated it caramelizes

45. Dextrose-Based Syrups Dextrose may be used as a substitute for sucrose (WHEN?) in syrups containing strong acids in order to eliminate the discoloration associated with inversion. Dextrose forms a saturated solution in water at 70% w/v, which is less viscous than simple syrup. It dissolves more slowly than sucrose and is less sweet. Preservatives are required to improve the keeping qualities of such syrups. Glycerin is added in 30% to 45% v/v as preservative.

46. Sorbitol-Based Syrups Sorbitol which is hexahydric alcohol made by hydrogenation of glucose has been used in the preparation of syrup. It is used mostly in the form of a 70% w/w aqueous solution. Sorbitol solution is not irritating to the membrane of the mouth and throat and does not contribute to the formation of dental carries. Sorbitol is metabolized and converted to glucose; however, it is not rapidly absorbed from the GlT as sugars. No significant hyperglycemia has been found ; it may be used as component of non-nutritive vehicles. Preservative should be used in solution containing less than 60% w/w sorbitol. It is chemically stable and inert with respect to drugs and other ingredients used in pharmaceutical preparations.

47. Artificial Syrups (Non-Nutritive Syrups) intended as substitutes for syrups and are to be administered to persons who must regulate their sugar and/or calorie intake accurately. e.g. persons suffering from diabetes mellitus. An example of non-nutritive artificial sweeteners is aspartame & saccharin

50. Preparation of Simple Syrup ( a) Solution with heat This is the usual method of making syrups: – in the absence of volatile agents or those injured by heat – when it is desirable to make the syrup rapidly. The sucrose is added to the purified water or aqueous solution and heated until dissolved sufficient purified water added to make the desired weight or volume. Excessive heating in the preparation of syrups must be avoided to prevent, caramelization Syrups cannot be sterilized by autoclaving without caramelization (yellow color). The specific gravity of syrup is an important property to identify its concentration. Syrup has a specific gravity of about 1.313, which means that each 100 ml of syrup weighs 1313 g.

51. Preparation of Simple Syrup (b) Agitation without Heat This process is used in those cases where heat would cause loss of valuable volatile constituents. The syrup is prepared by adding sucrose to the aqueous solution in a bottle of about twice the size required for the syrup. This permits active agitation and rapid solution. The stoppering of the bottle is important, as it prevents contamination and loss during the process.

53. HONEYS Are thick liquid preparations. At one time, before sugar was available, honey was used as a base, instead of syrup. There are few official preparations containing honey. e.g. Oxymel, or" acid honey "'is a mixture of acetic acid, water and honey