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aqueous or non aqueous solvent.

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Presentation on theme: "aqueous or non aqueous solvent."— Presentation transcript:

1 aqueous or non aqueous solvent.
Solutions are: Solution Dosage forms are prepared by dissolving the active ingredient(s) in an aqueous or non aqueous solvent.

2 Solutions can be formulated for different routes 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.

3 Advantages of SoIutions
(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 SoIutions
Bulky therefore difficult to transport and store. (2) Unpleasant taste or odours are difficult to mask. (3) Needs an accurate spoon to measure the dose. (4) Less stable than solid dosage forms. (5) Solutions often provide suitable media for microbial growth.

5 Formuation of Solutions
(Aqueous Solutions): √ H2O is the most widely used solvent for use as vehicle because its lack of toxicity, physiological compatibility and ability to dissolve a wide range of materials. √ At least Purified water BP should be used in all sort of solutions. √ Water for injections must be used in case of parenteral solutions and it must be pyrogen free. √ For CO2 sensitive drugs (phenobarbitone-Na, or aminophylline) or oxidation sensitive drugs (apomorphine, ergotamine) CO2 or airfree water for injection must be used.

6 Approaches to Improve Aqueous Solubility
The following methods may be used in order to improve aqueous solubility. (1) Cosolvency: Vehicles used in combination with water to improve the solubity of of the drug are called cosolvents. For example, a blend of propylene glycol and water is used to improve the solubility of cotrimoxazole. Paracetamol elixir is formulated as an elixir by the use of propylence glycol and syrup.

7 (2) pH control: ■ The solubility of a weak base can be increased by lowering the pH of its solution whereas the solubility of a weak acid is improved by a pH increase. ■ The chemical stability of a drug may also depend on pH. So it must be carefully controlled. ■ The solutions for parenteral, opthalmic and mucous membrane use must be carefully controlled to avoid pain and irritiation. ■ The bioavailability of drugs may be influenced by the pH of their solution.

8 (3) Solubilization ■ The solubility of insoluble or poorly soluble drugs in water can be improved by the addition of surface active agents. ■ The hydrophillic surfectants possessing HLB values above 15 are usually used as solubilizing agent. ■ The surfectant chosen must be nontoxic, nonirritant, miscible with solvent systems and compatible with other ingredients, free from disagreable odour and taste. ■ For example, the solubilization of iodine to produce iodophores is achieved by use of macrogel ethers.

9 (4) Complexation. ■ Poorly soluble drugs sometimes interact with a soluble material to form a soluble intermolecular complex. This complex could not cross lipid membrane. So a device must be developed to release drug from the complex before contact with biological fluids. ■ Hydrotropy; the increase in aqueous solubility of material by inclusion of additives. This method could also be used for complexation. ■ For example, complexation of iodine with a 10-15% solution of polyvinylpyrrolidone to improve the aqueous solubility of the active agent.

10 (5) Chemical Modification:
■ Chemical modification of drug may be necessary in order to produce a water soluble derivative. ■ For example, the synthesis of the sodium phosphate salts of hydrocortisone, prednisolone and betamethasone. (6) Particle Size Control: ■ As particle size decreases solubility will increases. ■ This phenomenon is very important for suspension formulation rather than solution.

11 Formulation of Solution
Non-aqueous solutions The use of alternative solvents : If complete solution of the active ingredients is not possible at all storage temperatures or if the drug is unstable in aqueous systems it may be necessary to use alternative solvent. For example, IM injection of solutions of drugs in oils is often used for depot therapy and some drugs (propionate and benzoate esters of testesterone and oestradiol) are specially synthesized to improve their oil solubilities.

12 Fixed Oils & Vegetable Origin: These are nonvolatile oils which
consist of fatty acid esters of glycerol. Olive oil, sesame oil, maize oil, cottonseed oil, soya oil and castor oil are suitable for parenteral use. For example, almond oil consists of glycerides mainly of oleic acid is used as solvent for oily phenol injection BP. Some fixed oils are sufficiently tasteless and odourless to be suitable for oral use as solvents of Vitamin A & D.

13 Alcohols: Ethyl alcohol is the most widely used solvent in this class
specially for external application. For example, Salicylate lotion BP. At concentration above 15%, it exhibits antimicrobial activity. Usually it is used as cosolvent with water. If required for external use then industrial methylated spirit (IMS) is usually included rather than the more expensive ethanol. An alcohol possessing similar properties is isopropyl alcohol, is used as a solvent for dicophane.

14 Polyhydric Alcohols: Alcohols having two hydroxyl groups are known
as glycols but due to their toxicity they are rarely used internally. Propylene glycol is an exception often used in conjunction with water or glycerol as a cosolvent It is used in formulation of Digoxin Inj BP, Phenobarbitone Inj. BP, Cotrimoxazole IV inj BP.

15 Dimethylsulfoxide (DMSO)
This is a highly polar compound and is thought to aid the penetration of drugs through the skin. For example, DMSO is used as a carrier for idoxuridine (antiviral agent) for application to human skin. Ethyl Ether: It is used as a cosolvent with alcohol in some collodions. Liquid Paraffin: The oily nature of this material makes it unpleasent to use externally, although it is often used as a solvent for the tropical application of drugs in emulsion formulations. Isopropyl myristate and isopropyl palmitate are oily materials, used as solvents for external use particularly in cosmetics.

16 Formulation Additives
Buffers To resist any change in pH. It must be compatible with other excipients and have low toxicity. Most pharmaceutically acceptable buffer systems are carbonates, citrate, gluconates, lactates, phosphates and tartarates. Isotonicity modifiers Solutions for injection Application to mucous membrane Large-volume solutions for ophthalmic application must be made isotonic to avoid pain and irritation. Most widely used isotonicity modifiers are: dextrose and NaCl Viscosity enhancement It is difficult for aqueous-based topical solutions to remain on the skin or in the eye; therefore low concentrations of jelling agents are added to increase the viscosity of the product.

17 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 2. Equipment, environment and personnel contribute to product contamination. 4. Consumer use may result in the introduction of microorganism. so a preservative should be added to the product Preservative used should be: effective against a wide spectrum of microorganisms stable for its shelf life non toxic, non sensitizing compatible with the ingredients in the dosage form free of taste and odour

18 Preservatives may be used alone or in combination to
prevent the growth of microorganisms. Alcohols Ethanol is useful as a preservative when it is used as a solvent. It needs a relatively high concentration (> 10%) to be effective. Propylene glycol also used as a solvent in oral solutions and topical preparations. It can function as a preservative in the range of 15 to 30%. It is not volatile like ethanol. Acids Benzoic acid and ascorbic acid have low solubility in water. They are used in a concentration range from 0.1 % to 0.5%. Only the non-ionized form is effective and therefore its use is restricted to preparations with a pH below 4.5.

19 Esters Parabens are esters (methyl, ethyl, propyl and butyl) of p-hydroxybenzoic acid. They are used widely in pharmaceutical products and are effective and stable over a pH range of 4 to 8. They are employed at concentrations up to about 0.2%. Frequently 2 esters are used in combination in the same preparation . To achieve a higher total concentration To be active against a wider range of microorganisms.

20 Quaternary Ammonium Compounds
Benzalkonium chloride is used at a relatively low concentration to 0.02%. This class of compounds has an optimal activity over the pH range of 4 to 10 and is quite stable at most temperatures. Because of the cationic nature of this type of preservative it is incompatible with many anionic compounds.

21 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.

22 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.

23 Mask unpleasant taste or odour
Flavours 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.

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

25 Syrups: Concentrated viscous liquid prepn containing
large amount of dissolved sugar (or sugar substituent) with or without added flavouring agents and medicinal substances.The concn of sugar in syrup should be 66.7%.

26 Syrups are two types: Non-medicated syrup: contain flavouring agents but not medicinal substances. For example, Cherry syrup. Cocoa syrup, orange syrup, raspberry syrup etc. 2) Medicated syrup: contain therapeutic agents. Now these syrups are used to extremporneous preparation of liquid dosage forms of medicines. Medicated syrup is formulated by the components ; sucrose, purified water, flavouring agent & other excipients.

27 Components of Syrup ► Sucrose or sucrose substitutes: provide sweeting effects and viscosity. ► Antimicrobial preservatives ► Flavourants ► Colourants. Medicated syrups contain special solvents, solubilizing agents, thickeners or stabilizers along with active ingredients.

28 Sugar used in Syrup: Sucrose is the most frequently used sugar
substance in syrups. Dextrose is also used as sugar substituent. Non-sugar substance: Sorbitol, glycerin and propylene glycol (PEG). Artificial sweeteners: Saccharin, Aspartame, Neotame etc. Why most syrups contain sucrose of 60-80%? Most syrups contain sucrose of 60-80%, ► not only because of the desirable sweetness and viscosity but also to enhance stability in contrast to unstable character of dilute sucrose solutions. ► Aqueous dilute sugar medium is an efficient nutrient medium for microbial growth particularly yeasts and molds. But concentrated sugar solutions are resistant to microbial growth.

29 Antimicrobial Preservatives:
Amount of preservative required to protect a syrup against microbial growth varies with the proportion of water available, the nature and inherent preservative activity of some formulative materials and the capability of the preservative itself. E.g. benzoic acid (0.1 to 0.2%), Na-benzoate(0.1 to 0.2%) and various combinations of methyl, propyl and butylparabens.

30 Flavourant Most syrups are flavoured with synthetic flavourants or with naturally occuring materials as volatile oils (e.g. orange oil), vanillin and others to render the syrup pleasant testing. Colorants To enhance the appeal of the syrup, a colouring agent is generally used which correlates with flavourant (e.g. green with mint, brown with chocolate etc).The colorant should be water soluble, nonreactive and color stable at different pH range.

31 Advantages and Syrup Syrups retard oxidation because it is partly hydrolysed into reducing sugar such as levulose and dextrose. 2. It prevents decomposition of many vegetable substances, syrups have high osmotic pressure which prevents microbial growth. 3. They are palatable due to presence of sugar, suitable vehicle for administration of bitter and bad odorous substances. 4. They are more quickly effective than solid dosages (e.g. tablet, capsule etc.) 5. They are homogenous formulation so the active ingredients are also homogenously distributed. 6. This is a suitable formulation for pediatric and geriatric patients.

32 Disadvantages of Syrup
It is possible in a closed container of syrup for surface dilution due to solvent evaporation. 2. Solvent evaporation condenses upper internal surface of the container and then flows back on to the surface of the product which provide an ideal medium for the growth of certain microorganism. 3. During storage and use of syrup involves crystallization of the sugar within the screw cap. This problem is solved by addition of polyhydric alcohols.

33 Elixirs Elixirs are clear, sweetened, hydroalcholic solutions intended for oral use and are usually flavoured to enhance their palatability. Nonmedicated elixirs are employed as vehicles and medicated elixirs for the therapeutic effect of the medicinal substances they contain.

34 Difference between Syrup and elixirs
Elixirs are clear, sweetened, hydroalcoholic solutions intended for oral use, are usually flavoured to enhance their palatability. Less sweet than syrup. Less viscous due to containing lower proportion of sugar. Less effective than syrup. Syrups are concn aq, prepn of sugar or nonsugar substitute with or without added of flavouring agent and also the medicaments. Usually more sweet than elixir. More viscous than elexir. More effective than elixir.

35 Difference between Syrup and elixirs
Elixirs are better able to maintain both water soluble acid, alcohol soluble components in solution Elixirs are preffered over syrup. Elixir containing over 10-20% of alcohol are usually self preserving. Syrups are unable to maintain alcohol soluble components in solution. From a manufacturing stand point, syrups are not preffered over elixir. Syrup containing over 60-80% of sugar were usually self preserving.

36 Formulation of Elixir Vehicles:
■ The elixirs are usually prepared by using water, alcohol, syrup glycerin, sorbitol, propylene glycol as vehicle. Among them water is used to dissolve the majority of ingredients. ■ The flavouring agents containing essential oils are soluble in alcohol. Certain ingredients of elixir are easily soluble in alcohol. In this case concn of alcohol is 5-40% (to make a clear soln). ■ Glycerin, sorbitol and propylene glycol are used as a vehicle for many ingredients which are not soluble in water and alcohol.

37 (2) Adjuvents: ■ Chemical Stabilizers: The various chemicals or solvents are used to make stable elixirs. For example, in neomycin elixir, citric acid is added to adjust the pH between 4 to 5 to prevent darkening of elixir on storage. ■ Colourant: The coalter dyes are commonly used in elixir. For example, amaranth compound, tartrazine, green sulphur. ■ Flavourant: The colourants used in elixirs are Raspberry syrup, lemon syrup, orange syrup etc.

38 (3) Container: (4) Storage: ■ Preservatives:
The mould growth and fermentation in elixirs are inhibited by using alcohol 20% or more, propylene glycol, glycerol as a vehicle. The high osmotic pressure of elixir prevents the growth of microorganism. Benzoic acid, methyl paraben, propyl paraben etc are also used as preservatives in many elixirs. (3) Container: Elixirs are dispensed in well closed, airtight glass bottles having screwcaps. (4) Storage: Elixirs are required to be stored in a cool place protected from light.

39 Why preservatives are added in the syrup?
Although syrups have 66.7% sugar content, it require addition of preservatives for following reasons; Solvent evaporation of syrup some times cause flow back of the evaporated solvent to the upper layer of syrup producing a dilute layer which provides an ideal media for microbial growth. This is why preservative is essential in syrup.

40 (2) Syrups are usually formulated in a temperature controlled
environment. These may be transferred to other region of uncontrolled temperature, it may cause the crystallization of the sugar molecule and may remain as sediment to the solution. Thus two layers are formed upper layer remain as solvent and the lower layer remain as solute. Since the solvent layer is less sugar content, it may be easily attacked by the microorganisms. This is why preservatives are added to the syrup formulation.

41 Concentration of Sucrose controlling in Syrup Why is so important?
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.

42 How heat may cause the Deterioration of Syrup?
When heat is used in the preparation of syrups, there is almost certain to be an inversion of a slight portion of the sucrose. C12H22O C6H12O6 Sucrose heat & acid Invert sugar (dextrose and levulose) The speed of inversion is greatly increased by acids; the hydrogen ion acts as a catalyst in this hydrolytic reaction. Invert sugar ♣ is more readily fermentable than sucrose ♣ tend to darken in color ♣ retard the oxidation of other substances. 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.

43 Manufacturing of Solutions
■ Very simple equipments like mixing vessels, agitation system and filtration system is necessary for formulation of syrup. Solutes are simply added to the solvent in a mixing vessel and stirring is continued until dissolution is complete. ■ Heat may be necessary in some cases for complete dissolution of materials. Care must be taken also for volatile and thermolabile materials. ■ Size reduction of solid materials may speed up the solution process. ■ Solutes needed in low concn are often predissolved in a small volume of the solvent and then added to the bulk. ■ Volatile materials such as flavours and perfumes are added at the end of a process and after cooling if necessary to reduce evaporation. ■ Finally the formulation is filtered for final clarification.

44 Stability of Solutions
Both the chemical and physical stability of solutions in their container are important. A solution must retain its initial clarity, colour, odour, taste and viscosity over its allocated shelf life. Major signs of instability are colour change, precipitation microbial growth chemical gas formation

45 Clarity can be easily assessed by visual examination or optical
density measurement after agitation. Colour may be assessed by visually or spectrophotometrically. The stability of flavours and perfumes is difficult to assess but now a days chromatographic methods are used. Organoleptic powers are screened by a panel accessors. If a suitable majority of the panel members are unable to detect a difference between stored sample and freshly prepared reference material, it may be assumed that the taste and odour of the sample has not significantly changed.

46 Different Types of solutions
Mixtures: Mixures are aqueous prepn either solution or suspension. Most mixture prepn are manufactured on a small scale and allocated shelf life of a few weeks before dispensing. (b) Draughts: A draught is a mixture of only one or two large doses of about 50 ml of solutions. (c) Linctuses: A linctus is a viscous preparation usually prescribed for the relief of cough. It is usually consists of a simple solution of the active agent in a high concentration of sucrose often other sweetening agents.

47 (d) Mouthwashes and Gargles: Aqueous solutions for the prevention
and treatment of mouth and throat infections can contain antiseptics, analgesics and astringents. They should be diluted with warm water before use. (e) Nasal Products Small volume solutions in an aqueous vehicle formulated at pH of 6.8 to avoid irritation in nasal mucous. Made isotonic with nasal secretions using NaCl. Viscosity is controlled by cellulose derivatives due to low buffering capacity of nasal mucous membrane. Active ingredients include antibiotics, antiinflammatories and decongestants.

48 (f) Ear Drops These are simple solutions of drugs in either water, glycerol, propylene glycol or alcohol/water mixtures for local use and include antibiotics, antiseptics, cleansing solutions and wax softeners. (g) Enemas Aqueous or oily solutions, emulsions and suspensions available for the rectal administration of medicaments for cleansing, diagnostic or therapeutic purposes.

49 (h) Lotions: (i) Liniments:
A solution, designed to apply to the skin without friction. It may contain humectants so moisture is retained on the skin after application or alcohol which evaporates quickly imparting cooling effect on skin. (i) Liniments: solutions or mixtures of various substances in oil, alcoholic solutions of soaps, or emulsions. They are intended for external application and should be so labeled. They are applied with rubbing to the affected area, the oil or soap base providing for ease of application and massage. Alcoholic liniments are used generally for their rubefaciant and counterirritant effects. Such liniments penetrate the skin more readily than do those with an oil base.

50 Liquid prepn for application to the skin or mucous membrane, often
(j) Paints: Liquid prepn for application to the skin or mucous membrane, often applied with a small brush. The solvents (e.g. alcohol, acetone) evaporates quickly leaving a film on the skin containing active agents. (k) Collodions: Are liquid preparations containing pyroxylin (a nitrocellulose) in a mixture of ethyl ether and ethanol. They are applied to the skin by means of a soft brush or other suitable applicator and, when the ether and ethanol have evaporated, leave a film of pyroxylin on the surface. The official medicated collodion, Salicylic Acid Collodion USP, contains % w/v of Salicylic Acid in Flexible Collodion USP and is used as a keratolytic agent in the treatment of corns and warts.

51 (l) Aromatic Water: Aromatic waters (medicated waters) are clear, saturated aqueous solution of volatile oils or other aromatic or volatile substances. ■ They are used principally as flavored or perfumed vehicles. ■Volatile oils solutions represent an incompatibility problem of salting out. This occurs after the incorporation of a very soluble salt in their solution. ■ Aromatic water will deteriorate with time therefore should be made in small quantities - protected from intense light and excessive heat by storing in air tight, light resistant containers. ■ If they become cloudy or otherwise deteriorate; they should be discarded. Deterioration may be due to volatilization, decomposition or mould growth.

52 Distillation process (Stronger Rose Water NF)
There are 2 official methods of preparation: Distillation process (Stronger Rose Water NF) Adv.: most satisfactory method Dis.: slow and expensive The drug should be coarsely ground and mixed with sufficient quantity of purified water in the distillation unit. After distillation any excess oil in the distillate is removed by filtration. Drug should not be exposed to the action of direct heat during distillation; otherwise, the odour of the carbonized substance will be noticeable in the distilled aromatic water. If the volatile principle in the water are present in small quantities the distillate is returned several times to the still with fresh portions of drug.

53 (b) Solution process (Peppermint water)
Aromatic water may be prepared by shaking volatile substance with purified water. The mixture is set aside for 12 hours & filtered. Talc (inert) may be used to increase the surface of the volatile substance, ensure more rapid saturation of the water and act as a filter aid.

54 (m) Infusions Infusions are concentrated solutions of active principles from animal or vegetable sources. These are prepared by extracting the drug using 25% alcohol but without application of heat. This is then diluted 1 to 10 in the final product. (n) Extracts: These similar product of infusions but concentrated by evaporation. (p) Tinctures: Alcoholic extracts of drugs but are relatively weak compared with extracts. (q) Spirits: Alcoholic solutions but of volatile materials which are used as flavoring agent.


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