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Slide 1:

LIQUID DOSAGE FORMS SHUBHRAJIT MANTRY Asst.Prof Kottam Institute of Pharmacy . A.P 6/29/2011 Kottam Institute of Pharmacy. A.P 1

Slide 2:

6/29/2011 Kottam Institute of Pharmacy. A.P 2

Liquid Dosage Forms :

Liquid Dosage Forms Solution: solutions are clear Liquid preparations containing one or more active ingredients dissolved in a suitable vehicle. Suspension: (Solid in Liquid dispersion) Liquid preparations containing one or more active ingredients suspended in a suitable vehicle. 6/29/2011 Kottam Institute of Pharmacy. A.P 3

Slide 4:

Emulsion (Liquid in Liquid dispersion): Emulsions are two phase system in which one liquid is dispersed through out another liquid in the form of small particles. Colloids: A system in which finely divided particles, which are approximately less than 1 µ m in size, are dispersed within a continuous medium in a manner that prevents them from being filtered easily or settled rapidly. 6/29/2011 Kottam Institute of Pharmacy. A.P 4

Slide 5:

Solutions 6/29/2011 Kottam Institute of Pharmacy. A.P 5

Slide 6:

In pharmaceutical terms, solutions are liquid preparations that contain one or more chemical substances dissolved in a suitable solvent or mixture of mutually miscible solvents. Dosage forms prepared by dissolving the active ingredient(s) in an aqueous or non aqueous solvent . SOLUTION 6/29/2011 Kottam Institute of Pharmacy. A.P 6

Slide 7:

Classification of solution (i) According to the route of administration a) Oral solutions—through oral route. b) Otic solutions—instilled in the ears. c) Ophthalmic solution—instilled in the eyes. d) Topical solutions—applied over the skin surface. 6/29/2011 Kottam Institute of Pharmacy. A.P 7

Slide 8:

(ii) According to composition and uses a) Syrup —aqueous solution containing sugar. b) Elixir —sweetened hydroalcoholic (combination of water and ethanol) solution. c) Spirit —Solution of aromatic materials in alcohol. d) Aromatic Water —Solution of aromatic material in water. e) Tincture / Fluid extract —Solution prepared by extracting active constituents from crude drugs. e.g. Compound cardamom tincture. They may also be solutions of chemical substances dissolved in alcohol or in hydroalcoholic solvent. e.g. Tincture of Iodine. f) Injection— Certain solution prepared to be sterile and pyrogen-free and intended for parenteral administration. 6/29/2011 Kottam Institute of Pharmacy. A.P 8

Slide 9:

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 : lotions. 6/29/2011 Kottam Institute of Pharmacy. A.P 9

Slide 10:

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. 6/29/2011 Kottam Institute of Pharmacy. A.P 10

Slide 11:

Disadvantages of Solutions (1) 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. major signs of instability: colour change, precipitation microbial growth chemical gas formation 6/29/2011 Kottam Institute of Pharmacy. A.P 11

Slide 12:

Additives 1) Buffers 2) Isotonicity modifiers 3) Preservatives 4) Antioxidants 5) Sweetening agents 6) Flavours and perfumes 6/29/2011 Kottam Institute of Pharmacy. A.P 12

Slide 13:

Additives Buffers To resist any change in pH Isotonicity modifiers *Solutions for injection *Application to mucous membrane *Large-volume solutions for ophthalmic application Most widely used isotonicity modifiers are: dextrose and NaCl 6/29/2011 Kottam Institute of Pharmacy. A.P 13

Additives (cont.) :

Additives (cont.) 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 of the product. 6/29/2011 Kottam Institute of Pharmacy. A.P 14

Additives (cont.):

Additives (cont.) Preservatives Solution may become contaminated for a number of reasons: 1. Raw materials used in the manufacture of solutions are excellent growth media for bacterial substances such as gums, dispersing agents, sugars and flavors 6/29/2011 Kottam Institute of Pharmacy. A.P 15

Additives, Preservatives (cont.):

Additives, Preservatives (cont.) 2. Equipment, environment and personnel contribute to product contamination. 3. Consumer use may result in the introduction of microorganism.  a preservative should be added to the product 6/29/2011 Kottam Institute of Pharmacy. A.P 16

Additives, Preservatives (cont.):

Additives, Preservatives (cont.) Preservative used should be: 1. Effective against a wide spectrum of microorganisms 2. Stable for its shelf life 3. Non toxic , non sensitizing 4. Compatible with the ingredients in the dosage form 5. Free of taste and odour 6/29/2011 Kottam Institute of Pharmacy. A.P 17

Additives, Preservatives (cont.):

Additives, Preservatives (cont.) Preservatives may be used alone or in combination to prevent the growth of microorganisms. 1. 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. 6/29/2011 Kottam Institute of Pharmacy. A.P 18

Additives, Preservatives (cont.):

Additives, Preservatives (cont.) 2. Acids *Benzoic acid and sorbic 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 (WHY?). 6/29/2011 Kottam Institute of Pharmacy. A.P 19

Additives, Preservatives (cont.):

Additives, Preservatives (cont.) 4. Quaternary Ammonium Compounds * Benzalkonium chloride is used at a relatively low concentration 0.002 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 . 6/29/2011 Kottam Institute of Pharmacy. A.P 20

Additives (cont.):

Additives (cont.) 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. 6/29/2011 Kottam Institute of Pharmacy. A.P 21

Additives (cont.):

Additives (cont.) 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. 6/29/2011 Kottam Institute of Pharmacy. A.P 22

Additives (cont.):

Additives (cont.) 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. 6/29/2011 Kottam Institute of Pharmacy. A.P 23

Slide 24:

Stability of solutions Both physical and chemical stability of solutions in their containers is very important A solution must retain its clarity, colour, odour, taste and viscosity over its shelf life. 6/29/2011 Kottam Institute of Pharmacy. A.P 24

Slide 25:

Classification of Solutions According to Vehicle (a) Aqueous solutions (b) Non-aqueous solutions 6/29/2011 Kottam Institute of Pharmacy. A.P 25

Methods of Preparation of Solutions :

Methods of Preparation of Solutions (a) Simple Solution (b) Solution by Chemical Reaction (c) Solution by Extraction 6/29/2011 Kottam Institute of Pharmacy. A.P 26

Slide 27:

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 KI3.I 3 KI.4I 4 ) .[ Strong Iodine Solution USP (Lugol's SoIution)]. 6/29/2011 Kottam Institute of Pharmacy. A.P 27

Slide 28:

(b) Solution by Chemical Reaction These solutions are prepared by reacting two or more solutes with each other in a suitable solvent e.g. Calcium carbonate and lactic acid used to prepare Calcium lactate mixture. * Calcium lactate used as an antacid and also to treat calcium deficiencies 6/29/2011 Kottam Institute of Pharmacy. A.P 28

(c) Solution by Extraction :

(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. 6/29/2011 Kottam Institute of Pharmacy. A.P 29

Slide 30:

Pharmaceutical Solutions Aqueous 1. Douches 2. Enemas 3. Gargles 4. Mouthwashes 5. Nasal washes 6. Juices 7. Sprays 8. Otic solutions 9. Inhalations Sweet &/or Viscid 1. Syrups 2. Honeys 3. Mucilages 4. Jellies Nonaqueous 1. Elixirs 2. Spirits 3. Collodions 4. Glycerins 5. Liniments 6. Oleo Vitamin 6/29/2011 Kottam Institute of Pharmacy. A.P 30

Slide 31:

Aqueous Pharmaceutical Solutions 6/29/2011 Kottam Institute of Pharmacy. A.P 31

Slide 32:

Douches * Douche is an aqueous solution, which is directed against a part or into a cavity of the body. * It functions as a cleansing or antiseptic agent. * Eye douches are used to remove foreign particles and discharges from the eyes. It is directed gently at an oblique angle and is allowed to run from the inner to the outer corner of the eye. 6/29/2011 Kottam Institute of Pharmacy. A.P 32

Douches (cont.) :

Douches (cont.) * Pharyngeal douches are used to prepare the interior of the throat for an operation and to cleanse it in supportive conditions. * Similarly, there are nasal and vaginal douches. * Douches most frequently dispensed in the form of a powder with directions for dissolving in a specified quantity of water. 6/29/2011 Kottam Institute of Pharmacy. A.P 33

Slide 34:

Enemas * These preparations are rectal injections employed to: *1. Evacuate the bowel (evacuation enemas), *2. Influence the general system by absorption (retention enemas) e.g. nutritive, sedative. *3. Affect locally the site of disease (e.g. anthelmintic property) *4. They may contain radiopaque substances for roentgenographic examination of the lower bowel. 6/29/2011 Kottam Institute of Pharmacy. A.P 34

Enemas (cont.):

Enemas (cont.) * Retention enemas are used in small quantities (about 30ml) and are thus called retention microenema . * Starch enema may be used either by itself or as a vehicle for other forms of medication 6/29/2011 Kottam Institute of Pharmacy. A.P 35

Slide 36:

Enema 6/29/2011 Kottam Institute of Pharmacy. A.P 36

Slide 37:

Gargles * Gargles are aqueous solutions frequently containing antiseptics, antibiotics and/or anesthetics used for treating the pharynx (throat) and nasopharynx by forcing air from the lungs through the gargle, which is held in the throat; subsequently, the gargle is expectorated. 6/29/2011 Kottam Institute of Pharmacy. A.P 37

Gargles (cont.):

Gargles (cont.) * Many gargles must be diluted with water prior to use. Although mouthwashes are considered as a separate class of pharmaceuticals many are used as gargles, either as is, or diluted with water. *The product should be labeled so that it cannot be mistaken for preparations intended for internal administration. 6/29/2011 Kottam Institute of Pharmacy. A.P 38

Slide 39:

Mouthwashes Mouthwashes can be used for therapeutic & cosmetic purposes * Therapeutic mouthwashes can be formulated to reduce plaque , gingivitis , dental caries and stomatitis . * Cosmetic mouthwashes may be formulated to reduce bad breath through the use of antimicrobial and/or flavoring agents. 6/29/2011 Kottam Institute of Pharmacy. A.P 39

Slide 40:

6/29/2011 Kottam Institute of Pharmacy. A.P 40

Mouthwashes (cont.) :

Mouthwashes (cont.) Mouthwashes are used as a dosage form for a number of specific problems in the oraI cavity; e.g. mouthwashes containing: * combination of antihistamines, hydrocortisone, nystatin and tetracycline have been prepared for the treatment of stomatitis, a painful side effect of cancer therapy. * pilocarpine for xerostoma (dry mouth) * tranexamic acid for the prevention of bleeding after oral surgery. * carbenoxolone for the treatment of orofacial herpes simplex infections 6/29/2011 Kottam Institute of Pharmacy. A.P 41

Slide 42:

Mouthwashes generally contain four groups of excipients 1. AIcohols: (10-20% in MW) may function as a preservative. aids in masking the unpleasant taste of active ingredients, functions as a solubilizing agent for some flavoring agents 2. Humectants: such as glycerin and sorbitol (5-20% in MW) * increase the viscosity of the preparation * enhance the sweetness of the product * improve the preservative qualities of the product. 6/29/2011 Kottam Institute of Pharmacy. A.P 42

Mouthwashes generally contain four groups of excipients :

Mouthwashes generally contain four groups of excipients 3. Surfactants: Non ionic and anionic surfactants aid in the solubilization of flavors and in the removal of debris by providing foaming action. Cationic surfactants such as cetylpyridinium chloride are used for their antimicrobial properties, but these tend to impart a bitter taste. 6/29/2011 Kottam Institute of Pharmacy. A.P 43

Mouthwashes generally contain four groups of excipients:

Mouthwashes generally contain four groups of excipients 4. Flavours: are used in conjunction with alcohol and humectants to overcome disagreeable tastes. The principle flavoring agents are peppermint, cinnamon, menthol or methyl salicylate. CoIouring agents: also are used in these products. 6/29/2011 Kottam Institute of Pharmacy. A.P 44

Slide 45:

Nasal Solutions Nasal solutions are usually aqueous solutions designed to be administered to the nasal passages in drops or sprays. * Ephedrine Sulfate or Naphazoline Hydrochloride Nasal Solution USP are administered for their local effect to reduce nasal congestion * Vasopressin (Minirin) Nasal Solution USP for its systemic effect for the treatment of diabetes insipidus 6/29/2011 Kottam Institute of Pharmacy. A.P 45

Nasal Solutions (cont.):

Nasal Solutions (cont.) * The current route of administration of peptides and proteins is limited to parental injection because of inactivation within the GIT. As a result there is considerable research on intranasal delivery of these drugs such as insulin . * Intranasal drug administration offers rapid absorption to the systemic circulation . This route is safe and acceptable alternative to the parental administration 6/29/2011 Kottam Institute of Pharmacy. A.P 46

Slide 47:

There is a direct route of transport from the olfactory region to the central nervous system (CNS) without prior absorption to the circulating blood. The olfactory receptor cells are in contact with the nasal cavity and the CNS and they provide a rout of entry to the brain that circumvents the blood brain barrier 6/29/2011 Kottam Institute of Pharmacy. A.P 47

Slide 48:

* Commercial nasal preparations include antibiotics, antihistamines and drugs for asthma prophylaxis. * Drops spread more extensively than the spray and three drops cover most of the walls of the nasal cavity, with the patient in a supine position and head tilted back and turned left and right. Pharynx 6/29/2011 Kottam Institute of Pharmacy. A.P 48

Slide 49:

* Nasal decongestant solutions are employed in the treatment of rhinitis of the common cold and for allergic rhinitis (hay fever) and for sinusitis . Sinuses are air-containing cavities in certain bones of the skull 6/29/2011 Kottam Institute of Pharmacy. A.P 49

Slide 50:

* Their frequent use or their use for prolonged periods may lead to chronic edema of the nasal mucosa, i.e. rhinitis medicaimentosa , aggravating the symptom that they are intended to relieve. Thus, they are best used for short periods of time (no longer than 3 to 5 days). * Nasal solutions are prepared so that they are similar in many respects to nasal secretions, so that normal ciliary action is maintained thus aqueous nasal solutions usually are isotonic and slightly buffered to maintain a pH of 5.5 to 6.5. 6/29/2011 Kottam Institute of Pharmacy. A.P 50

Slide 51:

Sprays * Sprays are solutions of drugs in aqueous vehicles and are applied to the mucous membrane of the nose and throat by means of an atomizer nebulizer. * The spray device should produce relatively coarse droplets if the action of the drug is to be restricted to the upper respiratory tract . Fine droplets tend to penetrate further into the respiratory tract than is desirable. 6/29/2011 Kottam Institute of Pharmacy. A.P 51

Slide 52:

Otic Solutions * The main classes of drugs used for topical administration to the ear include local anesthetics, e.g.: benzocaine ; antibiotics e.g.; neomycin ; and anti-inflammatory agents, e.g.; cortisone . * These preparations include the main types of solvents used, namely glycerin or water. * The viscous glycerin vehicle permits the drug to remain in the ear for a long time. 6/29/2011 Kottam Institute of Pharmacy. A.P 52

Otic Solutions (cont.) :

Otic Solutions (cont.) * Anhydrous glycerin , being hygroscopic, tends to remove moisture from surrounding tissues, thus reducing swelling. * Viscous liquids like glycerin or propylene glycol either are used alone or in combination with a surfactant to aid in the removal of cerumen (ear wax). * In order to provide sufficient time for aqueous preparations to act, it is necessary for the patient to remain on his side for a few minutes so the drops do not run out of the ear. 6/29/2011 Kottam Institute of Pharmacy. A.P 53

Slide 54:

6/29/2011 Kottam Institute of Pharmacy. A.P 54

Slide 55:

Sweet &/or Viscid Pharmaceutical Solutions 6/29/2011 Kottam Institute of Pharmacy. A.P 55

Slide 56:

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 6/29/2011 Kottam Institute of Pharmacy. A.P 56

Slide 57:

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. 6/29/2011 Kottam Institute of Pharmacy. A.P 57

Slide 58:

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 (WHY?). A saturated solution may lead to crystallization of a part of the sucrose under conditions of changing temperature. 6/29/2011 Kottam Institute of Pharmacy. A.P 58

Slide 59:

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, then strained and sufficient purified water added to make the desired weight or volume. 6/29/2011 Kottam Institute of Pharmacy. A.P 59

(a) Solution with heat (cont.) :

(a) Solution with heat (cont.) * Excessive heating in the preparation of syrups must be avoided to prevent inversion of sucrose, with increased tendency to fermentation. Syrups cannot be sterilized by autoclaving without caramelization (yellow color). 6/29/2011 Kottam Institute of Pharmacy. A.P 60

Slide 61:

(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. 6/29/2011 Kottam Institute of Pharmacy. A.P 61

Slide 62:

(C) Percolation * In this procedure, purified water or an aqueous solution is permitted to pass slowly through a bed of crystalline sucrose, thus dissolving it and forming a syrup a pledget of cotton is placed in the neck of the percolator * If necessary, a portion of the liquid is repassed through the percolator to dissolve all of the sucrose. 6/29/2011 Kottam Institute of Pharmacy. A.P 62

Slide 63:

Preservation of Syrups * The USP suggests that syrups be kept at a temperature not above 25°C. * Preservatives such as glycerin , methyl paraben , benzoic acid and sodium benzoate may be added to prevent bacterial and mold growth, particularly when the concentration of sucrose in the syrup is low. * The official syrups should be preserved in well dried bottles and stored in a cool dark place . 6/29/2011 Kottam Institute of Pharmacy. A.P 63

Slide 64:

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. * Some early formulae included glycerin, however, glycerin and propylene glycol are glycogenetic substances, i.e. they are materials which are converted into glucose in the body. * An example of non–nutritive syrup is “Diabetic Simple Syrup”. It contains compound sodium cyclamate (6% cyclamate sodium and 0.6% saccharin sodium ) 6/29/2011 Kottam Institute of Pharmacy. A.P 64

Artificial Syrups (cont.) :

Artificial Syrups (cont.) However, the cyclamate studies showed that the sweetener could produce cancer in animals and, as a result, this substance was removed from a wide variety of products. Similar studies have been carried out on saccharin . Much research has been done to find a safe synthetic substitute for sucrose. As a result, aspartame which is about 200 times sweeter than sucrose, is being used now in many commercial preparations as the sweetening agent. 6/29/2011 Kottam Institute of Pharmacy. A.P 65

Slide 66:

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 6/29/2011 Kottam Institute of Pharmacy. A.P 66


MUCILAGES The official mucilages are thick viscid, adhesive liquids, produced by dispersing gum (acacia or tragacanth) in water . Mucilages are used as suspending agents for insoluble substances in liquids; their colloidal character and viscosity prevent immediate sedimentation. Synthetic agents e.g. carboxymethylcellulose (CMC) or polyvinyl alcohol are nonglycogenetic and may be used for diabetic patients. 6/29/2011 Kottam Institute of Pharmacy. A.P 67

Slide 68:

Jellys * Preparations having a jelly-like consistency. They are prepared also from gums. * Are used as lubricants for surgical gloves and catheters * Lidocaine HCl Jelly USP is used as a topical anaethetic. 6/29/2011 Kottam Institute of Pharmacy. A.P 68

Slide 69:

Non-Aqueous Pharmaceutical Solutions 6/29/2011 Kottam Institute of Pharmacy. A.P 69

Slide 70:

Advantages * If the drug is not completely soluble or unstable in aqueous medium it may be necessary to use an alternative non-aqueous solvent. * Oily solutions of drugs are often used for depot therapy e.g. in muscles It is essential to test: toxicity – irritancy – flammability – cost – stability and compatibility of solvents to avoid problems * Solvents such as acetone , benzene and petroleum ether are not used for internal products. * Internal products may contain ethanol , glycerol , propylene glycol, certain oils. * For parental products the choice is very limited 6/29/2011 Kottam Institute of Pharmacy. A.P 70

Slide 71:

This section is devoted to four groups of non-aqueous solutions: 1. alcoholic or hydroalcoholic solutions, e.g. elixirs and spirits, 2. ethereal solutions, e.g. the collodions 3. glycerin solutions, e.g. the glycerites, 4. oleaginous soIutions e.g. the liniments, medicated oils, oleo- vitamins, sprays, and toothache drops. 6/29/2011 Kottam Institute of Pharmacy. A.P 71

Slide 72:

ELIXIRS * Are clear, pleasantly flavored, sweetened hydroalcoholic liquids intended for oral use. * They are used as flavors and vehicles e.g. Dexamethasone Elixir USP and Phenobarbital Elixir USP. * The main ingredients in elixirs are ethanol and water but glycerin, sorbitol, propylene glycol, flavoring agents, preservatives, and syrups are often used in the preparation of the final product. * An elixir may contain water and alcohol soluble ingredients . 6/29/2011 Kottam Institute of Pharmacy. A.P 72

Slide 73:

Incompatibility of elixir: * Alcohol precipitates water soluble substances e.g. tragacanth, acacia agar and many inorganic salts from aqueous solutions. * If an aqueous solution is added to an elixir, a partial precipitation of ingredients may occur. This is due to the reduced alcoholic content of the final preparation. 6/29/2011 Kottam Institute of Pharmacy. A.P 73

Slide 74:

SPIRITS * Alcoholic or hydroalcoholic solutions of volatile substances . The active ingredient may be gas, liquid or solid. * Generally, the alcoholic concentration of spirits is rather high. * Spirits may be used internally for their medicinal value, by inhalation but is mostly used as flavouring agents. * Spirits should be stored in tight, light-resistant containers and in a cool place, WHY? * Spirits are preparation of high alcoholic strength and when diluted with aqueous solutions or liquids of low alcoholic content turbidity may occur, WHY? 6/29/2011 Kottam Institute of Pharmacy. A.P 74

Slide 75:

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 10 % w/v of Salicylic Acid in Flexible Collodion USP and is used as a keratolytic agent in the treatment of corns and warts. * Collodion is made flexible by the addition of castor oil and camphor. 6/29/2011 Kottam Institute of Pharmacy. A.P 75

Slide 76:

GLYCERINS * Glycerins or glycerites are solutions or mixtures of medicinal substances in not less than 50% by weight of glycerin . * Most of the glycerins are extremely viscous. * Glycerin is a valuable pharmaceutical solvent forming permanent and concentrated solutions. * Glycerin is used as the sole solvent for the preparation of Antipyrine and Benzocaine Otic Solution USP. As noted under Otic Solutions, glycerin alone is used to aid in the removal of cerumen. * Glycerins are hygroscopic and should be: stored in tightly closed containers. 6/29/2011 Kottam Institute of Pharmacy. A.P 76

Slide 77:

LINIMENTS * Are alcoholic or oleaginous solutions or emulsions of various medicinal substances. * 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. * The oily liniments are milder in their action and may function solely as protective coatings. * Liniments should not be applied to skin that are bruised or broken. 6/29/2011 Kottam Institute of Pharmacy. A.P 77

Slide 78:

*Rubefacient A medicine for external application that produces redness of the skin. e.g. by causing dilation of the capillaries and an increase in blood circulation . *Count erirritant a medicine applied locally to produce superficial inflammation in order to reduce deeper inflammation . 6/29/2011 Kottam Institute of Pharmacy. A.P 78

Slide 79:

OLEO VITAMINS * Oleo vitamins are fish liver oils diluted with edible vegetable oil or solutions of the indicated vitamins (usually vitamins A and D). * The indicated vitamins are unstable in the presence of rancid oils and, therefore, those preparations, should be stored in small, tight containers, preferably under vacuum or under an atmosphere of an inert gas, protected from light. 6/29/2011 Kottam Institute of Pharmacy. A.P 79

Slide 80:

suspension 6/29/2011 Kottam Institute of Pharmacy. A.P 80

Pharmaceutical suspension :

Pharmaceutical suspension 6/29/2011 Kottam Institute of Pharmacy. A.P 81

Slide 82:

Definition A Pharmaceutical suspension is a coarse dispersion in which internal phase is dispersed uniformly throughout the external phase. The internal phase consisting of insoluble solid particles having a specific range of size which is maintained uniformly throughout the suspending vehicle with aid of single or combination of suspending agent. The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non oral use. Kottam Institute of Pharmacy. A.P 6/29/2011 82

Slide 83:

Classification Based On General Classes Oral suspension Externally applied suspension Parenteral suspension 2) Based On Proportion Of Solid Particles Dilute suspension (2 to10%w/v solid) Concentrated suspension (50%w/v solid) 3) Based On Electrokinetic Nature Of Solid Particles Flocculated suspension Deflocculated suspension 4) Based On Size Of Solid Particles Colloidal suspension (< 1 micron) Coarse suspension (>1 micron) Nano suspension (10 ng ) 6/29/2011 Kottam Institute of Pharmacy. A.P 83

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Advantages Suspension can improve chemical stability of certain drug. E.g. Procaine penicillin G Drug in suspension exhibits higher rate of bioavailability than other dosage forms. bioavailability is in following order, Solution > Suspension > Capsule > Compressed Tablet > Coated tablet Duration and onset of action can be controlled. E.g. Protamine Zinc-Insulin suspension Suspension can mask the unpleasant/ bitter taste of drug. E.g. Chloramphenicol palmitate 6/29/2011 Kottam Institute of Pharmacy. A.P 84

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Disadvantages Physical stability, sedimentation and compaction can causes problems. It is bulky sufficient care must be taken during handling and transport. It is difficult to formulate Uniform and accurate dose can not be achieved unless suspension are packed in unit dosage form 6/29/2011 Kottam Institute of Pharmacy. A.P 85

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A comparison of properties of flocculated and deflocculated suspension particles 6/29/2011 Kottam Institute of Pharmacy. A.P 86

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Features Desired In Pharmaceutical Suspensions The suspended particles should not settle rapidly and sediment produced, must be easily re-suspended by the use of moderate amount of shaking. It should be easy to pour yet not watery and no grittiness. It should have pleasing odour , colour and palatability. Good syringeability . It should be physically, chemically and microbiologically stable. Parenteral /ophthalmic suspension should be sterilizable . 6/29/2011 Kottam Institute of Pharmacy. A.P 87

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Applications Suspension is usually applicable for drug which is insoluble or poorly soluble. E.g. Prednisolone suspension To prevent degradation of drug or to improve stability of drug. E.g. Oxytetracycline suspension To mask the taste of bitter of unpleasant drug. E.g. Chloramphenicol palmitate suspension Suspension of drug can be formulated for topical application e.g. Calamine lotion. Suspension can be formulated for parentral application in order to control rate of drug absorption, E.g. penicillin procaine Vaccines as a immunizing agent are often formulated as suspension. E.g. Cholera vaccine X-ray contrast agent are also formulated as suspension. E.g. Barium sulphate for examination of alimentary tract Kottam Institute of Pharmacy. A.P 6/29/2011 88

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Theory of Suspensions Sedimentation Behaviour Sedimentation means settling of particle or floccules occur under gravitational force in liquid dosage form. Theory of Sedimentation Velocity of sedimentation expressed by Stoke’s equation V= 2r 2 ( ρ s- ρ o ) g or V= d 2 ( ρ s- ρ o ) g 9  18 Kottam Institute of Pharmacy. A.P 6/29/2011 89

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Where, v sed. = sedimentation velocity in cm / sec d = Diameterof particle r = radius of particle ρ s = density of disperse phase ρ o = density of disperse media g = acceleration due to gravity η = viscosity of disperse medium in poise Kottam Institute of Pharmacy. A.P 6/29/2011 90

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Factors Affecting Sedimentation Particle size diameter (d) V α d 2 Sedimentation velocity (v) is directly proportional to the square of diameter of particle. Density difference between dispersed phase and dispersion media (ρ s - ρ o ) V α (ρ s - ρ o ) Generally, particle density is greater than dispersion medium but, in certain cases particle density is less than dispersed phase, so suspended particle floats & is difficult to distribute uniformly in the vehicle. If density of the dispersed phase and dispersion medium are equal, the rate of settling becomes zero. Kottam Institute of Pharmacy. A.P 6/29/2011 91

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Viscosity of dispersion medium (η ) V α 1/ η o Sedimentation velocity is inversely proportional to viscosity of dispersion medium. So increase in viscosity of medium, decreases settling, so the particles achieve good dispersion system but greater increase in viscosity gives rise to problems like pouring, syringibility and redispersibility of suspensoin . Kottam Institute of Pharmacy. A.P 6/29/2011 92

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Advantages and Disadvantages due to viscosity of medium Advantages High viscosity inhibits the crystal growth. High viscosity prevents the transformation of metastable crystal to stable crystal. High viscosity enhances the physical stability. Disadvantages High viscosity hinders the re-dispersibility of the sediments High viscosity retards the absorption of the drug. High viscosity creates problems in handling of the material during manufacturing. Kottam Institute of Pharmacy. A.P 6/29/2011 93

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I- Sedimentation Parameters Two important parameters are considered: Sedimentation volume (F) or height (H) for flocculated suspensions F = V u / V O -------------- (A) Where, V u = final or ultimate volume of sediment V O = original volume of suspension before settling. Sedimentation volume is a ratio of the final or ultimate volume of sediment (Vu) to the original volume of sediment (V O ) before settling. 6/29/2011 Kottam Institute of Pharmacy. A.P 94

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Sedimentation volume can have values ranging from less than 1 to greater than1; F is normally less than 1. F=1,such product is said to be in flocculation equilibrium, and show no clear supernatant on standing 6/29/2011 Kottam Institute of Pharmacy. A.P 95

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Fig.1: Suspensions quantified by sedimentation volume (f) 6/29/2011 Kottam Institute of Pharmacy. A.P 96

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Degree of flocculation (β) It is a very useful parameter for flocculation Kottam Institute of Pharmacy. A.P 6/29/2011 97

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The Sedimentation Behavior of Flocculated and Deflocculated Suspensions: Flocculated Suspensions In flocculated suspension, formed flocks (loose aggregates) will cause increase in sedimentation rate due to increase in size of sedimenting particles. Hence, flocculated suspensions sediment more rapidly. Here, the sedimentation depends not only on the size of the flocs but also on the porosity of flocks. In flocculated suspension the loose structure of the rapidly sedimenting flocs tends to preserve in the sediment, which contains an appreciable amount of entrapped liquid. The volume of final sediment is thus relatively large and is easily redispersed by agitation. Kottam Institute of Pharmacy. A.P 6/29/2011 98

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Fig 2: Sedimentation behaviour of flocculated and deflocculated suspensions Kottam Institute of Pharmacy. A.P 6/29/2011 99

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Deflocculated suspensions In deflocculated suspension, individual particles are settling, so rate of sedimentation is slow which prevents entrapping of liquid medium which makes it difficult to re-disperse by agitation. This phenomenon also called ‘cracking’ or ‘claying’. In deflocculated suspension larger particles settle fast and smaller remain in supernatant liquid so supernatant appears cloudy whereby in flocculated suspension, even the smallest particles are involved in flocs, so the supernatant does not appear cloudy. Kottam Institute of Pharmacy. A.P 6/29/2011 100

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Flocculating Agents Flocculating agents decreases zeta potential of the suspended charged particle and thus cause aggregation (flock formation) of the particles. Examples of flocculating agents are: Neutral electrolytes such as KCl, NaCl. Surfactants Polymeric flocculating agents Sulfate, citrates, phosphates salts Kottam Institute of Pharmacy. A.P 6/29/2011 101

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Neutral electrolytes e.g. NaCl, KCl besides acting as flocculating agents, also decreases interfacial tension of the surfactant solution. If the particles are having less surface charge then monovalent ions are sufficient to cause flocculation e.g. steroidal drugs. For highly charged particles e.g. insoluble polymers and poly-electrolytes species, di or trivalent flocculating agents are used. Kottam Institute of Pharmacy. A.P 6/29/2011 102

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Method of Floccules Formation The different methods used to form floccules are mentioned below: 1 . Electrolytes Electrolytes decrease electrical barrier between the particles and bring them together to form floccules. They reduce zeta potential near to zero value that results in formation of bridge between adjacent particles, which lines them together in a loosely arranged structure. Kottam Institute of Pharmacy. A.P 6/29/2011 103

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If we disperse particles of bismuth subnitrate in water we find that based on electrophoretic mobility potential because of the strong force of repulsion between adjacent particles, the system is peptized or deflocculated. By preparing series of bismuth subnitrate suspensions containing increasing concentration of monobasic potassium phosphate co-relation between apparent zeta potential and sedimentation volume, caking, and flocculation can be demonstrated. Kottam Institute of Pharmacy. A.P 6/29/2011 104

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Fig 3: Caking diagram, showing the flocculation of a bismuth subnitrate suspension by means of the flocculating agent. Kottam Institute of Pharmacy. A.P 6/29/2011 105

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The addition of monobasic potassium phosphate to the suspended bismuth subnitrate particles causes the positive zeta potential to decrease owing to the adsorption of negatively charged phosphate anion. With continued addition of the electrolyte, the zeta potential eventually falls to zero and then increases in negative directions. Only when zeta potential becomes sufficiently negative to affect potential does the sedimentation volume start to fall. Finally, the absence of caking in the suspensions correlates with the maximum sedimentation volume, which, as stated previously, reflects the amount of flocculation. Kottam Institute of Pharmacy. A.P 6/29/2011 106

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Surfactants Both ionic and non-ionic surfactants can be used to bring about flocculation of suspended particles. Optimum concentration is necessary because these compounds also act as wetting agents to achieve dispersion. Optimum concentrations of surfactants bring down the surface free energy by reducing the surface tension between liquid medium and solid particles. This tends to form closely packed agglomerates. The particles possessing less surface free energy are attracted towards to each other by van der-waals forces and forms loose agglomerates. Kottam Institute of Pharmacy. A.P 6/29/2011 107

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3. Polymers Polymers possess long chain in their structures. Starch, alginates, cellulose derivatives, carbomers, tragacanth The part of the long chain is adsorbed on the surface of the particles and remaining part projecting out into the dispersed medium. Bridging between these later portions, also leads to the formation of flocs. Kottam Institute of Pharmacy. A.P 6/29/2011 108

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Viscosity of Suspensions Viscosity of suspensions is of great importance for stability and pourability of suspensions. As we know suspensions have least physical stability amongst all dosage forms due to sedimentation and cake formation. So as the viscosity of the dispersion medium increases, the terminal settling velocity decreases thus the dispersed phase settle at a slower rate and they remain dispersed for longer time yielding higher stability to the suspension. On the other hand as the viscosity of the suspension increases, it’s pourability decreases and inconvenience to the patients for dosing increases. Thus, the viscosity of suspension should be maintained within optimum range to yield stable and easily pourable suspensions. Kottam Institute of Pharmacy. A.P 6/29/2011 109

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Different Approaches To Increase The Viscosity of Suspensions Various approaches have been suggested to enhance the viscosity of suspensions. Few of them are as follows: 1. Viscosity Enhancers Some natural gums (acacia, tragacanth), cellulose derivatives (sodium CMC, methyl cellulose), clays(bentonite, veegum), carbomers, colloidal silicon dioxide (Aerosil), and sugars (glucose, fructose) are used to enhance the viscosity of the dispersion medium. They are known as suspending agents. Kottam Institute of Pharmacy. A.P 6/29/2011 110

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List of Suspending Agents Alginates Methylcellulose Hydroxyethylcellulose Carboxymethylcellulose Sodium Carboxymethylcellulose Microcrystalline cellulose Acacia, Tragacanth , Xanthan gum Bentonite Carbomer Powdered cellulose Gelatin Kottam Institute of Pharmacy. A.P 6/29/2011 111

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2. Co-solvents Some solvents which themselves have high viscosity are used as co-solvents to enhance the viscosity of dispersion medium: Glycerol, propylene glycol, sorbitol. Kottam Institute of Pharmacy. A.P 6/29/2011 112

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Most suspending agents perform two functions i.e. besides acting as a suspending agent they also imparts viscosity to the solution. Suspending agents form film around particle and decrease interparticle attraction. A good suspension should have well developed thixotropy. At rest the solution is sufficient viscous to prevent sedimentation and thus aggregation or caking of the particles. When agitation is applied the viscosity is reduced and provide good flow characteristic from the mouth of bottle. Kottam Institute of Pharmacy. A.P 6/29/2011 113

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Thixotropy Thixotropy is defined as the isothermal slow reversible conversion of gel to sol. Thixotropic substances on applying shear stress convert to sol(fluid) and on standing they slowly turn to gel (semisolid). Kottam Institute of Pharmacy. A.P 6/29/2011 114

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Other Formulation Aspects Introduciton A perfect suspension is one, which provides content uniformity. The formulator must encounter important problems regarding particle size distribution, specific surface area, inhibition of crystal growth and changes in the polymorphic form. The formulator must ensure that these and other properties should not change after long term storage and do not adversely affect the performance of suspension. Choice of pH, particle size, viscosity, flocculation, taste, color and odor are some of the most important factors that must be controlled at the time of formulation. Formulation Components The various components, which are used in suspension formulation, are as follows. Kottam Institute of Pharmacy. A.P 6/29/2011 115

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· Components Function API Active drug substances Wetting agents They are added to disperse solids in continuous liquid phase. Flocculating agents They are added to floc the drug particles Thickeners They are added to increase the viscosity of suspension. Buffers and pH adjusting agents They are added to stabilize the suspension to a desired pH range. Osmotic agents They are added to adjust osmotic pressure comparable to biological fluid. Coloring agents They are added to impart desired color to suspension and improve elegance. Preservatives They are added to prevent microbial growth. External liquid vehicle They are added to construct structure of the final suspension. Kottam Institute of Pharmacy. A.P 6/29/2011 116

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wetting Agents Hydrophilic materials are easily wetted by water while hydrophobic materials are not. However hydrophobic materials are easily wetted by non-polar liquids. The extent of wetting by water is dependent on the hydrophillicity of the materials. If the material is more hydrophilic it finds less difficulty in wetting by water. Inability of wetting reflects the higher interfacial tension between material and liquid. The interfacial tension must be reduced so that air is displaced from the solid surface by liquid. Non-ionic surfactants are most commonly used as wetting agents in pharmaceutical suspension. Non-ionic surfactants having HLB value between 7-10 are best as wetting agents. High HLB surfactants act as foaming agents. The concentration used is less than 0.5 %. A high amount of surfactant causes solubilization of drug particles and causes stability problem. Ionic surfactants are not generally used because they are not compatible with many adjuvant and causes change in pH. Kottam Institute of Pharmacy. A.P 6/29/2011 117

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Surfactants Surfactants decrease the interfacial tension between drug particles and liquid and thus liquid is penetrated in the pores of drug particle displacing air from them and thus ensures wetting. Surfactants in optimum concentration facilitate dispersion of particles. Generally we use non-ionic surfactants but ionic surfactants can also be used depending upon certain conditions. Disadvantages of surfactants are that they have foaming tendencies. Further they are bitter in taste. Some surfactants such as polysorbate 80 interact with preservatives such as methyl paraben and reduce antimicrobial activity. Kottam Institute of Pharmacy. A.P 6/29/2011 118

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All surfactants are bitter except Pluronics and Poloxamers. Polysorbate 80 is most widely used surfactant both for parenteral and oral suspension formulation. Polysorbate 80 is also adsorbed on drug particle and decreases its zeta potential. This effect of polysorbate80 stabilizes the suspension. Polysorbate 80 stabilized suspensions through steric mechanism. At low concentration of polysorbate 80,only partial stabilization of suspension was observed. Kottam Institute of Pharmacy. A.P 6/29/2011 119

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In absence of polysorbate 80, difficulty was observed in re-dispersion of sedimented particles. Polysorbate 80 is most widely used due to its following advantages It is non-ionic so no change in pH of medium No toxicity. Safe for internal use. Less foaming tendencies however it should be used at concentration less than 0.5%. Compatible with most of the adjuvant. Kottam Institute of Pharmacy. A.P 6/29/2011 120

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Hydrophilic Colloids Hydrophilic colloids coat hydrophobic drug particles in one or more than one layer. This will provide hydrophillicity to drug particles and facilitate wetting. They cause deflocculation of suspension because force of attraction is declined. e.g. acacia, tragacanth, alginates, guar gum, pectin, gelatin, wool fat, egg yolk, bentonite, Veegum, Methylcellulose etc. Kottam Institute of Pharmacy. A.P 6/29/2011 121

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Solvents The most commonly used solvents used are alcohol, glycerin, polyethylene glycol and polypropylene glycol. The mechanism by which they provide wetting is that they are miscible with water and reduce liquid air interfacial tension. Liquid penetrates in individual particle and facilitates wetting. Kottam Institute of Pharmacy. A.P 6/29/2011 122

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Quality Control of Suspensions T he following tests are carried out in the final quality control of suspension: Appearance Color, odor and taste Physical characteristics such as particle size determination and microscopic photography for crystal growth Sedimentation rate and Zeta Potential measurement Sedimentation volume Redispersibility and Centrifugation tests Rheological measurement Stress test pH Freeze-Thaw temperature cycling Compatibility with container and cap liner Kottam Institute of Pharmacy. A.P 6/29/2011 123

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Ideal Requirements of Packaging Material It should be inert. It should effectively preserve the product from light, air, and other contamination through shelf life. It should be cheap. It should effectively deliver the product without any difficulty. Kottam Institute of Pharmacy. A.P 6/29/2011 124

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THANK YOU For further details: Shubhrajit Mantry Asst. Prof. Kottam Institute of Pharmacy Mobile. No.- 8142576104 Email ID: 6/29/2011 Kottam Institute of Pharmacy. A.P 125