Pharmaceutics 3 Theory Past Paper PDF

2020 Pharmaceutics 3 Dr. Noha Younis Chapter One Ointments Definition: An ointment is homogeneous, viscous semisolid preparation, most commonly a greasy, oily (Oil-80%, Water-20%) with high viscosity that is intended for external application to skin or mucous membranes...

2020 Pharmaceutics 3 Dr. Noha Younis Chapter One Ointments Definition: An ointment is homogeneous, viscous semisolid preparation, most commonly a greasy, oily (Oil-80%, Water-20%) with high viscosity that is intended for external application to skin or mucous membranes. - They are used as emollients, protective, therapeutic, or prophylactic purposes and where a degree of occlusion is desired. - Ointments are used topically on a skin and the mucous membrane of the eye (an eye ointment), chest, vulva, anus and nose. - Ointments have very moisturizing characteristic and are effective for dry skin. - They have more greasiness so mostly disliked by patients. Types of Ointment a) Medicated ointment: For the application of API to skin for protective, therapeutic, or prophylactic purpose. b) Non-medicated ointment: These are used for physical effect. They are use as protectant(barrier), emollients, or lubricants. Classification of ointments according to place of action: a) Epidermic-Meant for action on epidermis. b) Endodermic meant for action on deeper layers of cutaneous tissues (penetrate into skin). c) Diadermic-Meant to penetrate deep and release medicaments in body fluids (systemic circulation) Characteristics of an ideal ointment: 1) It should be physically and chemically stable. 2) In ointment base, finely divided active ingredients should be uniformly distributed, smooth and free from grittiness. 1 3) The base of ointment should not possess any therapeutic action (Should be inert, odorless). 4) Should not retard wound healing, have a low sensitization index and low index of irritation and non-dehydrating. 5) The base should melt at body temperature and release the medicament efficiently at the site of application. 6) Have minimum number of ingredients and compatible with common medicaments and with the skin. 7) Pharmaceutically elegant 8) Easily washable with water. 9) Economic and easy to transport. Advantages of an ointment: 1) They have site-specific action with less side effect. 2) They avoid first pass metabolism of drug. 3) Convenient for unconscious patients having difficulty in oral administration. 4) Comparatively they are chemically more stable and easier to handle than liquid dosage forms. 5) They are suitable dosage forms for bitter taste drugs. Disadvantages of an ointment: 1) These oily semisolid preparations are staining and cosmetically less aesthetic. 2) Application with fingertip may contaminate the formulation or cause irritation when applied. 3) As compared to solid dosage forms, semisolid preparation is bulkier to handle. 4) Semisolid dosage form are more flexibility in dose, dose accuracy is determined by the quantity to be applied. 2 5) Physio-chemically less stable than solid dosage form Types of ointment bases: The vehicle or carrier of an ointment is known as ointment base. The choice of ointment base depends upon the - The nature of medicament - Stability of ointment - Clinical indication of the ointment. Ointment bases with example: Type of Ointment bases (according to USP): 1) Oleaginous ointment base or hydrocarbon ointment base 2) Absorption ointment bases 3) Water removable bases or water washable base 4) Water soluble base 1) Oleaginous ointment base or hydrocarbon ointment base (water in Oil) These bases have following properties. a) Small amount of aqueous component can be incorporated into these bases. b) These bases have emollient effect. c) These bases are difficult to wash off as these are w/o type of bases. d) These bases do not dry out and prevent drainage on oozing areas and prevent evaporation of cutaneous secretion and act as occlusive dressing. e) These bases keep the medicament in prolonged contact with skin. f) These bases may not release the medicine g) May get rancid. 3 Oleaginous ointments are preferred for dry, chapped skin in the environment of low humidity because of its occlusive properties Examples: A) petrolatum (Soft paraffin) - semisolid hydrocarbons obtained from petroleum - there are two kinds: 1- Yellow soft paraffin: Pale yellow, free of odor, melting point 38-56°C 2- white Soft paraffin White, odorless, melting point 38-56°C ** white paraffin used when the medication is white or colorless. ** both white and yellow soft paraffin have no noticeable action on the skin and not absorbed. ** they are suitable for epidermal preparations. ** in eyes ointment the yellow soft paraffin only used because it doesn’t irritate eyes. B) Hard paraffin: -solid hydrocarbon obtained from petroleum. - colorless or white, odorless mass. - used to harden or stiffen ointments. C) Liquid paraffin (liquid petrolatum, white mineral oil): - Consist of mixture of liquid hydrocarbons and obtained from petroleum. - colorless, transparent, tasteless, and odorless. - insoluble in water and alcohol but soluble in ether and chloroform. -used with soft and hard paraffin to get desired consistency of ointment. 4 2) Absorption ointment bases - they are hydrophilic character - they are anhydrous bases which can absorb a large amount of water but keep their ointment like consistency. These bases categorize into two groups: A) Permit the incorporation of aqueous solution with the formation of water in oil type of bases. B) These are already w/o type of bases and permit the additional amount of aqueous solution. These bases have following properties. a) Useful as emollients b) Difficult to remove from skin Advantages of absorption bases: 1- compilate with most medication. 2- heat stale 3- could be use in their anhydrous form or emulsified form. 4- they absorb a large quantity of water. Disadvantages: Possess undesirable properties of greasy difficult to remove from skin but it is more easily to remove than oily bases. Example: a) Anhydrous lanolin (Wool Fat): - obtained from wool of sheep - insoluble in water but can absorb about 50%of its weight of water - used in ointments when high proportion of water incorporated. 5 - Because it is sticky in nature it does not used alone. b) hydrous lanolin (Wool Fat): - Obtained from wool sheep - yellowish white ointment like, has specific odor. - insoluble in water but soluble in ether and chloroform. - Hydrous wool fat is a mix of 70%w/wool fat and 30% purified water, so it is w/o emulsion. c) Wool Alcohol: - Obtained from wool fat y treating it with alkali. - Used as an emulsifying agent for preparation of w/o emulsion& used to absorb water in ointment bases. d) bees wax - purified wax obtained from honeycomb of bees. - there are two types of yellow bee’s wax and white bees wax (obtained by bleaching of yellow bees wax). - use to as stiffening agent in pasts and ointments. e) Cholesterol: - obtained from animals - increase the incorporation of aqueous in oils and fats. 3) Water removable bases or water washable base (emulsifying bases) - These bases are also called as oil in water type of emulsion bases. -These are water washable bases. Mostly these bases are preferred for cosmetic purpose. - Having cream like consistency 6 - O/W bases divided to: 1- positive charge: cetrimide (not compilate with negative ions) 2- negative charge: - emulsifying wax (lauryl sulfate, Br salts) 3- non-charge: cetomacrogol (PEG) incompatible with phenol compounds - Humectant could be added to the water phase like glycerin, sorbitol, carbowax Advantages of these base are: a) Some medicament is more effective in these bases. b) These bases may be diluted with water. - Example : Vanishing cream. 4) Water soluble base These bases are greaseless bases contain only water-soluble ingredients. Advantages of these bases are: a) These are completely water washable. Example: - polyethylene glycol polymers (PEG), carbowax are water soluble, non- volatile, inert substance, not hydrolysis, not support the bacterial growth or mold growth. - PEG available according to their molecular weight in liquid, semisolid and solid. Those polymers having the molecular weight between 200 to 1000 are liquids & those having M.W higher than 1000 are wax like solids. - Release medication rapidly. 5)Other Bases: Animal fats and plant fats ▪ Spermaceti (obtained from whale heads ▪ Carnauba wax (obtained from palm leaves 7 Table 1: Properties of ointment base Factors affecting the selection of the appropriate base: 1) Desired release rate of the drug substance from the ointment base. 2) Desirability of topical or percutaneous drug absorption. 3) Desirability of occlusion of moisture from skin. 4) Stability of the drug in the ointment base. 5) Effect, if any, of the drug on the consistency or other features of the ointment base. 6) Desirability for easy removal of base by washing with water. 7) Characteristics of the surface to which it is applied. ADDITIVES IN OINTMENT PRESERVATIVES: The antimicrobial compounds and their quantities should be carefully decided upon if the same are to prevent contamination, deterioration or spoilage of ointment bases by bacteria and fungi. The first consideration in 8 selection is the irritancy or toxicity of the compound to the tissue to which the ointment is to be applied. For instance, methyl and propyl parabens are irritant to nasal passages. Boric acid may also get absorbed through the nasal passages in sufficient amounts to be toxic. Quaternary ammonium compounds or phenylmercuric nitrates are better tolerated by nasal tissues. On occasions the plastic containers or rubber closures may 'take up' some amount of the preservatives thus reducing their availability for antimicrobial action. Sometimes the preservatives get complexed by other ingredients and are thus not available in sufficient concentration for antimicrobial action. In the presence of tween 80, methylparaben, benzalkonium chloride, benzoic acid etc. get inactivated to appreciable extents. The bactericidal activity also depends upon partition coefficient of the antimicrobial compound between aqueous and oily phases. If both the phases are to be protected additional amounts may be needed. ANTIOXIDANTS: Antioxidants should be included to avoid the oxidative degradation of the base. It may be more desirable to select two antioxidants instead of one. The concentration of antioxidants depends upon their partition coefficients between the aqueous and oil phases if both the phases are present in a base. Generally, compounds like butylated hydroxy anisole, propyl gallate, nor dihydroguaiaretic acid etc. are used in ointment bases. CHELATING AGENTS: Whenever it is anticipated that traces of metallic ions are likely to catalyze oxidative degradations small amounts of substances such as citric acid, maleic acid, phosphoric acid etc. may be added to chelate the metallic ions. PERFUMFES: Most ointments have a pleasant smell imparted by incorporation of selected perfume blend. The selection of a perfume blend is a very critical. The blends selected must be compatible with other ingredients. Essential oils from plant materials used as perfumes. The floral group blends such odors as jasmine, 9 rose, lily and gardenia. The woody is group characterize by sandal wood, cedar wood. METHOD OF PREPARATION OF OINTMENT: Preparation of ointment mainly depend on nature of ingredients. Ointments are mainly prepared by two general method: a) Incorporation(trituration) b) Fusion the following general aspects should be considered. (i) If insoluble substances are to be incorporated in the ointment base then they should be in impalpable powder form. (ii) For efficient incorporation of insoluble substances, they should first be levigated with a little quantity of base to form a smooth cream and then incorporated into the remainder of the base. (iii) Water-soluble salts are best incorporated by dissolving them in a small quantity of water and then incorporating in the base. (iv) Drugs soluble in ointment bases may also be incorporated by fusion (melting the highest melting point ingredient of the base and mixing the medicament into it). Remaining ingredients are then added and mixed by stirring. a) Incorporation This can be achieved using. (I) Mortar and pestle, (ii) Ointment slab and spatula, and (iii) An ointment mills. In this finely subdivided insoluble medicament are evenly distributed by grinding with a small amount of the base followed by dilution with gradually increasing amounts of the base. 10 b) Fusion In this method the ingredients are melted together in descending order of their melting points and stirred to ensure homogeneity. EVALUATION PARAMETERS OF OINTMENT The different methods of evaluation of ointment are: (1) Physical methods ▪ Test of rate of absorption ▪ Test of non-irritancy ▪ Test of rate of penetration ▪ Test of rate of drug release ▪ Test of rheological properties ▪ Test of content uniformity (2) Microbiological methods ▪ Test of microbial content 11  ▪ Test of preservative efficacy Examples of ointments: boric acid 10% ▪ boric acid(borax) 100g ▪ liquid paraffin 50g ▪ simple ointment 850g ZnO ointment 20% - ZnO 200g - liquid paraffin 150g - simple ointment 650g White field ointment ▪ benzoic acid 60g ▪ salicylic acid 30g ▪ polyethylene glycol 1000g Ophthalmic ointments Definition Ophthalmic ointments are sterile, homogeneous, semi-solid preparations intended for application to the conjunctiva or the eyelids. They are usually prepared from non-aqueous bases, e.g. soft paraffin (Vaseline), liquid paraffin, and wool fat. They may contain suitable additives, such as antimicrobial agents, antioxidants, and stabilizing agents. All materials used in the ophthalmic ointment should be impalpable to avoid eye discomfort and possible irritation. Advantages: - Longer contact time. - Flexibility in drug choice. - Improved drug stability and greater storage stability. 12 Disadvantages: - Sticking of eyes lids. - Blurred vision. - Poor patient compliance - Interfere with the attachment of new corneal epithelial cells to their normal base. - Matting of eyelids MANUFACTURE There are a number of important aspects that require assessment in the manufacture of ophthalmic products. these include the following. Sterility Tonicity pH and buffering Inherent toxicity of the drug Need for a preservative Solubility Stability in an appropriate vehicle Viscosity Aseptic felling Packaging and storage of the finished product. Water for Injection (WFI) should be used in the manufacture of aqueous ophthalmic preparations. Organoleptic inspection Evidence of physical instability is demonstrated by: - a noticeable change in consistency, such as excessive "bleeding" (separation of excessive amounts of liquid). - formation of agglomerates or grittiness. 13 - discoloration. - emulsion breakdown. - crystal growth. - shrinking due to evaporation of water. - evidence of microbial growth. Uniform consistency Ophthalmic ointments should be of uniform consistency. When a sample is rubbed on the back of the hand, no solid components should be noticed. Containers Ophthalmic ointments are normally supplied in small, sterilized, collapsible tubes fitted with a tamper-evident applicator. The containers or the nozzles of the tubes are shaped so that the ointment can be applied without contaminating what remains in the tube. The content of such a container is limited to not more than 5 g of the preparation. Suitable single-dose containers may also be used. Creams Definition: Creams are defining as “a semisolid dosage form containing one or more drug substances dissolved or dispersed in a suitable base”, they are lighter than ointments. Creams are formulated to provide preparation that are essentially miscible with skin secretion. they are intended to be applied to the skin or certain mucous membranes for protective, therapeutic, or prophylactic purposes especially when occlusive effect is not necessary. Creams are semisolid emulsions of either O/W (aqueous cream) or W/O (oily cream) type. 14 O/W are water washable and can be easily removed from the skin and clothing but have tendency to bacterial growth therefore a preservative should be added. In preparing creams hygiene precaution must be considered. Should be stored in well close container to prevent the evaporation & contamination, stored in cool place. USES: The provision of a barrier to protect the skin - This may be a physical barrier or a chemical barrier as with sunscreens. - To aid in the retention of moisture (especially W/O creams) - Cleansing & Emollient effects - As a vehicle for drug substances such as local anaesthetics, anti- inflammatories (NSAIDs or corticosteroids), hormones, antibiotics, antifungals or counter-irritants. TYPES of creams: A cream may be water in oil or oil in water depending on the emulsifying agent used. 1- oil-in-water (O/W) creams which are composed of small droplets of oil dispersed in a continuous phase (Aqueous cream) Contains: synthetic waxes e.g., (cetomacrogols & macrogols) Properties: ▪ Causes rapid absorption & penetration. ▪ Thin, white & smooth consistency ▪ More comfortable and cosmetically acceptable as they are less greasy and more easily washed off using water. Example: vanishing cream 2- water-in-oil (W/O) creams which are composed of small droplets of water dispersed in a continuous oily phase. 15  - W/O cream: oily Contains: emulsifying agents of natural origins (bees wax, wool alcohols, wool fat) properties: ▪ Creamy, white or translucent and stiff. ▪ More difficult to handle but many drugs which are incorporated into creams are hydrophobic and will be released more readily from a W/O cream than an O/W cream ▪ more moisturizing as they provide an oily barrier which reduces water loss from the stratum corneum, the outermost layer of the skin. e.g.: Moisturizing & Cold cream The requirements of a cream are as follows: *It should liquefy at body temperature. *Its viscosity should be low enough to permit easy spreading but high enough to retain in suspension particles of dirt and insoluble foreign matter. *It should penetrate the epidermis (via natural openings) and contain enough light oils to permit flushing the pores. *It should be an emulsion type with a small percentage of water. Evaluation of creams: Methods of Evaluation 1) Rheology test 2) Determination of PH 3) Sensitivity test (Patch Test) 4) Photo Patch test 5) Peroxide Stability test 6) Test for thermal stability 7) Irritancy test 16 8) Drug Content Uniformity Method of preparation: TRITURATION: -Used for finely divided insoluble powder particles or liquids -insoluble powder are added by geometric dilution -Liquids are added by making well in center. -Air pocket formation avoided. -Involved the use of glass slab when small quantities are used -Mortar and pestle used when we have large quantities. LEVIGATION: ▪ Incorporation of insoluble coarse particles. ▪ Also known as “Wet grinding”. ▪ insoluble coarse powder is rubbed with molten base or liquid or a semi solid base. ▪ A considerable shearing force is applied to avoid grittiness. ▪ All equipment & spatula to be cleaned by IMS. (70% ethanol should be used) ▪ Determine the miscibility of the substances being incorporated. ▪ Melt the fatty base. substances with the highest melting point to be melt first. These bases then cooled to 60°C * Hygiene (aseptic condition) Cold cream: Water-in-oil (w/o) creams which are composed of small droplets of water dispersed in a continuous oily phase. More difficult to handle but many drugs which are incorporated into creams are hydrophobic and will be released more readily from a w/o cream than an o/w cream. More moisturizing RX. -Spermaceti 125g White bees wax 120g 17 Liquid paraffin 560g Sodium orate 5g Purified water 190g Vanishing cream: oil-in-water (O/W) creams which are composed of small droplets of oil dispersed in a continuous phase. More comfortable, less greasy and more easily washed off with water. Emulsifying agents (bees wax, wool alcohols, wool fat). RX. Stearic acid 15g White bees wax 2g White soft paraffin 8g Triethanolamine 1.5g Propylene glycol 8g Purified water 65.5g Difference Between Ointment and Cream Ointments creams consists of 80 percent oil and 20 percent Emulsion W/O or O/W water (oily base) spreadability factor (not be able to spread) cover large areas. Greasier Less greasy thicker consistencies lighter consistencies not easily absorbed by the skin quickly absorbed by the skin 18 Difference Between Cold Cream and Vanishing Cream: Cold cream Vanishing cream W/O O/W Used at night (night cream) Used at daytime (day cream) Not well absorbed. Well absorbed Contains 45-80% of its weight’s Contains 15-25% of its weight’s oily agents. oily agents Water base not alkaline Water base are alkaline Humectant not added. Humectant added PASTES Definition: Pastes defined as semisolid preparations used externally incorporating a high percentage of insoluble particulate solids (fine powder), sometimes as much as or more than 50%. The use of this high amount of insoluble particulate matter renders a thickness and stiffness to the system more than ointments but less greasy. Because of the stiffness, they remain in place after application and are used effectively to absorb serous secretions. - Pastes as such are not suited for application to hairy parts of the body. - Examples of insoluble ingredients serving as the dispersed phase include starch, zinc oxide, and calcium carbonate. 19 - Pastes make good protective barriers. In addition to forming an unbroken film, pastes also absorb and neutralize certain harmful chemicals before they reach the skin surface. This last feature is attributed to the presence of insoluble particulate matter within the paste formulations. For example, for the treatment of diaper rash, when spread over the baby’s bottom, the pastes absorb irritants formed by bacterial action on urine. - Pastes also provide a protective layer over skin lesions and, when covered with suitable dressings, prevent excoriation of the patient’s skin by scratching. Pastes afford emollient action as do ointments. In addition, the water- impermeable film formed on application is opaque and thus can often serve as a sunblock. - Pastes are less greasy than ointments. - The ability to absorb exudates by nature of the powder or other absorptive components. Zinc Oxide 25% BP RX. Zn oxide 250g Starch 250g White Vaseline 1000g Liniments Definition: Are alcoholic or oleaginous solutions or emulsions of various medicinal substances. -Alcoholic liniments are used generally for their rubefacient 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 are intended for external application and should be so labeled. 20 -They are applied with rubbing to the affected area, the oil or soap base providing for ease of application and massage. -Liniments should not be applied to skin that are bruised or broken. Dispended in colored bottles, labeled for external use only, stored in tightly closed container in cool place. - used in the treatment of Sciatica, Fibrositis, Neuralgia 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. Counter irritant: A medicine applied locally to produce superficial inflammation in order to reduce deeper inflammation. Camphor liniment 20% USP RX. Camphor 2oog Cotton oil 800g COLLODIONS - Are liquid preparations containing pyroxylin (a nitrocellulose) in a mixture of ethyl ether and ethanol (4% W/V pyroxylin in 3:1 mixture of ether and alcohol). - 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. - Flexible Collodion, USP is prepared by adding 2% of Camphor and 3% castor oil to the Collodion. - 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. GLYCERITES 21 - Glycerin’s or glycerites are solutions or mixtures of medicinal substances in not less than 50% by weight of glycerin. - Most of the glycerin’s are extremely viscous. - Glycerin is a valuable pharmaceutical solvent forming permanent and concentrated solutions. - As noted under Otic Solutions, glycerin alone is used to aid in the removal of cerumen. - Glycerin’s are hygroscopic and should be stored in tightly closed containers. Examples: Ichthammol glycerin 10% Phenol glycerin 16% Tannic acid glycerin 20% SUPPOSITORY Definition: It is semi-solid or solid dosage form meant to be inserted into Body cavity like rectum, urethra, vagina, where they melt or soften to release the drugs and produce their local or systemic effect. It is coming under semi solid preparation because it is prepared by melting all ingredients (bases and other additives along with active ingredient). All types of suppositories are melting at normal body temperature after introducing in body cavity and produce their effect. Advantages and disadvantages of Suppository: ADVANTANGE: ▪ It is the alternated dosage form for drugs which have less bioavailability when it is taken orally. ▪ Drugs having bad odour and taste can be used in suppository form. ▪ It is suitable for unconscious patients which cannot taken drugs orally. ▪ It is suitable for drugs which produce irritating effect in GIT. 22  ▪ It is suitable for infants and old people who find difficulty in swallowing of drugs. ▪ It is suitable for the drugs which are destroyed by portal circulation. DISADVANTAGE: ▪ The manufacturing process is more difficult as compares other formulation. ▪ The drugs which cause irritation to mucous membrane cannot be administrated by this form. ▪ It is inconvenient for adults. ▪ The most important problem is storage condition because it stored at low temp. (10-20 0c). Other than the bases get liquefied. ▪ Leakage problem is also most critical problem along with suppository after introducing in body cavity at elevated temperature. TYPES OF SUPPOSITORY: (A)RECTAL SUPPOSITORY- ▪ It is inserted in the rectal. ▪ The weight of suppository used in children is about 1g and in adult about 2g. ▪ The shape of suppository used in rectal is torpedo shape. The length is about 3 cm. (B) URETHRAL SUPPOSITORY (bougies) ▪ The weight of this type of suppository is about 2g and 60-75 mm long in Females. ▪ Those intended for males weigh 4 gm each and are 100-150 mm long. ▪ It is available in pencil shape. (C) VAGINAL SUPPOSITORY (pessaries) ▪ It is in oviform shape. ▪ It is about 3-5g in weight. ▪ It is containing the drugs which are used in treatment of the infections of female genitourinary tract and meant for contraception. 23  ▪ It is containing the combination of polyethylene glycol of different molecular weights as suppository bases. (D) NASAL SUPPOSITORY ▪ These suppositories are meant for introduction into nasal cavity. ▪ It is about 1g in weight. ▪ The glycero- gelatin is used as suppository bases. (E) EAR CONES ▪ It is also known as AURINARIES. ▪ These are meant for introduction into the ear. ▪ It is cylindrical in shape. ▪ It is about 1g in weight. IDEAL PROPERTIES OF SUPPOSITRIES BASES: ▪ Bases should be existing in solid form at room temperature and good in appearance. ▪ It should not irritate and produced inflamed sensation in body cavity. ▪ It should be stable during storage condition, No change in colour, shape, odour. ▪ It should retain hardness and shape during handle, and not stick to the mould. ▪ It should melt at body temperature. ▪ It should release the drug rapidly. ▪ It should not react with drugs and additives. ▪ It should have good emulsifying and wetting property. ▪ It shouldn’t decompose when heated during preparation. ▪ It should have acid value less than 0.2 or zero. ▪ It should have iodine value less than 7. ▪ It should have saponification no. range between200-245. TYPES OF SUPPOSITORY BASES: (1) HYDROPHILIC BASES: (A) EMULSIFYING BASES 24 These are synthetic bases. 1) Massa Estrinum (Adeps Solidus) - This is a mixture of the monoglycerides, diglycerides, and triglycerides of the saturated fatty acids. - Several grades are available to suit climate changes. -They possess a melting range of 33 to 38°C. 2) Massupol - This consists of glyceryl esters, mainly of lauric acid, to which a very small amount of glyceryl monostearate has been added. - They exhibit a melting range of 34 to 37°C and are suitable for mass production. 3) Witepsol - They consist of hydrogenated triglycerides of lauric acid with added monoglycerides. - They are suitable for formulation of eutectic mixtures and tropical suppositories. E.g. Witepsol H 15 disintegrates almost as fast in the rectum as cocoa butter. The melting times were 4 minutes for cocoa butter, 6 minutes for Witepsol. - Shouldn’t be ice-cooled so it may brittle or fracture Advantages of Emulsifying Bases 1. The physical characteristics are not altered by overheating (not get rancid). 2. They do not adhere to the mould, which needs no lubricant. Indeed, lubrication is a disadvantage as it may spoil the glossy appearance of the product. 3. They solidify rapidly. 4. As they all contain an emulsifying agent, they can absorb fairly high 25 percentages of aqueous liquids. 5. The emulsifying agents are monoglycerides which form water-in-oil emulsions and this would seem more rational than the use of oil-in water emulsifying agents. Difference Between Witepsol and Cocoa Butter Suppository: 1. Witepsol enables the suppository to ascend more in the rectum before disintegration, while a cocoa butter suppository, melting more rapidly at a lower temperature and more likely to cause leakage. 2. Unlike cocoa butter, the Witepsols are not subject to structural changes at temperatures above their melting points. 3. They absorb water, due to the presence of glycerol mono as emulsifiers. The interval between softening and melting is small and the masses congeal just one or two degrees below their softening points. (B) WATER SOLUBLE BASES (1) GLYCERO-GELATIN- - This occurs as a gel - It is a mixture of gelatin, glycerol, and water. - According to BP the composition of the bases – GELATIN- 14% w/w GLYCEROL– 70% w/w WATER– QS - For gets a stiff mass, the quantity of gelatin should be increased to 32.5% and reduced the glycerol to 40%. ADVANTAGES ▪ Suppository prepared by glycero-gelatin bases are strong and translucent unlike cocoa butter suppositories. ▪ This base is dispersing slowly in the body cavity fluids and provides prolonged release and action of drugs. 26 DISADVANTAGES ▪ It absorbs moisture and promotes microbial growth, so this reason preservatives are used. ▪ The bases are show incompatibility with tannic acid and proteins. precipitants due to the gelatin. ▪ It causes dehydration and irritation of rectal mucosa. ▪ It exerts undesirable laxative action. ▪ It requires special storage condition at about 10-15 0c. ▪ Handling and manufacturing of these type of suppository are difficult. (2) POLYETHYLENE GLYCOL (MACROGOLS (PEG)) - It is also called as PASTONALS (GERMANY), CARBOWAXES (U.S). - They are long chain polymers of ethylene oxide. - They found in liquid and solids (Liquids have molecular weight about 200- 600 and solid have molecular weight about more than 1000). - Their physical properties can be varied by suitable admixture of high and low polymers. High polymers give hard products that disintegrate and release their drug slowly. Softer, less brittle preparations that disperse and liberate their drug more quickly are obtained by mixing high with either medium or medium and low polymers or by adding plasticizers. - They melt at 37-61°C - The PEG suppositories can be prepared by both moulding and cold compression methods. ADVANTAGES ▪ This base is thermostable: The mixtures have melting point above 42oC. Hence, cool storage is not required, they are satisfactory for use in hot climates, and administration is easy because they are not slippery to handle. ▪ Because of this high melting point, they do not melt in the body but gradually dissolve and disperse, freeing their medication slowly and providing longer action than fatty bases. 27  ▪ It does not support microbial growth. ▪ It does not move out from body cavity after introducing. ▪ It has good water absorbing capacity. ▪ It is chemically stable, and it does not get degraded or hydrolyzed. ▪ Products have clean smooth appearance. ▪ It does not stick to the mould since they contract on cooling. DISADVANTAGES ▪ They are hygroscopic, so careful storage is required and could cause irritation for mucous membrane of the rectum. ▪ Its good solvent properties can result in retention of the drug in the liquefied base in the body with consequent reduction in therapeutic activity. ▪ Products sometimes fracture on storage, particularly if they contain High solubility of macrogols which can lead to a super saturated solution in the water and subsequent crystallization and this the mass granular and brittle. ▪ Crystal growth of certain medicaments may occur particularly if they are partly in solution and partly in suspension in the base. This makes the product brittle and crystals may be irritating because they are large and takes longer time to dissolve. ▪ They are incompatible with bismuth salts, tannins and phenol. ▪ They dissolve certain plastics necessitating care in choosing containers. (2) LIPOPHILIC BASES (Oily Bases) (a) COCOA BUTTER (Theobroma oil) - It is natural triglyceride obtained from seeds of Theobroma Cocoa. - Among all fatty acid about 40% are unsaturated fatty acid. - It can exist in more than one crystalline form or exhibits polymorphism. - At room temperature, it is yellowish- white with a paint, chocolate like odour. 28 - It consists of a mixture of ester of oleic acid, palmitic acid, stearic acid and other fatty acid with glycerol. - Its melting point 30-35°C, to avoid melting during preparation we should add bees wax, glyceryl esters - It’s widely used as suppository base because it melts at body temperature. ADVANTAGE ▪ It is liquified readily on warming and sets rapidly on cooling. ▪ It has emollient effect which is useful to relieve inflammation. ▪ It shows good release of water-soluble drugs. ▪ It does not cause irritation in mucous membrane. DISADVANTAGES ▪ It is susceptible to rancidification, so it should be stored in dry place away from light and should overheating during preparation. ▪ It gives soft suppository when formulated along with chloral hydrate, phenol, volatile oil, which have lower melting point. ▪ The physical characteristic of the base could change due to overheating. ▪ It required extra lubricant during pouring in moulds. ▪ Sometimes leakage may be occurred. ▪ Couldn’t absorb liquids and secretions. (B) Emulsified Theobroma oil - Used as base when large quantities of aqueous solution incorporated - It forms by adding the following ▪ 5% glyceryl monostearate ▪ 10% Lanette wax ▪ 2-3% Cetyl alcohol ▪ 4% bees wax ▪ 12% Spermaceti (C) Hydrogenated oils 29 Example: Cocoa nut oil, palm oil, pea oil, synthetic fat bases Advantages over the Theobroma oil: ▪ Overheating doesn’t affect solidifying ▪ Resistant to oxidation. ▪ Emulsifying and water absorption are good. ▪ Lubrication of mould is not required. ▪ They are colorless-odorless but synthetic fat bases have disadvantages. ▪ Rapid cooling ▪ When melting they are more fluid than cocoa butter and to solve this problem, we should add thickening agent (Mg stearate, bentonite) Additives used in suppositories: ANTI OXIDANTS - It is protecting the drugs and bases from getting degraded due to oxidation. - These are commonly used in all types of suppositories. EXAMPLES: ▪ Ethyl or propyl gallate ▪ Ascorbic acid ▪ Butylated hydroxy anisole (BHA) ▪ Butylated hydroxy toluene (BHT) ▪ Hydroquinone ▪ Tocopherol EMULSIFYING AGENTS These are increase the water absorbing capacity of fatty bases. EXAMPLES ▪ Poly sorbates (TWEEN 61) ▪ Wool alcohol 30  ▪ Wool fats HARDENING AGENTS These are involved in those formulation where the melting point of the bases is decrease by the drugs. These are the agents which are used to bring the melting point to normal. EXAMPLES ▪ Beeswax ▪ Macrogols at high molecular weight. PRESERVATIVES These are the agents which are used in prevent the growth of microbial in suppository which contains water soluble bases. EXAMPLES ▪ Chlorocresol ▪ Methyl paraben ▪ Propyl paraben THICKENING AGENTS These are the agents which are used to increases the viscosity of molten bases and prevent sedimentation of suspended in solid bases. EXAMPLES ▪ Aluminum monostearate ▪ Colloidal silica ▪ Magnesium stearate ▪ Stearyl alcohol PLASTICIZERS These are the agent which are used to improved flexibility of suppositories. It is also used to make the less brittles to suppositories. EXAMPLES 31  ▪ Castor oils ▪ Glycerin ▪ Glycol ▪ Tween 80 ▪ Tween 85 METHODS OF PREPARATION OF SUPPOSITORIES: Molds used in the preparation of suppositories. Molds are the metals devised with different shape, it is consisting of two or more parts which are joined with a screw. Inside the molds the cavities are made up of aluminum, brass, stainless steel, plastics. Molds have different capacities like 1,2,4,8gm. LUBRICANTS USED IN MOLDS ▪ Cocoa butter and glycero-gelatine bases are required lubrication of molds. ▪ This is preventing sticking of bases to the wall of molds cavity and it is also useful in easy removal of suppositories from the molds. ▪ The lubricants are form a film between the wall of mold cavity and base of suppositories, so it prevents adhering of bases to the molds. ▪ The nature of lubricants should be different from nature of bases. EXAMPLES (1) For cocoa butter bases: Alcohol (90%) 50ml, Glycerol 10ml, Soft soap10 gm. (2) Liquid paraffin (3) Arachis oils Methods of Preparation 1. Hand molding 32 - It is the oldest and simplest method of suppository preparation and may be used when only a few suppositories are to be prepared in a cocoa butter base. - It has the advantage of avoiding the necessity of heating the cocoa butter. - A plastic-like mass is prepared by triturating grated cocoa butter and active ingredients in a mortar. The mass is formed into a ball in the palm of the hands, then rolled into a uniform cylinder with a large spatula or small flat board on a pill tile. The cylinder is then cut into the appropriate number of pieces which are rolled on one end to produce a conical shape. * Effective hand rolling requires considerable practice and skill. * The suppository "pipe" or cylinder tends to crack or hollow in the center;" especially when the mass is insufficiently kneaded and softened. 2. Compression Molding - It is a method of preparing suppositories from a mixed mass of grated suppository base and medicaments which is forced into a special compression mold. - The method requires that the capacity of the molds first be determined by compressing a small amount of the base into the dies and weighing the finished suppositories. When active ingredients are added, it is necessary to omit a portion of the suppository base, based on the density factors of the active ingredients. 3. Fusion Molding - It involves first melting the suppository base, and then dispersing or dissolving the drug in the melted base. - The mixture is removed from the heat and poured into a suppository mold. - When the mixture has congealed, the suppositories are removed from the mold. 33 * The fusion method can be used with all types of suppositories and must be used with most of them. The PACKING OF SUPPOSITORIES (1) DISPOSABLE MOLDS- These are meant for packing the suppositories. These are made of plastics or aluminum foil. (2) MODERN PACKING MACHINE It is consist of roll of packing material which cut in the required size and rolled around each suppository. STORAGE CONDITION ▪ It is stored at 10-15 0c. ▪ Used airtight container. ▪ The suppositories with cocoa butter stored at < 30 0c. ▪ The suppositories with glycero-gelatin stored at < 35 0c. EVALUATION OF SUPPOSITORIES ▪ Test of appearance (size, shape) ▪ Test of physical strength ▪ Test of dissolution rate ▪ Test of melting range ▪ Test of softening time ▪ Test of uniformity of drug content STABILITY PROBLEMS OF SUPPOSITORIES: BLOOMING: During storage, cocoa butter suppositories sometimes show deposition of white powder on the surface. This result in suppositories of disagreeable appearance. HARDENING: During storage, the suppositories made of fatty bases become hard. It is occurring due to crystallization of bases. This also effect the melting and rate of absorption of drugs. 34 Chapter two Solid state Solid is one of the three fundamental states of matter (the others being liquid and gas). In solids molecules are closely packed. It is structurally rigid and resistance to changes of shape or volume. Unlike liquid, a solid object does not flow to take on the shape of its container, nor does it expand to fill the entire volume available to it like a gas does. The following are the characteristic properties of the solid state: (i) They have definite mass, volume and shape. (ii) Intermolecular distances are short. (iii) Intermolecular forces are strong. (iv) Their constituent particles (atoms, molecules or ions) have fixed positions and can only oscillate about their mean positions. (v) They are incompressible and rigid. Classification of solids: Solids can be classified as: crystalline or amorphous based on the nature of order present in the arrangement of their constituent particles. A crystalline solid usually consists of a large number of small crystals, each of them having a definite characteristic geometrical shape. In a crystal, the arrangement of constituent particles (atoms, molecules or ions) is ordered. It has long range order which means that there is a regular pattern of arrangement of particles which repeats itself periodically over the entire crystal. Sodium chloride and quartz are typical examples of crystalline solids. An amorphous solid (Greek amorphous = no form) consists of particles of irregular shape. The arrangement of constituent particles (atoms, molecules or ions) in such a solid has only short-range order. In such an arrangement, a regular and periodically repeating pattern is observed over short distances only. Such portions are scattered and in between the arrangement is disordered. 35 The structure of amorphous solids is similar to that of liquids. Glass, rubber and plastics are typical examples of amorphous solids. Due to the differences in the arrangement of the constituent particles, the two types of solids differ in their properties. CRYSTALLINE SOLIDS AMORPHOUS SOLIDS They have a regular arrangement They do not have a regular of atoms, molecules or ions. arrangement of atoms, molecules or ABCABCABCABC ions.ACBBACCBBBA Definite characteristic geometrical Irregular geometrical shape shape Have Sharp Melting point Gradually soften over a range of (because all bonds are equally temperatures (because all bonds are strong not equally strong) Have lower solubility Have higher solubility Have higher stability Have lower stability They are known as true solids They are known as pseudo solids. They are anisotropic, i.e., they They are isotropic, i.e, they have have different directions for same directions for different physical different physical properties properties. Examples are NaCl, ice LiCl, Examples are rubber, glass, wax, methanol, diamond, etc. plastic, etc. Crystal: is the smallest unit in the solid state can be: 36 a- molecules(naphthalene) b- ions (NaCL) crystal differ in shape can be either triclinic, cubic, … Polymorphism is the ability of substance to exist in more than one crystal form (two or more), this give rise to differences in physical properties of material (solubility, melting point,…) e.g. riboflavin we use the more soluble crystals to increase absorption of it. Factors affecting polymorphism: 1- solvent used 2- temperature 3- additive substances Crystallization: Is the process of achieving crystals out from solution Mechanism of crystallization: The solution must e saturated to get the crystal out the solution when it became supersaturated and this is done by: 1- lower temperature of the solution 2- evaporate solvent 3- change PH 4- chemical reaction 5- the formation of crystals from solution involves two steps: a- creation of crystalline nuclei b- the growth of these nuclei into crystals How to get nuclei: a- introduction of minute crystals of the dissolved substances, this operation is known as seeding 37 b- using thread, crashing the glass of the beaker, (rough surface). c- the driving force for nucleation and growth of crystals is the super saturation of the solution. d- large crystals obtained as a result of slow cooling of the solution just above saturation point, due to the reduction in number of spontaneous nuclei, so crystals grow from these few nuclei e- raid cooling increase degree of supersaturation resulting in large number of nuclei and small crystals. Factors affecting crystallization: Factor Number Size of Shape of crystals of crystals crystals 1-cooling velocity - rabid large small - slow few large 2- Stirring (attrition) Large Small irregular 3- presence of impurities a- solid inactive and -Increase Crystallization insoluble b- salt impurities - Increase Crystallization c- soluble impurities - decrease Crystallization d- alcohol in water -Increase Crystallization e- Alcohol in alcohol -decrease Crystallization 4- Viscosity: -Higher viscosity Large Higher growth of nuclei - lower viscosity small smaller growth of nuclei 5- solvent used a- water - result in hydrate crystal 38 b- other solvent - result in non-aqueous (ethanol) solvent E.g. theophylline present in two forms a- hydrate: solubility 6.5mg/L b- non-aqueous solvate: solubility 12.5mg/L Effect of polymorphism on stability of drugs: Polymorphs of a pharmaceutical solid may have different physical and chemical solid-state properties. The most stable polymorphic form of a drug substance is often used because it has the lowest potential for conversion from one polymorphic form to another while the metastable form may be used to enhance the bioavailability. Depending upon relative stability there are two form of polymorphs 1) stable form 2) meta form. Stable form having least aqueous solubility. Meta form having high aqueous solubility. Since the rate of conversion to the more stable form is often rapid when mediated by the solution phase, the less stable polymorph with the grater apparent solubility dissolves, while the more stable polymorph with the lower apparent solubility crystallizes out upon sanding. One polymorph may convert to another during manufacturing and storage, particularly when a metastable form is used. Depending upon their relative stability, one of the several polymorphic form will be physically more stable than others. Stable polymorph represents the lowest energy state, has highest melting point and least aqueous solubility. Metastable form represents the higher energy state, have lower melting point and high aqueous solubility. Metastable form converted to the stable form due to their higher energy state. 39  Metastable form shows better bioavailability and therefore preferred in formulations. Dosage form Problem Solution 1- Solution: e.g. Amorphous form 1- add co- Chloramphenicol has spontaneously changes solvent(alcohol)to prevent many forms into the stale form (crystal), drug precipitation solubility decrease 2- use crystals of moderate solubility and stability 2- Creams and During storage The substance(drug) Ointments polymorphism may occur should be very fine and and cause skin irritation homogenous to prevent skin irritation and deterioration of drug 3- Suppositories e.g. If heated more than its Don’t heat over the melting Cocoa butter melting point it does not point freeze at the same point and need much lower temp to freeze at it 4- Suspension Cake formation (can’t be removed by shaking),due to overgrinding of drug material some substance change from fine powder into crystal Causes of crystal growth: a- temp. fluctuation - avoid temp. fluctuation b- solid present in - use another crystal form metastable state which has with moderate solubility greater solubility than stale and stability state 40  c- small crystals have a -Use the particle of narrow greater solubility than large size range crystals—supersaturation-- - addition of surface-active -crystallization agents d- change of crystal structure due to presence - Grinding solids in of dispersing solvent presence of dispersing fluid Dissolution is defined as the process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase. it reflects release rate of the drug and reflect absorption. Rate of dissolution is the amount of drug substance that goes in solution per unit time under standardized conditions. Drug dissolution process of solid dosages is theoretically described by Noyes–Whitney–Nernst equation. Describes the relationship between particle size, diffusion layer coefficient, and drug saturated solubility (Dissolution) The rate of change in concentration of dissolved material with time it directly proportional to the concentration difference between the two sides of diffusion layer. Smaller Particles dissolve faster (bigger A = bigger specific surface) Agitating the solution increases dissolution by clearing out the diffusion layer Increasing the temperature increased dissolution dm/dt = D x A x (Cs - C) / s dm/dt- is Diffusion rate s- is thickness of the diffusion layer 41 D - diffusion coefficient of solute A - surface area of solid undergoing dissolution Cs - concentration of solvate at saturation C - concentration of the drug in the bulk solution phase at time t Factors Affecting Dissolution Rate of solid drugs: 1- Cs: concentration of substance in the dissolution layer(saturated) affected by: a- PH can change dissolution rate, depending on the drug molecule e.g. Atropine (alkaline)—if change PH will precipitate. b- Salt addition react with substance and precipitate it. 2- C: concentration of drug in water C never equal Cs in the body, because drug that dissolved will absorbed to blood so Cs>C 3- A: surface area of solid Particles 4- D: distribution factor, depend on: a- chemical and physical properties of substances b- the viscosity of the external media increase viscosity will decrease D and so decrease dissolution 5- thickness of distribution layer, to decrease it, by stirring the substance. Also, it affected by particle size, agitation (stirring/shaking) and temperature. 42 Chapter Three Powder dosage forms Powders Definition: Powders are the solid dosage form of drug in fine state of division in dry form, intended for internal or external use. Powders can be administered singly (simple powders) or as a mixture of different medicinal powders (compound powders). Powders available in crystalline form or amorphous form Advantages 1- Good chemical stability compared with fluids. 2- Useful for bulky drugs with large dose. 3- Easy to swallow even in large bulk, especially if mixed with drink food (useful for stomach- tube feeding) 4- The smaller particle size of powders causes more rapid dissolution in body fluids, increases drug bioavailability, and decreases gastric irritation compared with tablets. 5- Less incompatibility than liquids. 6- Easier to carry than liquids. Disadvantages 1- Not suitable for drugs unstable in atmospheric conditions 2- Not suitable for bitter, nauseating, deliquesnt and corrosive drugs. 3- Inaccuracy of dose in case of bulk powder 4- Not suitable for volatile drugs. TYPES OF POWDERS 1) Divided powders - packets 43 - cachets - capsules 2) Undivided (Bulk) powders - dusting powder - effervescent powder OR 1- Bulk powders for internal use. 2- Bulk powders for external use. 3- Simple & compound powder for internal use. 4- Powder enclosed in cachets & capsule. 5- Compressed powders(tablets) Bulk powder: for external use, and it supplied non-potent drug. Supplied in cardboard, glass, or plastic container also, in sifter top container. Types: 1- dusting powder 2- Insufflations 3- Snuffs 4- Dentifrices Dusting Powder: These are meant for external application on to the skin and are generally applied in a very fine state of subdivision to avoid local irritation. Types: Medical Surgical 1) Medical dusting powders: They are used for superficial skin conditions; they should not be used for application to open wounds or application or broken skin. The label should clearly specify this point. We need not sterilize the ingredients of these powders, but we must be sure that they are not containing pathogens. 44 2) Surgical dusting powders: Uses: - in body cavities, on major wounds as a result of burns and umbilical cords of infants. Surgical dusting powders must be sterilized before their use. Dusting powder Requirements: Homogenous and very fine Free from irritation. Flow easily. Have good covering capacity. Have good adsorptive and absorptive capacity. Spread uniformly over body surface. Cling to skin surface after application. Protect the skin from irritation caused by friction, moisture and chemical irritants. Dentifrices (Tooth Powders): Dentifrices are preparations which are generally used with the help of tooth brush for cleansing the surfaces of the teeth. They are available in the form of fine powders and pastes. They contain Abrasive like calcium sulfate, magnesium carbonate, sodium carbonate in fine powder Detergent or soap, Binder, Humectant, Sweetening agent e.g. saccharin sodium Flavour e.g. peppermint oil, clove oil. Opacifiers, Colouring agent. Insufflation: These are fine powders which are used to produce either a local effect, such as in the treatment of ear or nose or throat infections or a systemic effect, such as when they are inhaled into the lungs and get absorbed from the lungs. If a drug is destroyed in the GIT, when it is taken orally, then making it into an insufflation is a good option. Making a drug into a fine powder, packing it into containers called inhalers, seeing that the powder goes and lodges in the lungs and then releases the drug there involves a lot of technology. But if that can be managed, it is a good dosage form, because absorption of drug from the lungs is very fast, the lungs are highly perfused, and the area offered for absorption is equal to the area of a tennis court! Snuffs: These are finely divided solid dosage forms of medicament are inhaled into nostrils for its antiseptics, bronchodilator and decongestion action Simple powder & compound powder for internal use: Simple powder & compound powder for internal use Simple powder: - contain only one ingredient Compound powder: - contain two or more than two substances mix together 45 Cachets: Cachets Enclosure in cachets provides a means of administering nauseous or disagreeable powders in a tasteless form. Cachets are moulded or enclosed with made from rice flour. Use: They are used for administering the drug with unpleasant taste and a large dose. cachets are hard to swallow therefor, before administration, a cachet should be immersed in water for few seconds and then placed on the tongue and swallowed with water. e.g. Sodium aminosalicylate cachets Sodium aminosalicylate and isoniazid cachets. Advantages of cachets: 1- easy to prepare (no complicated machinery is needed) 2- large doses of drug can be dispended. 3- they disintegrate quickly in the stomach. Disadvantages: 1- easily damaged 2- not protected from light and moisture. 3- required moistening before swallowing. 4- they cannot be filled by machines(manual) Types of cachets: -: 1) Wet seal cachets. 2) Dry seal cachets. 3) compound cachets. Cachets are incompatible with iodine because cachets contain starch, and with oxidizing or reducing agents. 46 PREPARANING OF POWDERS: 1- Reduction of particle size of all ingredients to the same range to prevent stratification. 2- Sieving. 3- Weighing of each ingredient. 4- Mixing. 5- Packaging. CHALLENGES ENCOUNTERED IN POWDER FORMULATION 1- Hygroscopic and Deliquescent Powder Problem: Absorption of moisture from air leading to partial or complete liquefaction. Solution: A- Applied in a granular form to decrease the exposed surface to air. B- Packed in aluminum foil or in plastic film packets, sometimes it may be waxed. C- Addition of light magnesium oxide to reduce the tendency to damp D- Addition of adsorbent materials such as (starch, kaolin, MgCO3, Lactose,..). 2- Efflorescent powders Problem: Crystalline substances which during storage loose their water of crystallization and change to powder (to be efflorescent). The liberated water converts the powder to a paste or to a liquid. Solution: 47 - Using the anhydrous form, and treating it in a manner similar to hygroscopic powders Examples: Alum- atropine sulfate- citric acid- codeine phosphate… 3- Eutectic Mixtures Problem: Mixture of substances that liquefy when mixed, rubbed or triturated together. The melting points of many eutectic mixtures are below room temperature. Solution: A- using inert adsorbent such as starch, talc, lactose to prevent dampness of the powder B- dispensing the components of the eutectic mixture separately. Examples: Menthol- thymol- phenol- salol- camphor, acetanilide, phenacetin, aspirin, antipyrine,…). 4- Incorporation of Liquids Solution: A- The liquid is triturated with an equal weight of the powder and the remaining powder is added in several portions with trituration. B- Adsorbent should be incorporated, usually light kaolin. 5- Incorporation of Extracts Problem: Some plant extracts are available as powders or as semisolid (e.g., liquid extract of liquorice). Solution: A- The powdered extracts have no problems and treated generally as powders 48 B- Semisolid extract should be mixed with an equal quantity of lactose and reduced to a dry powder by evaporation before incorporation with other ingredients C- Careful heating, if present, to save potency of the extract. 6- Potent Drug Problem: Limited precision and accuracy of the used balances to weight small amounts of potent drugs which might be poisonous drug. Solution: Drug triturates: A- Suitable diluents like lactose are mixed with the potent drug to form 10 - 20%w/w drug triturates. B- Very fine powders should be used in the triturates C- Geometric dilution to prepare drug triturates 7- Incompatible salts Problem: Chemically incompatible salts when triturated together produce discoloration, chemical deterioration or loss of potency. Solution: A- Compounding such substances with minimum pressure B- Use a convenient method for mixing the powder like tumbling in a jar or spatulation on a sheet of paper. C- Each substance should be powdered separately in a clean mortar and then combined with other ingredients gently. D- Powder and dispense separately. 8- Explosive mixtures Problem: 49 Oxidizing agents (ex. Pot. Salts of chlorate, dichromate, permanganate and nitrate- Sod. Peroxide- silver nitrate and silver oxide) explore violently when triturated in a mortar with a reducing agent (ex. sulfides- sulfur- tannic acid- charcoal). Solution: A- Comminute each salt separately. B- Subject to a minimum pressure. SPECIAL POWDERS Effervescent Powders Definition: Mixture of organic acid and alkali effervesces when subjected to water due to reaction between the acid and the base with evolution of co2 Examples: Citric or tartaric acids with sodium carbonate or bicarbonate Uses: The liberated carbon dioxide has the following advantages: - It masks the bitter and nauseous taste. - It promotes gastric secretions which accelerate absorption. - It acts as a carminative. - psychological impression at the patient specially preferred by children Formulation: 1. Bulk powders or divided powders - Packed in separate packages of contrasting colors. - The contents are mixed in a quantity of water at the time of dosing. - The liquid is consumed just after the reaction begin to subside. 2- Effervescent Granules Definition: Sweetened effervescent powders formulated as granules. 50 Methods of Granulation: 1- Wet method: By the addition of a binding liquid (Alcohol is frequently used). 2- Dry method: Heating effloresced powder to liberate the water of crystallization which then acts as the binding agent Wet Granulation Procedure: 1- The powders are mixed without pressure in a suitable container. 2- Alcohol is added in portions with stirring until a dough like mass is formed. 3- The materials are then passed through sieve # 6. 4- The resulted granules are dried at a temperature not exceeding 50ºC. 5- The granules are packed in airtight containers. Dry granulation Procedure: 1- All ingredients, except citric acid monohydrate, are dried and passed through sieve # 60. 2- The powders are thoroughly mixed and citric acid crystals are added at last (un-effloresced citric acid contains one molecule of water of crystallization). 3- The mixture is spread in a shallow dish and placed in an oven previously heated (99- 105ºC). Upon heating citric acid crystals, the water of crystallization effloresces and citric acid transforms to the powder form. 4- The use of a water bath surrounding the beaker (or any container) in which the powders are stirred is a more convenient method to prevent local overheating. 5- No stirring until the powders become moist and form doughy mass. 51 6- The mass is then granulated by passage through sieve # 6 and dried. Packaging: * Effervescent granules or powders suffer from the short shelf life, especially if they are filled into wide-mouthed screw capped containers. * Recently, the stability of effervescent granules and powders is greatly improved by their packing in aluminum bags tightly closed. Test evaluation of Effervescent Powders: 1- weight 0.25g from the effervescence powder and put it in graduated beaker then add 5ml distilled water, finally calculate the following: a- effervescence time (start of effervescent). b- the carbon dioxide volume produced. c- duration period to complete effervescent. d- solution purity after effervescent. Capsules Definition: Capsules are solid unit dosage forms in which one or more medicinal ingredients are enclosed in a Small Shell or container usually made of gelatin. ADVANTAGES OF CAPSULES: 1- Capsules mask the taste and odour of unpleasant drugs. 2- They are slippery when moist and hence easy to swallow with a draught of water. 3- As compared to tablets fewer adjuncts are required. 4- The shells are physiologically inert and easily and quickly digested in the gastrointestinal tract. 5- They are economical. 6- They are easy to handle and carry. 7- The shells can be opacified (with titanium dioxide) or coloured, to give protection from light. 52 DISADVANTAGES OF CAPSLUES: 1- The drugs which are hygroscopic absorb water from the capsule shell making it brittle and hence are not suitable for filling into capsules. 2- The concentrated solutions which require previous dilution are unsuitable for capsules because if administered as such lead to irritation of stomach. Types of capsules Types of capsules according to the structure: 1. Hard gelatin capsules: They incorporate solid form of drug ingredients. 2. Soft gelatin capsules: They incorporate liquid and semisolid form of drug ingredients. Types of capsules according to its dissolving: 1. Enteric coated capsules (Gloutid capsules). 2. Sustained release capsules (Spansules). Among the above, hard gelatin and soft gelatin capsules are routinely used. Hard gelatin capsules: These capsules are hard by external touch. They also called dry filled capsule {DFC} because they incorporate solid powder form of drug ingredients. They are filled in the space held by gelatin shells. Hard capsules are made up of base consisting of plasticizers and water. It may also contain colours, sugars, flavours, dyes and preservatives. Gelatin is obtained from animal bones and frozen pork skin. Shells are made up of two cylindrical halves; one is large in diameter but shorter in length known as cap and other is shorter in diameter but longer in length called body. The drug is filled in body over which cap is fitted. Hard capsule shells are available in different sizes depending on the quantity of drug to be filled. 53 Difficulties in filling capsules: - Adding deliquescent or hygroscopic powders in capsules may absorb water from the gelatin and lead to cracking of the capsules. So, in this case magnesium bicarbonate, MgO might be added. - When quantity of the drug is very small, a diluent is added to increase the bulk of powder which can be filled easily in capsules (e.g. sucrose) - If there are incompatible ingredients, so must place one ingredient in smaller capsule and then place this capsule in large capsule containing the other ingredient. Soft gelatin capsules: These capsules are soft, elastic in nature, unlike hard gelatin type, their shells can’t be opened, they are one piece hermetically sealed, they can only be ruptured and dissolved. These are prepared from gelatin and water in which glycerin, sorbitol or propylene glycol are added as a plasticizer and gives capsules flexibility. To prevent bacterial and fungal growth, preservatives can be used. These are available in different shapes and sizes e.g., spherical, cylindrical, oval etc. the spherical capsules are called pearls. the content in soft gelatin capsules varies from 0.1 to 30ml. These are used for filling drugs in liquid form and semisolids. Multivitamins, liver oil, fish oil are dispensed in soft capsules. These are prepared and filled in one continuous operation on automatic and semi-automatic machines. Ophthalmic ointments are packed in unit dose capsules. Enteric coated capsules (Gloutid cap): These are capsules which are designed to release the drug in the intestine. They resist degradation in the stomach and stay intact till they reach intestine. Once they reach intestine, 54 they release their contents. This is due to their insolubility in acidic pH in stomach. But again, they are soluble in basic pH which is present in intestine. Drugs that must be coated are: - Drugs cause irritation to stomach and lead to nausea and vomiting. - Drugs interfere with digestion (tannins, AgNO3) - Drugs are unstable in the gastric fluid. - Drugs required delayed action. Coating materials: Formaldehyde, cellulose acetate, mixture of waxes, other esters can be used for enteric coating. Sustained release capsules (Spansules): - These are capsules designed to release drug ingredients slowly over a period of hours. So, they are long acting types and release drug gradually for prolonged effect. A single such capsule can be taken once in day instead multiple times of normal capsules. - The finely powdered drug is converted into pellets, these pellets are divided into groups(10 groups), first group untreated to produce rabid effect, other groups are coated with selected materials one by one to produce thickness of varying degree so it would be set free group after group depending on the coating thickness. - For coating materials may include: - Cellulose esters, fats, keratin, gluten, bees wax, gelatin polyvinyl QUALITY CONTROL OF CAPSULES: Whether capsules are produced on a small scale or large scale all of them are required to pass through certain tests i.e., quality control tests to test the quality of the finished product. Quality control tests are divided into PHYSICAL TEST ▪ Disintegration test ▪ Weight variation CHEMICAL TEST ▪ Dissolution test ▪ Content uniformity 55  ▪ Stability testing ▪ Moisture permeation test PACKAGING AND STORAGE OF CAPSULES: Capsules should be packed in a well-closed glass or plastic containers and stored in a cool place. PHARMACEUTICAL ASPECTS: ▪ The availability of a drug for absorption of solid dosage forms decreases as below: SOLUTION > SUSPENSION > POWDER FILLED CAPSULE > COMPRESSED TABLET > COATED TABLET ▪ The physiologic availability of drugs is often improved by liquid drug substance i.e., it contains the drug in liquid form or in suspension. ▪ Orally administered drugs, particularly if used chronically, can be irritating to the stomach. The dosage form of such drugs can affect gastric tolerance. ▪ When compared the ulcerogenic potential of soft gelatin capsule of dexamethasone with tablet the capsule had reduced ulcerogenic potential. Tablets Definition: Tablets are solid dosage form manufactured either by dry granulation, wet granulation or direct compression containing medicaments with or without excipients, intended to produce desired pharmacological response. Advantages: - Light (easy to carry) and compact - Easy to swallow - Better patient compliance - Bitter taste of the drug can be masked by coating - Cheaper to other solid medication - No need to measure the required dose. 56 - Some tablets can be divided into halves and quarters when a fractional dose is required. - Good stability - Less incompatibility Disadvantages: - Difficult to swallow in case of children and elderly patients. - Drugs with poor wetting, show slow dissolution profile. - Some drug resists compression, due to their amorphous nature. How to achieve good tablets: - should be accurate &uniform in weight. - Drug must be good distributed in each tablet. - The size & shape should be easy to administrate. - They shouldn’t be hard that it may not disintegrate in the stomach - It shouldn’t be any incompatibilities - Should be chemically and physically stable during storage. - Shouldn’t break during transporting. - Should be attractive in appearance. - Shouldn’t be any manufacturing defect. - Shouldn’t be easy& cheap in production Various types of tablets are being manufactured according the manufacturing process, route of administration and type of dosage form. Types of tablets: A- Molded tablets B- compressed tablets 57 Molded tablets: - Tablet Triturates are made from moist material using triturate mold, must be completely and rapidly soluble. - This powder is mixed and moisted with an alcohol to have soft mass. - Prepared by forcing the soft mass into cavities of a mold. - Generally, contains potent drug with small doses &diluents like lactose, dextrose or sucrose. Compressed tablets (CT): 1- Compressed Oral tablets: - - These tablets are prepared by compression technique in which tablets are not coated with any material and required to e disintegrated in stomach in a very short time, so the medicine should be freely soluble in gastrointestinal fluids or required addition of disintegrant agent. - Compressed tablet like paracetamol 2- Chewable tablet -these tablets are placed to mouth which are chewed and swallowed. - they are given to children who have difficulty in swallowing and to adult’s dislike swallowing. - Antacid and multivitamins are prepared as chewable - must add substances have very acceptable taste & flavor. - so, they should disintegrate in a short time & produce cool sweet taste. 3- soluble tablets: - These tablets required to be dissolved completely in liquids to produce solution. - These tablets usually used to prepare mouth wash, gargles, skin lotion, douches and vitamins. 4- Sugar coated tablets: 58 - These are compressed tablets which are coated with sugar, in order to mask the bitter or unpleasant taste and odor of the drug or to protect the drug from atmospheric condition. - Should use coloring agents for elegancy. 5- Film-Coated Tablets (FCT): - These are compressed tablets covered with a thin layer or film of a water- soluble material. A number of polymeric substances may be used for film coating. Film coating imparts the same general characteristics as sugar coating, in addition it offers reduced time period required for the coating operation. - It used to protect the drug from atmospheric condition. 6- Enteric coated tablets (ECT): - These are compressed tablets which are coated with substance, which disintegrates in intestine. 7- Multiple Compressed Tablets (MCT) or multilayered tablets: - These tablets are subjected to more than one compression cycle, in which the granules are incompatible. 8- Delayed release tablet (sustained release tablets): Required to release the drug at certain time and give prolong effect. 9- press coated tablets: Used to prepare tablets with incompatible ingredients which compressed around previously compressed tablets. Tablets used in oral cavity includes 1. Sublingual tablet 2. Buccal tablet 3. Lozenges 11- Buccal and Sublingual Tablets: 59 - buccal tablet are small flat oval tablets. These tablets are formulated and compressed with sufficient pressure to give a desired buccal tablet. These tablets are administered by inserting in buccal pouch(cheek) which may dissolve slowly. Sublingual tablets placed below the tongue may dissolve rapidly and are absorbed readily. - These tablets contain large amount of sweeting agents. - Nitroglycerine, mannitol and hexanitrate should be dissolved and release the drug in 1-2 min. 12- lozenges tablets: - should dissolve slowly in the mouth to produce continuous effect on the mucous membrane of the throat. - It should be added a quantity of binder agent to slow the release of active ingredient Shouldn’t add disintegrating agent - Must contain sweeting & flavoring agents. 13- Effervescent tablet: - Tablets used to prepare solution - They contain sodium bicarbonate and citric acid with tartaric acid along with the drug. In the presence of water, they react liberating carbon dioxide which acts as a disintegrator and thus produces effervescence. Tablets which are administered via another route includes: 14- Vaginal tablet They are oval or almond shape to ease insertion 15- Implantation tablet - Implants-these are small tablets which are prepared for insertion under the skin. 60 - must be sterile and must have slow release for long period of time from 3-6 months interval. Tablets preparation (Expedients) Tablets are usually prepared by compression technique, which includes various ingredients (excipients) like diluents, binders, disintegrants, lubricants, glidants, etc. 1- Diluents: Diluents are normally used as a filler, in order to increase the bulk of the tablet that make easily to be compressed, usually used when the quantity of the drug is small. Example for diluents includes lactose, starch, mannitol, NaCL, sucrose, CaCO3, CaSO4, CaPO4, etc. 2- Binders and adhesives: - Some substance could compress directly but majority need to be granulated before compression. - Binders are either added in dry form or wet form (using alcohol or water or both), they serve as a binding agent in the formulation, it used during granulation to cohesiveness the powders. - Commonly used binders includes starch, carboxy methyl cellulose (CMC), methyl cellulose (MC), acacia, tragacanth, gelatin, glucose, sucrose. - The type of the binder added vary with the formulation. The amount of binder added, and type of binder influences the tablet properties. - the percentage of binder should be higher in the tablets if we need prolong time of action(lozenges), and those need short time must add low proportion of binders. 3- Disinetegrants: - These are added, in order to aid in disintegration or breaking of tablet in GIT. -two types of disintegrents: 61 1- swell up when contact with moisture 2- substance react with effervesces when contact with moist. Disintegrants type 1 like maize starch, potato starch (they have affinity to water and swell up when contact water). Disintegrants type 2 like clays(bentonite), methyl cellulose, CMC, agar, gum. Those produce better wetting of granules→ result fast dissolution rate. 4- Lubricants: Substances which added to granules before compression to improve flowability of granules from hoper to the die cavity y reducing interparticle friction to prevent adhesion of powders to the surface pf die and punches. examples: stearic acid, magnesium stearate, calcium stearate, starch, sucrose. Lubricants could be sub classified to: a- Glidant: They reduce the friction, thus aid in free flow of granules or powder. Commonly used glidants includes starch and talc b- Lubricants: prevents sticking of tablets to dies and punches c- Anti adhesive: help the granules not to stick the other parts of machine during compression. Talc could be glidant or antiadhesive but not lubricant. 5- Coloring agents: Helps in elegant appearance of the product or to identify the different types of tablets. Only approved colors should be added from FDA colors requirements: 1- shouldn’t affect absorption 2- shouldn’t be incompatible with active ingredients or other additives. Could be added in mixed powders before granulation or dissolve in binder, the later gives uniform color. 62 Examples of coloring agents like brilliant blue 6- Sweeting agent: Sweeting agent are added in order to mask the bitter taste of the drug. Ex: mannitol, lactose and sucrose. Artificial sweeting agents: aspartame, cyclamate and saccharin. 7- Flavouring agent: - Added in order to impart flavor or odor to the table formulation Ex: Menthol, clove oil, vanilla, other volatile oils and fruit flavors. - Volatile substances are dissolved in suitable organic solvent and spray over the granules before compression. - Fruit flavor added to powder before compression granulation. 8- Granulating agents: Ex: water, acacia, tragacanth, starch, liquid glucose, syrups, alcohol. Role of excipients in tablet formulation: - modify the drug release characteristics - Enhance the solubility and bioavailability of dosage form - Imparts weight, volume - Increases better patient compliance Tablet preparation methods: Tablets are prepared by three methods -wet granulation method -dry granulation method -direct compression Wet granulation method 63 It is the most common and widely used method. This method involves various steps like weighing of ingredients, mixing, granulation, screening of damp pass, drying, lubrication and compression of tablets. The main active ingredient, diluent, disintegrant are blended together, then it is allowed to pass through the sieve (sifting). Solutions of the binding agent are added to the initial mixture with stirring. The amount of binding agent added should be sufficient, in order to avoid over wetting of the tablet. If the powder is not wetted properly, the granules will be too soft and can be broken down during lubrication, which is difficult during compression of tablet. Tray drying is most common method of drying the tablet granules. Tray drying was the most widely used method of drying tablet granulations in the past, which might be replaced by fluid –bed dryers as a novel approach. After drying the granules, they are allowed to pass through the screen, usually 60-100 mesh nylon cloth is used. After dry granulation, lubricant is added as fine powder, which is required for proper filling of the die cavity. Dry granulation method This method is used for tablet preparation, in case tablet ingredients are highly sensitive to moisture, or unable to with stand elevated temperatures during drying, slugging may be used to form the granules. Dry granulation or double compression usually eliminates various steps, which involves slugging of the powder mass. The active ingredient, diluent and lubricant are blended together, to form the slug. Thus, the compressed slug is passed through the mesh or through the mill, and the remaining lubricant is added to the granulation, blended properly and compressed to form the tablets. Direct compression Direct compression involves direct compressing the powdered material into tablets. Direct compression is adopted, if drug constitutes major portion of tablet [86-90] total weight. Tablets containing 25% or less of drug substances can be formulated, with a suitable diluent which acts as a carrier or vehicle for the drug. 64 Tablets prepared by above method are subjected to compression machine which may be single station or multiple station. Tablet should possess following characteristics. - Should be free from defects like cracks, discoloration, chips etc. - Should able to withstand mechanical stress - Physically and chemically stable During processing of tablets during compression, there several processing problems encountered such as: -picking, sticking, capping, lamination, mottling… Picking: small surface of the tablet may be removed by a punch during compression. So, tablet show pitted surface instead of smooth one. These caused due to: ▪ presence of scratches on surface of the punches ▪ using wet granules 2- Sticking: adhesion of tablet to the die wall, so the lower punch can’t remove freely, which may occur due to excessive moisture in the tablet (using damp granules). It could be avoided by: ▪ using dry granules ▪ adding lubricants ▪ use chromium plated punches. 3- Capping: it is partial or complete separation of tablet from the top or bottom crowns of the tablet from the main body. 4- Lamination: Segregation or separation of a tablet into two or more distinct layers. Capping and lamination may occur due to ▪ air entrapment during processing(compression). 65  ▪ Presence of excess fine powder in granules or less of fine powder in granules. ▪ Tears of punches or dies. These defects can be avoided y regranulations or altering the pressure adjustments. 5- Mottling: Unequal distribution of color on tablet surface results in mottling, zones of different shades appeared. This is caused due to: ▪ differences in colors between drugs and excipients ▪ Migration of color during drying May be avoided by using: ▪ Good color ▪ Good solvent ▪ Mix color with binder ▪ Drying at low temperature 6- weight variation: It is due to: ▪ Poor flow of granules to the die. ▪ Presence of small & large size of granules. ▪ Too fine granules ▪ Ingredient separation ▪ Poor mixing of lubricants ▪ Change in the adjustment of punches. 7- binding in the die: When the ejection of tablets is difficult, so the tablets edges become rough This defect due to poor lubrication of granules. 66 8- Hardiness variation: The tablets greatly hard due to: ▪ weight variation ▪ space between upper and lower punches ▪ pressure applied excessive fatty lubricant(waxes) **** hard tablet may not disintegrate in required time, and soft tablet broken during handling, transporting, dispensing. Evaluation tests After tablet compression, tablets are subjected various evaluation tests to ensure the tablets withstand sufficient mechanical strength, etc. 1- General appearance: it includes overall appearance of the tablet like size, shape, odor, taste, color, surface, consistency, textures physical flaws. 2- Tablet thickness: using calipers, it should be controlled with ± 5% variation of standard value. 3- Weight variation test: Twenty tablets are weighed randomly from each batch, and the average weight of the tablet is determined. As per the IP specification, if the tablets weight is < 80mg- deviation up to 10% is allowed 80-250mg - deviation up to 7.5% is allowed >250 mg- deviation up to 5% is allowed And must not more than two tablets fall outside the range. 4- Hardness test: It is defined as the force required to break the tablet. This test is performed in order to ensure that the tablet withstands mechanical shocks during manufacture, packaging and shipping of tablet.it could be determined by holding the tablet between fingers and throwing it lightly on the floor, if it doesn’t break that means proper hardness obtained. Also, various types of hardness testers can be used to measure the hardness of the tablet. 67  5- Friability test: Friability test is performed, in order to ensure the mechanical strength of the tablet during transportation, packing, handling etc. friabilator is the instrument, used to carry out the friability test. 6- Disintegration test: Disintegration is the breakdown of tablet into finely divided particulates or granules in GI tract. five tablets placed in tube which has pores and then the tube suspended in water bath or suitable liquid and maintained the temperature at 37°C, and the tube moved up and down for 30 times per minute. Good tablet should be disintegrating after 15-30 minute (BP). Disintegration time for uncoated tablets should be 15 minutes, 60minutes for sugar coated tablets, and 30 minutes for film coated tablets, 1-2 minutes for sublingual. 7- Dissolution test: the time required for the given percentage of drug in tablet, to go into solution, under specified set of conditions as in invitro test. The tablet placed in the basket contain 1000ml of suitable solvent at 37°C then taking 5ml after interval of time and assay the solute concentration. from 12 tablets tested, ten tablets should give right concentration. 8- Uniformity of content (percentage of active ingredients): Every tablet must contain the stated concentration of active ingredients, it allows to contain between 110-90% of active ingredients according to BP. Tablet coating: 1- sugar coating (dragification): used to: ▪ mask unpleasant taste ▪ elegancy ▪ protect ingredients from decomposition. agents used: sugar, gum(acacia), talc, starch ***** disintegrate in oral and stomach. 68 2- film coating: used as sugar coating. Agents: CMC, PEG or carbowax ***** disintegrate in oral and stomach. 3- compression coating/press coating/dry coating: No solvent is used. Only compress dried granules around pre-compressed tablets. ***** disintegrate in stomach. 4- enteric coating: used for: ▪ drugs decomposed in stomach (erythromycin, hormones, alkaloids) ▪ drugs that can irritate stomach (aspirin, thiazide) ▪ the action needed in intestine (parasite killer) ▪ absorption take place in intestine. ▪ Delayed action is required(aspirin) ▪ Drugs induce vomiting (ipecac – emetine) Agents: MC, waxes, FFA Differences between pastilles and lozenges: pastilles lozenges base Glycerin + gelatin Sugar + gum consistency soft hard disintegration rapid slowly used chewing sucking Ex: paritol Strep sills- lemocin c Uses: Anti-septic Give good breath Mucolytic 69  Astringent Chapter four Drug incompatibilities Drug Incompatibility “It is defined as when two or more ingredients of a prescription are mixed together , the undesired changes that may takes place in the physical, chemical or therapeutic properties of the medicament is termed as incompatibility that may affect the safety of such therapy.” 4.2. Classification of Incompatibility 3 classes of drug incompatibility: 1- Therapeutic incompatibility 2- Chemical incompatibility 3- Physical incompatibility Therapeutic incompatibility: It occurs due to when drug or excipients, which are antagonist to one another. In that modification of the therapeutic effect of one drug by the prior concomitant administration of another. It is also occurred when prescribing certain drug to the patient with the intention to produce specific degree of action but the nature of the action that produced different from that intended by the prescriber. Therapeutic incompatibility is also called as drug interactions. Therapeutic incompatibility occurs due to following reasons: 1- Overdose or improper dose of a single drug 2- Wrong dosage form 70 3- Contraindicated drugs: Some drugs are not prescribed for lactating mother because it will excrete into milk. - E.g. Phenytoin, Phenobarbitone, Chloramphenicol etc. 4- Synergistic effect or antagonistic effect: like combination of bactericidal and bacteriostatic antibiotic. Alter of absorption rate (STOMACH-INTESTINE) 1- PH effect the solubility degree: A- Rx: Aspirin (acidic) NaHCO3 (Basic) Acid + Base = salt + H2O The salt will not be absorbed and eliminate directly B- Rx Bisacodyl (DULCOLAC®) AL(OH)3 Bisacodyl is enteric coated tablets so it is intended to disintegrate and absorb in the intestine, but when prescribed with antacid like AL(OH)3, this antacid will increase the PH in the stomach, so bisacodyl will be released in the stomach not in the intestine. So enteric coated tablets such as (Bisacodyl, Erythromycin,) not given with antacid. 2- Complex formation: Some drugs when given together form insoluble complex that cannot be absorbed. A- Rx: Tetracycline MgO B- Rx: Tetracycline Milk 71  tetracycline is inactivated by the milk due to the presence of calcium. It forms insoluble complex with milk and not show any effect on systemic circulation tetracycline is inactivated by divalent like Mg+2, Ca+2, Fe+2, Or trivalent such as AL+3, Fe+3, so tetracyclines shouldn’t be taken with substances containing such elements. Also, it is not allowed to prescribe tetracyclines with antacids. But the following prescription could be dispensed. a- Rx: Tetracycline NaHCO3 b- Rx: Digoxin Eucarbon Here in this prescription Eucarbon will adsorb the digoxin on its surface, so digoxin will not absorb. All critical medicine cannot be absorbed by Eucarbon such as oral contraceptive, ant diabetic agents … 3- Alter the motility of GI: Some drugs for example acetyl choline, metoclopramide increase the GI motility, so result in decrease of the absorption, other agents such as adrenaline and amphetamine decrease GI motility and leads to increase the absorption of other drugs when given together. A- Rx: Metoclopramide (PLASIL®) Ampicillin In this prescription the absorption of ampicillin will be decreased. 72 B- Rx: Vit A Paraffin Laxative like paraffin oil, castor oil will decrease the absorption of vit A because it will increase the G.I motility. 4- Competitive binding to plasma proteins: Drugs bind to albumin in different affinity like the following prescription Rx. Aspirin Phenylbutazone Aspirin bind to albumin with high affinity (93%) and remain 7% free, which will compete with phenylbutazone that lead to increase the free form of phenylbutazone in the blood which means increasing the toxicity. Drugs that have high affinity to bind to plasma proteins: ▪ Oral anti-coagulants ▪ Oral hypoglycemia ▪ Anti-hypertensive ▪ Anti- inflammatory 2- Alter hepatic enzyme (alter metabolism) Drugs that increase liver enzyme (inducer) and increase other drugs metabolism and decrease its concentration in plasma are: ▪ Barbiturate ▪ Phenytoin ▪ Rifampicin Rx.