Pharmaceutics 3 Theory - Last Version PDF

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...

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. 73  Aspirin Barbiturate Drugs that inhibit liver enzyme (inhibitor) and decrease other drugs metabolism which will increase its concentration in plasma, such drugs are: ▪ Alcohol (ethanol) ▪ Smoking 1- Alteration of drugs elimination from kidney: This elimination depends on: a- PH: Acidic drugs become on unions in acidic media, so the elimination of acidic drugs will be reduced with drugs enhance acidic media of urinary tract. Rx. Sulfonamide Aspirin On the other hand, the acidic drugs will be eliminated rapidly when taken with basic drug. Rx Sulfone amide NaHCO3 b- Solubility: Some drugs eliminated from the kidneys by active transport, if two of these drugs are prescribed together, competitive elimination between them will be occur, in this case the stronger (high affinity) and high concentration drug will be eliminated first and that leads to accumulate the second drug in the body which will increased its toxicity. 74  Rx Probenecid Indomethacin Probenecid is much stronger than indomethacin that’s will increase the indomethacin concentration in plasma and increase its toxicity. 2- Alteration of ion exchange level: Some drugs depend in its action on Na/K Atpase pump like digoxin and some diuretics that lead to hypokalemia which will increase digoxin toxicity on cardiac muscle. Rx Digoxin Furosemide (Lasix) 3- Synergistic Action Rx Phenobarbitone Alcohol In this prescription both drugs inhibit the CNS which may lead to death. Rx Warfarin Aspirin Warfarin is an anticoagulant and aspirin is an anti-platelet, so take both drugs together may cause bleeding. Rx Amino glycoside 75  Edecrin (ethacrynic acid) Both drugs have toxic effect on hearing so giving both drugs together could cause deafness. Rx Erythromycin Penicillin Rx Tetracycline cephalosporine in these prescriptions, tetracycline and Erythromycin are bacteriostatic antibiotic which they are incompatible with bactericidal antibiotic such as penicillin and cephalosporine. Bactericidal is active in growth phase only and bacteriostatic inhibit this phase so bactericidal as penicillin will be inhibited. 4- Adverse action: Rx Warfarin Vit K Warfarin is anticoagulant drug, it inhibits the synthesis of coagulating factors, and vit k is an essential vitamin for synthesis of these factors. So, they work against each other. Rx Glibenclamide Acetified Syrup 76 Glibenclamide is a hypoglycemic agent, and the Syrup is consisting of high percentage of sugar (85%). Rx Oxytocin Folic acid Oxytocin is labor inducer hormone, and folic acid is a supplement usually given for pregnant woman. Rx Cimetidine Indomethacin Cimetidine is usually taken in the treatment of peptic ulcer and the most common side effect of Indomethacin is gastric ulcer. Rx Indomethacin S.R 75mg 1X3 Indomethacin in this prescription is sustained release dose, so it must be given once daily. Physical incompatibility: It is usually alteration in color, odor, taste or consistency due to immiscibility, insolubility, precipitate formation or liquefaction that may cause non-uniformity unsightly or unpalatable mixture. 1- insolubility may due to: ▪ Change in PH ▪ Reducing method ▪ Using inappropriate surface-active agent ▪ Using inappropriate solvent 77  ▪ Formation of insoluble complex 2- Forming a precipitation Rx. Benzalkonium chloride (+ve charge) Na-lauryl sulfate (-ve charge) Benzalkonium and Na-lauryl sulfate has different charge so precipitation will occur when they mixed together. 3- Immiscible because of solvent type Rx. Ephedrine sulfate Menthol Liquid paraffin Ephedrine sulfate is water soluble so it will not be dissolved in oils. 4- Immiscibility because inappropriate emulsifying agent. Founds in emulsions, creams, lotions, and some ointments were water and oil are immiscible together and to overcome this problem we should add or change the emulsifying agent. 5- Uniformity Because of: ▪ Improper mixing during preparation. ▪ Microbial growth ▪ Inappropriate storage condition ▪ Factors related to emulsifying agents: a- The concentration of emulsifying agent. b- Inappropriate type of emulsifying agent. 78  c- Inappropriate step when adding emulsifying agent during preparation. 6- Eutectic mixture a- Mixing solids with low melting points could trigger them to liquify at room temperature (e.g. camphor, menthol, chloral hydrate, phenol, acetyl salicylic acid, Na salicylate, phenazone). Rx Camphor 5g Menthol 5g b- Type of crystal Rx Ammonium chloride Light magnesium carbonate When using anhydrous salt with hydrous agent, the water of crystallization will liquify the mixture. Chemical incompatibility occur because of chemical interaction between the ingredients of prescription and form harmful product. 1- Oxidation Factors enhance oxidation: ▪ Presence of O2 ▪ Light ▪ High temperature ▪ Chang PH ▪ Type of dosage form (liquid dosage form more suitable to oxidation reaction) ▪ Oxidant agents such as heavy metals, peroxides. 79 ▪ Solvent type (water enhance oxidation reaction). ▪ Present of unsaturated bond (in lipids it is induce rancidity). To avoid the oxidation of product: 1- Addition of antioxidant agent e.g. thiosulfate, polysulfide, Vit C for liquid preparations and Vit E for oleaginous preparations. 2- Addition of chelating agents to form stabilize complex such as EDTA, benzalkonium, etc. 3- Replace O2 with N2 gas. 4- Select suitable dosage form (solid (high stability) – semisolid – liquid (low stability)). 5- Protect the preparation from light by storing them in dark place or using amber glasses or adding oxybenzone to the glass (light absorber). 6- Addition of buffer to avoid change in PH. 7- Keep the drug container well closed. 8- Storing the drug in suitable temperature. Drugs that oxidized rabidly such as: ▪ Catechol’s (Adrenaline, Nor adrenaline) ▪ Vitamins ▪ Fixed oils and volatiles oils ▪ Tetracyclines 2- Hydrolysis: Water can decompose drug by breaking bond, most common groups may break down by hydrolysis are ▪ Esters such as o procaine o Benzocaine o Codeine phosphate o Aspirin ▪ Amides such as o Chloramphenicol o Sulfonamide o Procainamide 80  ▪ Nitrites such as o NO3 o NO2 o N2O To avoid Hydrolysis: 1- Select appropriate solvent not water. 2- Add hygroscopic agents such as CaCO3. 3- Coat the dosage form (tablet or granules). 4- Add buffer 5- Using Suspension instead of solutions 6- Forming complexation 7- Add active surface agents. 3- Polymerization: Polymer is forming long chain polymer from small units. Example of this incompatibility: ℎ𝑒𝑎𝑡 1 − 𝐹𝑜𝑟𝑚𝑎𝑙𝑑𝑒ℎ𝑦𝑑𝑒 −−→ 𝑝𝑎𝑟𝑎𝑓𝑜𝑟𝑚𝑎𝑙𝑑𝑒ℎ𝑦𝑑𝑒 (toxic precipitate) To avoid this reaction, we should decrease the temperature and add ethanol 15%. ℎ𝑒𝑎𝑡 2 − 𝑝𝑒𝑛𝑖𝑐𝑖𝑙𝑙𝑖𝑛 −−→ 𝑝𝑜𝑙𝑦𝑚𝑒𝑟 (cause allergy). Factors enhance polymerization: Temperature, light, solvent type, PH and impurities. 4- Isomerization Isomer is a chemical compound that has the same numbers of atoms and the same chemical composition but differ in the order of the atoms. A- Optical Isomerization: Is altering in the chemical projection from Levo (L) to Dextro (D) or from D to L. 81  Examples: 𝟏. 𝑳 − 𝒂𝒅𝒓𝒆𝒏𝒂𝒍𝒊𝒏𝒆 ( (𝒎𝒐𝒓𝒆 𝒂𝒄𝒕𝒊𝒗𝒆) → 𝑫 − 𝒂𝒅𝒓𝒆𝒏𝒂𝒍𝒊𝒏𝒆 (𝒍𝒆𝒔𝒔 𝒂𝒄𝒕𝒊𝒗𝒆) 𝟐. 𝑳 − 𝒕𝒖𝒃𝒐𝒄𝒖𝒓𝒂𝒓𝒊𝒏𝒆 (𝒍𝒆𝒔𝒔 𝒂𝒄𝒕𝒊𝒗𝒆) → 𝑫 − 𝒕𝒖𝒃𝒐𝒄𝒖𝒓𝒂𝒓𝒊𝒏𝒆 (𝒎𝒐𝒓𝒆 𝒂𝒄𝒕𝒊𝒗𝒆) 𝒉𝒆𝒂𝒕& 𝒂𝒍𝒌𝒂𝒍𝒊𝒏𝒆 𝟑. 𝑳 − 𝒉𝒚𝒐𝒔𝒚𝒂𝒎𝒊𝒏𝒆 − − −−→ 𝑨𝒕𝒓𝒐𝒑𝒊𝒏𝒆(𝒍𝒆𝒔𝒔 𝒂𝒄𝒕𝒊𝒗𝒆, 𝟓𝟎% 𝒂𝒄𝒕𝒊𝒗𝒆) Factors influence optical isomerization: Temperature, PH and solvent type. B- Geometric isomerization: If the active group at the same side, it will be called Cis and if the active group in in the opposite site it will call Trans. Vit C (Cis) is more active than Vitamin C (trans) 5- Decarboxylation It is removing carboxy group from the compound. 𝒉𝒆𝒂𝒕 1- 𝑵𝒂𝑯𝑪𝑶𝟑− − − − −→ 𝑵𝒂+ + 𝑪𝒐𝟐 All drugs contain HCO3 will lose the carboxyl group with heating. 𝒉𝒆𝒂𝒕 𝟐 − 𝒑𝒓𝒐𝒄𝒂𝒊𝒏𝒆 − − −−→ 𝒂𝒏𝒊𝒍𝒊𝒏𝒆 (𝒃𝒓𝒐𝒘𝒏 𝒄𝒐𝒍𝒐𝒓) 6- CO2 absorption Some compounds absorbed CO2 and form precipitate. 𝑐𝑜2 𝑁𝑎 − ℎ𝑒𝑥𝑎𝑏𝑎𝑟𝑏𝑖𝑡𝑎𝑙 −−→ 𝐻𝑒𝑥𝑎𝑏𝑎𝑟𝑏𝑖𝑡𝑜𝑛𝑒 (𝑝𝑟𝑒𝑐𝑖𝑝𝑖𝑡𝑎𝑡𝑒) 7- Combination When different compounds with different charges reactive with each other as surfactants. 8- Complexation 82  Producing precipitate by complexation for example tetracycline with heavy metal. REFERENCE 1. Leon Lachman , Herbert A. Lieberman , The theory and practice of industrial pharmacy, CBS publishers &distributors ,special Indian edition 2009. WWW.GOOGLE.COM Indian pharmacopeia 2007 edition. 2. Shelke Usha Y, Mahajan Ashish A., Review on: an Ointment.International Journal of Pharmacy and Pharmaceuticle Research, 2015; 4(2): 171-191. 3. Sandhu Premjeet, Bilandi Ajay, Additives in Topical Dosage Form. International Journal of Pharmaceuticle, Chemicle and Biologicle Sciences, 2012; 2(1): 78-96. 4. Debjit Bhowmik, Harish Gopinath, A Recent Advances In Novel Topical Drug Delivery System. The Pharma Journal, 2012; 1(9): 12-31. 5. Clarence T. Ueda, Vinod P. Shah Topical and Transdermal Products. The United States Pharmacopeial convention, Inc, 2009; 35(3): 750-764. 6. Topical medication, wikipedia, http://en.wikipedia.org/wiki/Topical_medication [Accessed: 17 May 2016]. 7. V Manimaran lecturer, Department of Pharmaceutics, SRM College of Pharmacy, Ointments, www.srmuniv.ac.in/sites/default/files/downloads/OINTMENTS.pdf [Accessed: 17 may 2016]. 83 8. The Pharmaceutics And Compounding laboratory, Ointments: Preparation and Evaluation of Drug Release, www.pharmlabs.unc.edu/labs/ointments 9. http://apps.who.int/phint/pdf/b/6.2.1.3.Ophthalmic-preparations.pdf https://www.researchgate.net/publication/265377388_Sterile_Ophthalmic_ Preparations_and_Contamination_Control 84