Drug Incompatibility Lecture Notes PDF

Drug Incompatibility Dr. Mohamed Rahamathulla  Learning Outcomes After completion of this chapter, you will be able to: 1. Understand the concept of Incompatibility 2. Understand the reasons of Incompatibility 3. Classify the Incompatibility 4. Understand th...

Drug Incompatibility Dr. Mohamed Rahamathulla  Learning Outcomes After completion of this chapter, you will be able to: 1. Understand the concept of Incompatibility 2. Understand the reasons of Incompatibility 3. Classify the Incompatibility 4. Understand the concept of Physical, chemical & therapeutic Incompatibility with example. 2  Definition Incompatibility is an undesirable result of mixing of two or more antagonistic substances which may affects the safety efficacy and appearance of the pharmaceutical dosage forms. 3  Incompatibility may be due to i. Drug-Drug Incompatibility ii. Drug Excipient Incompatibility Drug + 1st Drug + 2nd Drug Excipients Mixed Mixed Undesired / unwanted Product Undesired / unwanted Product 4  Incompatibility may be due to iii. Dosage Error Incompatibility :Example Rx Rx Codeine Phosphate 5 g Codeine Phosphate 5 mg Prepare 10 powders Prepare 10 powders Correct Dosage Error Prescription Incompatibility iv. Incompatibility may occur not only during compounding & dispensing but also at any stage during formulation, Manufacturing, Packaging & administration of drugs. 5  Types of Drug Incompatibility 1. Physical incompatibility 2. Chemical incompatibility 3. Therapeutic incompatibility 1. Physical incompatibility When two or more than two substances combined together a physical changes take place and an undesirable product is formed it is called as physical incompatibility. It is due to insolubility, immiscibility, precipitation, liquefaction of solid materials. 6  General methods of Correction of Physical Incompatibility 1. Change the order of mixing of ingredients in prescription 2. By Emulsification 3. Addition of suspending agents 4. Change in the forms of ingredients 5. By addition, substitution or Omission of therapeutically inactive substances 7  Example of Physical Incompatibility with there methods of correction Example 1: Immiscibility Rx Castor Oil 15ml Water up to 60ml Make an Emulsion In this prescription castor oil & water are immiscible with each other. To overcome this incompatibility an emulsifying agents is used to make a good emulsion. 8 Example 2: Insolubility. Insolubility means the inability of material to dissolve in a particular solvent. Majority of Physical incompatibility are due to Insolubility of organic or inorganic compounds in to a particular solvent. Some solids are insoluble in solvent there are of two types: A) Diffusible Solids B) Indiffusible Solids 9 A) Diffusible Solids: These are insoluble in water but get evenly distributed on shaking throughout the liquid for sufficient long time. Eg: Magnessium carbonate B) Indiffusible Soilds: These are insoluble in water but do not get evenly distributed on shaking throughout the liquid for sufficient long time, So Suspending agents are incorporated. This suspending agents increases the thickness of the preparation and maintained the uniform distribution of insoluble substances. Eg: Chalk powder, Acetyl salicylic Acid, Phenacetin, Zinc Oxide & Calamine etc. 10 Incase of Indiffusible solids; Two types of suspending agents are added, a) Compound Tragacanth Powder ( 2g/100ml), CTP: It is used when vehicle is other than water or Chloroform water b) Tragacanth Mucilage (1/4th of it’s total volume), TM: It is used when vehicle is Water or Chloroform water Rx Phenacetin 3g Caffeine 1g Orange Syrup 12ml Water up to 90ml Make a Mixture In this prescription Phenacetin is a indiffusible substances so, suspending agents are used to make a stable mixure. 11 Example 3: Precipitation When the drug is insoluble in the vehicle it may be precipitated. Eg: Resins are insoluble in Water When tincture containing resinous matter is added in water , resins agglomerated forming indiffusible precipitate. Rx Tincture benzoin compound 5ml Glycerine 15ml Rose water up to 100ml Tincture benzoin compound contain resins which may be precipitated when combined with water. So addition of tincture with rapid stirring yields a fine colloidal dispersion. 12 So there is no need of suspending agent.  Example 4: Liquefaction When certain low melting points solids (Ex: camphor, Phenol, Menthol, Thymol, Chloral hydrate, Aspirin) are mixed together a liquid or semisolid mass is formed known as Eutectic mixture. This is due to lowering of melting points of the mixture to below room temperature. This types of substances create problems when they are dispense in powder form so, such types of substances can be dispensed as follows: 1. Dispense a separate powder 2. Low melting point substances triturate together to form a liquid. Add absorbent like light kaolin or light magnesium carbonate to produce a free flowing powder. 3. The individual medicament weigh separately & mixed with absorbent lastly combined together then filled in to a suitable container. 13 Rx Menthol 5g Camphor 5g Ammonium Chloride 30g Light Magnessium Carbonate 60g Make an insufflation In this prescription Menthol, Camphor & Ammonium Chloride get liquefied on mixing with each other. To dispense this prescription Menthol, Camphor & Ammonium Chloride are triturate together to form a liquid. Add light magnesium carbonate & mixed it thoroughly to make a free flowing powder. 14  Chemical Incompatibility.2 When two or more than two substances combined together a Chemical interactions take place and an undesirable product is formed it is called as chemical incompatibility. Types of Chemical Incompatibility 1. Tolerated: In this type, the chemical interaction can be minimize by changing the order of mixing but not alteration made in the formulation. 2. Adjusted: In this type, the chemical interaction can be minimize by addition or substitution of one of the reacting substance with another of equal therapeutic value. 15 The Chemical Incompatibility is may be due to; 1. Intentional: When the prescriber knowingly prescribe the incompatible drugs is called the intentional chemical incompatibility. 2. Un-Intentional: When the prescriber Unknowingly prescribe the incompatible drugs is called the Un-intentional chemical incompatibility. 16  Precipitate Yielding Interactions There are two methods for dispensing of diffusible & indiffusible solids; 1. Method A: 2. Method B: 3. Method A: Use when diffusible precipitate is formed. Divide the vehicle in to two equal portion. Dissolve one of the reacting substance in one portion of the vehicle & second reacting substance with second portion of the vehicle. Lastly slowly add one portion in to the another with rapid stirring. Rx Sodium hydroxide 2g Sodium chloride 2g Water q.s. 100ml 17 1. Method B: Use when Indiffusible precipitate is formed. Divide the vehicle in to two equal portion. Dissolve one of the reacting substance in one portion of the vehicle. Weight a suitable quantity of Compound tragacanth powder/ Tragacanth Mucilage & transfer in to mortar, to it add second portion of the vehicle to produce smooth mucilage then add second reacting substance. Lastly mixed two portion by slowly adding one portion in to the another with rapid stirring. Rx Sodium hydroxide 2g Sodium chloride 2g Water q.s. 100ml 18  Example of chemical incompatibility with there methods of correction 1. Alkaloidal Incompatibility a) Alkaloidal salts with alkaline substances b) Alkaloidal salts with soluble iodides c) Alkaloidal salts with Salicylates d) Alkaloidal salts with Tannins e) Alkaloidal salts with soluble iodides & Bromides 2. Soluble Salicylate incompatibility a) Soluble salicylate with ferric salts b) Soluble salicylate & benzoate with acid c) Soluble salicylate with Alkali bicarbonates 3. Soluble iodides incompatibility a) Oxidation of iodides with ferric salts b) Oxidation of iodides with Potassium chlorate c) Oxidation of iodides with Quinine Sulphate 4. Chemical Incompatibility causing evolution of carbon dioxide a) Sodium bicarbonates with soluble calcium & magnesium salts b) Sodium bicarbonates with soluble calcium & magnesium salts 5. Miscellaneous chemical incompatibility a) Potassium Chorate with Oxidisable Substances: b) Soluble barbiturate with ammonium bromide c) Incompatibility of Liquorice Liquid extract 19  Alkaloidal Incompatibility.1 a) Alkaloidal salts with alkaline substances Alkaloids are very slightly soluble in water where as alkaloidal salts are soluble in water. When this alkaloidal salts are reacts with alkaline substances Diffusible precipitate is formed. Hence follows method A for precipitate yielding interaction. Rx Strychnine Hydrochloride solution 6ml Aromatic sprit of Ammonia 4ml Water up to 120ml Make a Mixture 20 b) Alkaloidal salts with Soluble iodide Eg: When Strychnin is prescribe with pottassiun iodide insoluble hydroiodide is formed which is diffusible ppt Hence follow methods A for ppt. yielding interactions. c) Alkaloidal salts with Salicylates Example Rx Quinine Hydrochloride 0.12g Sodium Salicylate 4g Water up to 100ml Make a Mixture In this Prescription, 21 2. Soluble Salicylate incompatibility a) Soluble salicylate with ferric salts Example Rx Ferric Chloride Solution 2ml Sodium Salicylate 3g Water q.s. 90ml Make a Mixture In this Prescription 22 b) Soluble salicylate & benzoate with acid Example Rx Sodium Salicylate 3g Syrups of Lemon 15ml Water q.s. 60ml Make a Mixture In this Prescription Syrup of lemon contains citric acid when it react with Sodium Salicylate it gives Salicylic Acid as indiffusible ppt. To correct this follows method B for precipitate yielding interactions or replace the lemon syrups with simple syrups. 23 Soluble iodides incompatibility.3 a) Oxidation of iodides with ferric salts When ferric salts reacts with soluble iodides it get converted in to ferrous salt. To prevent this incompatibility , the prescriber may substitute ferric salts with iron & ammonium citrate. Ultimately the iron is converted in to an organic compound which does not yield ferric ions. b) Oxidation of iodides with Potassium chlorate When soluble iodides reacts with Potassium chlorate free iodine is liberated. To prevent this incompatibility the two reacting substance dispensed separately. 4. Chemical Incompatibility Causing Evolution of Carbon dioxide When carbonates and bicarbonates are dispensed in the presence of acidic drugs they react together with evaluation of carbon dioxide. If the reaction is not allowed to complete there may be a chances of bursting of the bottle. To prevent these bursting, the reaction must be completed before transferring the mixture in to dispensing bottle. Hot water can also be use to increased the rate of reaction. a) Sodium bicarbonates with soluble calcium & magnesium salts When Sodium bicarbonates combined with soluble calcium & magnesium salts, due to double decomposition reaction carbon dioxide is formed along with insoluble carbonates which is a diffusible ppt. These reaction is slow at room temperature so use hot water to increase the rate of reaction. This mixture is dispensed when effervescence is ceased. The precipitation of carbonate formed are diffusible in nature hence follow method A for precipitate yielding interactions. 25  5. Miscellaneous Chemical Incompatibility a) Potassium Chorate with Oxidisable Substances: When potassium chlorate is prescribed along with oxidisable substances charcoal, sulphur sugar organic compound or any oxidisable substance, during dispensing if heating /trituration is done there are chances of explosion. To avoid this ingredients should be powdered separately in dry mortar & mix gently with clean spatula on ointment tile,without any friction. 26  3. Therapeutic Incompatibility Therapeutic Incompatibility may be a result of prescribing certain drugs to produces a specific degree of pharmacological action but the nature or intensity of action produced is different from that intended by the prescriber. Therapeutic Incompatibility may be due to following reasons: 1) Error in dosage 2) Wrong name or dosage form 3) Contra-indicated drugs 4) Synergistic & Antagonistic drugs 5) Drug Interaction 27 1. Error in dosage: It is the most serious type of error in dispensing so, it is the duty of pharmacist to check the prescription before dispensing. Rx Codeine Phosphate 0.5 g Prepare 10 powders This is an example of over dosage. The intension of physician may be to prescribe 5 mg but he has given 0.5 g (500mg). In this case refer the prescription back to the prescriber for correction of over dosage of Codeine phosphate. 2. Wrong name or dosage forms: Certain drugs have quite similar names like Prednison & prednisolon, Digoxin & Digitoxin so it may create a problem during dispensing. Many times drugs are available in different dosage forms and hence it is necessary to mention the dosage forms of a drugs. 3. Contra-indicated drugs Certain drugs are contraindicated in particular patient whom are allergic to it. Eg: Penicilline & Sulpha drugs are contraindicated in patients who are allergic to it. So in this case refer prescription back to the prescriber for correction. 28 4. Synergistic & antagonistic drugs Synergism: Example Rx Amphetamine Sulphate 20mg Ephedrine sulphate 100mg Syrups q.s. 100ml Make a Mixture In this combination Amphetamine sulphate & Ephedrine sulphate are sympathomimetic drugs so there is need to reduced the dose of each drugs or refer the prescription back to the prescriber for correction. Antagonism: Example Rx Acetyl salicylic acid 0.6g Probenicid 0.5 g Acetyl salicylic acid & Probenicid are used in the treatment of gout but the combination of these two drugs leads to neutralization so, refer the prescription back to the prescriber for correction. 29 5. Drug Interaction When two or more drugs are administered together effect of one drugs is alter by the simultaneous administration of another drug. Example Rx Tetracycline hydrochloride 250mg Prepared 10 capsules Direction: Take 1 capsule every six hour with milk Tetracycline is inactivated by calcium which is present in milk so tetracycline capsules should not be given with milk so, refer the prescription back to the prescriber for correction or change the direction take 1 capsule every 6 hours with water. 30 Thank You