Incompatibilities in prescription

Incompatibility & Their types

1. Incompatibilities in Prescription Prepared & presented by Ms. Nisha S. Mhaske Lecturer, PRES’s COPD, Chincholi. Email : [email protected] Loknete Dr.Balasaheb Vikhe Patil ( Padmabhushan Awardee ) Pravara Rural Education Society’s College of Pharmacy (D.Pharm) Nashik.

2. Learning Outcomes

3. Contents Incompatibility Types of incompatibility Physical incompatibility Chemical incompatibility Therapeutic incompatibility Reasons & method of correction of incompatibility

4. Incompatibility Definition- “Incompatibility occurs as a result of mixing of two or more Antagonistic Substances & an undesirable product is formed which may affect the safety, efficacy & appearance of the pharmaceutical preparation.” Incompatibility occurs during : Compounding Formulation Manufacturing Packaging Dispensing Storage Administration of drugs

5. Types of Incompatibility Physical Incompatibility Therapeutic Incompatibility Chemical Incompatibility Examples Immiscibility Insolubility Precipitation Liquefaction Types Tolerated Adjusted

6. Physical Incompatibility “When two or more than two substances are combined together, a physical change takes place and an unacceptable product is formed.” Reasons of physical incompatibility:- Immiscibility Insolubility Precipitation Liquefaction Method of correction of physical incompatibility :- Change the order of mixing of ingredients of the prescription Emulsification Addition of suspending agent Change in the form of ingredients By addition, substitution or omission of therapeutically inactive substance to help in compounding of the prescription.

7. Examples & their method of correction of physical incompatibility Immiscibility Oils and water are immiscible with each other. They can be made miscible with water by emulsification. eg ., Rx Castor oil ----- 15 ml Water --up to -- 60 ml Make an emulsion. Method of Correction- castor oil is immiscible with water. To overcome this incompatibility an emulsifying agent is used to make good emulsion.

8. 2. Insolubility It means the inability of material to dissolve in a particular solvent system. Majority of physical incompatibilities are due to insolubility of the inorganic as well as organic compounds in a particular solvent. e.g., Rx Phenacetin 3 g Caffeine 1 g Ornage syrup 12 ml Water upto 90 ml Make a mixture In above example, phenacetin is an indiffusible substance. Compound powder of tragacanth or mucilage of tragacanth is used as a suspending agent to make stable suspension. Method of Correction- suspending agent- chalk, aromatic chalk powder, acetyl salicylic acid, phenacetin , zinc oxide and calamine etc. are added in liquid preparations as a indiffusible solids, so as to increase the thickness of the preparation. It also helps to maintain uniform distribution of the insoluble substances for sufficient long time after shaking the bottle and facilitating uniform measurement of each dose.

9. 3. Precipitation A drug in solution may be precipitated, if drug is insoluble in solvent e.g., resins are insoluble in water. eg ., Rx Tincture Benzoin compound 5 ml Glycerin 15 ml Rose water upto 100 ml Make an lotion Tincture benzoin compound contains resins. The change in solvent system results in an unavoidable precipitate. Addition of tincture with rapid stirring yields a fine colloidal dispersion. So there is no need of any suspending agent. Method of correction- by adding some suitable thickening agent.

10. 4. Liquefaction When certain low melting point solids are mixed together, a liquid or soft mass known as eutectic mixture is produced. This occurs due to the lowering of the melting point of mixture to below room temperature. eg . Camphor, menthol, thymol , phenol, chloral hydrate and aspirin. Method of correction- there are 2 methods: Triturate together to form liquid and mix with an absorbent like Light kaolin or light magnesium carbonate to produce free flowing powder. The individual medicament is powdered separately and mixed with an absorbent and then combined together lightly and filled in suitable containers. eg ., Rx Menthol 5 g Camphor 5 g Ammonium chloride 30 g Light magnesium carbonate 60 g Make an insufflations In this menthol, camphor and ammonium chloride get liquefied on mixing with each other. So, triturate that 3 ingredients together to form liquid. Add light magnesium carbonate and mix it thoroughly to make free flowing powder.

11. Chemical Incompatibility Reaction between two or more substances which lead to change in chemical properties of pharmaceutical dosage form. Chemical incompatibility may be a result of chemical interactions between the ingredients of a prescription and a toxic or inactive product may be formed. While dispensing such prescriptions, the precautions should be taken either to prevent the formation of harmful product or to correct them and the prescriber must be informed in this regard. Chemical incompatibilities often occur due to oxidation- reduction, acid base hydrolysis or combination reactions. These reactions may be noticed by precipitation, effervescence, decomposition, color change or by explosion. Chemical Incompatibilities are of two types- Tolerated- in this, chemical interaction can be minimized by changing the order of mixing or mixing the solutions in dilute forms but no alteration is made in the formulation. Adjusted- in this, chemical interaction can be prevented by addition or substitution of one of the reacting ingredients of a prescription with another of equal therapeutic value. Eg .- caffeine citrate can be substituted with caffeine in sodium salicylate and caffeine citrate mixture.

12. The chemical incompatibility may be Intentional - when the prescriber knowingly prescribes the incompatible drug Un-intentional – when the prescriber prescribes the drugs without knowing that there is incompatibility between the prescribed drugs.

13. Precipitate Yielding Interactions Principle of incompatibility Generally, it is observed that reaction between strong solutions proceeds at a faster rate and precipitates formed are thick which do not diffuse readily. The light diffusible precipitates are formed when dilute solutions of reacting substances are mixed. hence, the reacting substances should be diluted to the maximum extent before mixing them. The precipitates so formed may be diffusible or indiffusible . The method A & B is followed in dispensing the prescription yielding diffusible and indiffusible precipitated respectively.

14. Method A The method is followed when diffusible precipitates are formed in very small quantity. Divide the vehicle in to 2 equal portions. Dissolve one of the reacting substances in one of the portion and the other in the other portion. Mix the two portions by slowly adding one portion to the other by rapid stirring.

15. Method B The method is followed when indiffusible precipitates are formed in large quantity. Divide the vehicle in to 2 equal portions. Dissolve one of the reacting substances in one portion. Weigh a suitable quantity of compound tragacanth powder (2gm per 100 ml of finished product) and transfer in a mortar and use part of second portion of vehicle to produce a smooth mucilage. Then add other reacting substances. Mix the two portions by slowly adding one portion to the other with rapid stirring. A secondary label “Shake the bottle before use” should be fixed on the container whenever method A & B is followed in dispensing the prescription.

16. Examples of chemical incompatibilities and methods of their correction Alkaloidal incompatibility Alkaolidal salts with alkaline substances Alkaloidal salts with soluble iodides Alkaloidal salts with tannins Alkaloidal salts with salicylates Alkaloidal salts with soluble iodides and bromides Soluble salicylates incompatibilities Soluble salicylates with ferric salt Soluble salicylates with alkali bicarbonates Soluble salicylates and benzoates with acids Soluble iodides incompatibility Oxidation of iodides with ferric salts Oxidation of iodides with potassium chlorate Oxidation of iodides with quinine sulphate

17. Chemical incompatibilities causing evolution of carbon dioxide gas Sodium bicarbonate with soluble calcium or magnesium salts Bismuth subnitrate and sodium bicarbonate Borax with sodium bicarbonate and glycerin Miscellaneous chemical incompatibilities Soluble barbiturates with ammonium bromide Potassium chlorate with oxidisable substances Incompatibility of emulsifying agents Colour stability of dyes Incompatibilities of liquorice liquid extract.

18. 1. Alkaloidal Incompatibilities Incompatibility Example Reaction Correction Alkaloidal salts with alkaline substances Rx Strychnine hydrochloride solution— 6 ml Aromatic spirit of ammonia-- 4 ml Water upto --120 ml Make a mixture Diffusible precipitate forms Method A Alkaloidal salts with soluble iodides Strychnine with soluble iodides forms very insoluble hydroiodide . Diffusible precipitate Method A Alkaloidal salts with tannins Alkaloidal salt with tannins, tha alkaoids form tannates Diffusible precipitate Method A Alkaloidal salts with salicylates Quinine hydrchliordie combines with sodium salicylate Indiffusible precipitate Method B Alkaloidal salts with soluble iodides and bromides Alkaloid with soluble iodides and bromides forms insoluble hydroiodides & hydrobrmides Insoluble but diffusible precipitate forms Method A

19. Soluble salicylates incompatibilities Incompatibility Example Reaction Correction Soluble salicylates with ferric salt Rx Ferric Chloride solution– 2 ml Sodium Salicylate – 3 gm Water up to -- 90 ml Make a mixture Indiffusible precipitates Method B Soluble salicylates with alkali bicarbonates Sodium salicylate and sodium benzoate react with sodium bicarbonate Dark brown color is formed Add liquid extract of liquorice Soluble salicylates and benzoates with acids Sodium salicylaye and sodium benzoate react with acid Salicylic acid & benzoic acid precipitate forms. Indiffusible precipitates Method B

20. 3. Soluble Iodides Incompatibility Incompatibility Example Reaction Correction Oxidation of iodides with ferric salts Ferric salt react with soulble iodide forms ferrous salt Substitute ferric salt with iron and ammonium citrate. Oxidation of iodides with potassium chlorate Soluble iodides react with potassium chlorate Free iodine is liberated Two reacting substances must be dispensed separately Oxidation of iodides with quinine sulphate Quinine sulphate is not freely soluble in water. It is made soluble in Dil.H2SO4 The sulphuric acid liberates hydroiodic acid from the potassium iodide & the hydroiodic acid is partly oxidised by the sulphuric acid, yielding iodine. The iodine, hydroiodic acid and quinine suphate then combine to form a compound called herapathite or iodosulphite of qunine . Patient should be supplied with a mixture for 3 days only. In case, patient requires a mixture for more than 3 days both the solutions are prepared in half the volume of water & supplied in a separate bottle.

21. 4. Chemical Incompatibilities Causing Evolution of carbon Di-oxide Gas When carbonates and bicarbonates are dispensed in the presence of an acid or acidic drug in mixture, they react together with the evolution of carbon dioxide gas. Incompatibility Reaction Correction Sodium bicarbonate with soluble calcium or magnesium salts Decomposition reaction forms. Carbon dioxide is evolved. Diffusible precipitates Reaction must be accelerated by using hot water. Method A Bismuth sub nitrate and sodium bicarbonate Carbon dioxide is evolved. Reaction must be accelerated by using hot water & mixture should not be transferred to a bottle until the effervescence ceases. Borax with sodium bicarbonate and glycerin Carbon dioxide is evolved. Mixture should not be transferred to a bottle until the effervescence ceases.

22. 5. Miscellaneous Chemical Incompatibilities Incompatibility Example Reaction Correction Soluble barbiturates with ammonium bromide Soluble barbiturate with ammonium bromide in presence of water Indiffusible precipitates Method B Potassium chlorate with oxidisable substances Potassium chlorate with charcoal, sulphur, sugar organic compounds, during dispensing if heating or trituration is done there are chances of explosion. Separately powdered substance in dry and clean mortar and mixed with a clean spatula on ointment tile without any friction. Incompatibility of emulsifying agents Emulsion s prepared with alkali metal, ammonium and triethanolamine soaps are incompatible with salts producing polyvalent cations . Due to double decomposition, a polyvalent soap is formed which inverts the emulsion. Sometimes an emulsifying agent cause an inversion in an emulsion product. Colour stability of dyes The color of the most of the dyes used in pharmaceutical formulations are influenced by their ionization which depends on pH of the solution. Incompatibilities of liquorice liquid extract. Liquorice liquid extract is not useful as a flavoring agent in acidic mixtures. Diffusible ppt forms, hence Method A used.

23. Therapeutic incompatibility Therapeutic incompatibility may be as a result of prescribing certain drugs to a patient with the intention to produce a specific degree of pharmacological actions, but the nature or intensity of the action produced is different from that intended by the prescriber. This occurs due to following reasons:- Error in dosage Wrong dose or dosage form Contra-indicated drugs Synergistic and antagonistic drugs Drug interaction

24. 1. Error in dosage Many therapeutic incompatibilities result from errors in writing or interpreting the prescription order. The most serious type of the dosage error in the dispensing is overdose of a medication. E.g., Atropine sulphate capsules Rx Atropine sulphate - 0.005g Phenobarbitone - 0.015g Aspirin - 0.300g Causes:- In this prescription, the quantity of the atropine sulphate in each capsule is more than its recommended dose. Remedy:- The prescription is referred back to the prescriber to correct the overdose of the atropine sulphate. The recommended dose of atropine for a single capsule is 0.25 to 2mg.

25. 2. Wrong dose or dosage form There are certain drugs which have quite similar names and there is always a danger of dispensing the wrong drug. E.g., Prednisone and Prednisolone Digoxin and Dig toxin Some times many drugs are available in the different dosage forms and hence, if the dosage form is not clearly mentioned on the prescription, it becomes necessary to seek clarification from the prescriber. The responsibility of the pharmacist becomes to check the prescription intensively and if he finds these types of errors he should immediately consult the prescriber for the clarification.

26. 3. Contra-indicated drugs There are certain drugs which may be contra-indicated in a particular disease or a particular patient who is allergic to it. For Example, Corticosteroids are contra-indicated in the patients having peptic ulcers. The penicillin and sulpha drugs are contra-indicated in the patients who are allergic. Vasoconstrictors are contra-indicated in hypertensive patients. Barbiturates and morphine should not be given to the asthmatic patients. E.g., Sulphadiazine capsules Causes:- Ammonium chloride is a urinary acidifier. It causes the deposition of the Sulphonamide crystals in the kidney. Remedy: - Before prescribing such substances a doctor must be careful. If he does not, a Pharmacist shows his caliber to point out such type of the doctor’s error. Such must Immediately be referred back to the concerned doctor and get corrected.

27. 4. Synergistic and antagonistic drugs When two drugs are prescribed together, they tend to increase the activity of each other which is known as SYNERGISM. When two drugs are prescribed together, they tend to decrease the activity of each other which is known as ANTAGONISM. For example, A combination of aspirin and paracetamol increases the analgesic activity. A combination of penicillin and streptomycin increases the antibacterial activity. Amphetamines show its antagonists effect with the barbiturates. E.g., Amphetamine sulphate syrup Causes:- In this prescription, there is a combination of two sympathomimetic drugs There by causing additive effect. Remedy:- The prescription is referred back to the prescriber for necessary corrections

28. 5. Drug interaction The effect of one drug is altered by the prior or simultaneous administration of another drug. The drug interaction can usually be corrected by the proper adjustment of dosage if the suspected interaction is detected. E.g., Tetracycline capsule - 250mg capsules Direction: - Take one capsule every 6 hours with milk. Causes:- Tetracycline is inactivated by calcium present in milk. So, it should not be taken with milk. Remedy:- In this prescription, the therapeutic incompatibility is unintentional. So, the prescription is referred back to the prescriber to change the direction.

29. Conclusion Incompatibility is defined as a change resulting and an undesirable product is formed, which may affect the safety, efficacy, appearance and stability of the pharmaceutical product. It is of three types. It includes physical, chemical and therapeutic incompatibilities. This presentation gives the detailed information about the types, causes and how to overcome these types of incompatibilities. The occurrence of chemical incompatibilities can be overcome by two methods which include method A&B.

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