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PHARMACEUTICAL INCOMPATIBILITIES

PHARMACY STUDENTS

santhipriyanagam
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PHARMACEUTICAL INCOMPATIBILITIES

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  1. INCOMPATIBILITIES N.SANTHI PRIYA ASSOCIATE PROFESSOR DEPARTMENT OF PHARMACEUTICS

  2. DEFINITION • The undesired change taking place in the physical , chemical or therapeutic properties of the medicament of a prescription are mixed together , is termed as INCOMPATIBILITY • While handling a prescription containing combinations many a times problems associated with therapeutic ,physical and chemical properties of the drugs arise

  3. UNINTENTIONAL INCOMPATIBILITY • TOLERATED – interaction is minimized but composition of the prescription is not altered • ADJUSTED – interaction is prevented by addition or substitution of constituents without affecting the medicinal action of the preparation INTENTIONAL INCOMPATIBILITY The prescriber wants that the prescription , be dispensed as it is

  4. 3 CLASSES • THERAPEUTIC INCOMPATIBILITY • PHYSICAL INCOMPATIBILITY • CHEMICAL INCOMPATIBILITY

  5. THERAPEUTIC INCOMPATIBILITY • When the response to one or more drugs in the patient is of a nature or intensity different from that intended , it is known as therapeutic incompatibility REASONS • Dosage errors • wrong dose or dosage form • Contraindicated drug • Synergistic or antagonistic drugs • Drug interactions

  6. DOSAGE ERROR • Dispensing of an overdose of prescription • Any experienced pharmacist should be able to detect such an error while checking the prescription Ex: • Atropine sulphate-0.06gm • Phenobarbital-0.015gm • Asprin-0.300gm If the quantity of atropine sulphate for a single capsule is more than the recommended maximum dose,The physician should be contacted EX-2 Codeine phosphare-0.5gm ONE POWDER TO BE TAKEN AT BED TIME

  7. Wrong dose or dosage form • Possibility of dispensing the wrong drug because of confusingly similar names • Ex: • Prednisone and prednisolone • Protamine and protamide • Digoxin and disgitoxin

  8. Contraindicated drugs • Certain drugs are contraindicated in a particular disease or when a particular patient is allergic to it • Corticosteroids-contraindicated to patients having peptic ulcer • Morphine,barbiturates-dangerous in severe asthma • Pencillin and sulphur drugs - allergic to patients • Vasoconstrictors-should not be given to hypertensive patients

  9. Example-contraindication Sulphadiazine-0.25gm Sulpharmerazine-0.25gm Ammonium chloride -0.5gm Ammonium chloride being a urinary acidifier , would cause deposition of sulphonamide crystals in kidney Hence this contraindicated combination should be avoided

  10. Synergistic or antagonistic drugs Synergistics: • Penicillin derivatives+probenicid • Aspirin +paracetamol Antagonistics: Amphetamine X barbiturate Stimulants X sedatives Cholinergic drugs X anticholinergic drugs Purgatives X antidiarrhoeals Antacids X antibiotics

  11. CHEMICAL INCOMPATIBILITY • Chemical changes which occour due to the interaction of the prescribed substances leading to the formation of a harmful or dangerous product • They often occour by • OXIDATION – REDUCTION • HYDROLYSIS • COMBINATION OF BOTH

  12. Oxidation – reduction • Oxidation -Loss of electrons • Reduction - Gain of electrons Oxidization of prescriptions • On exposure to air • Higher storage conditions • Light • Over dilution • Incorrect pH adjustments • Presence of catlysis

  13. Trace metal ion catalysis - complexing agents like disodium edetate , sodium calcium edetate • Autooxidation of fats and oils ,phenols,aldehydes,vitamins - antioxidants like propylgallate, thymol,BHT,BHA,hydroquinone • Light Reduces siver,mercury,gold salts to metallic form

  14. Acid base reactions • Precipitation • Gas formation • Color development or color change

  15. Precipitation

  16. Evolution of gas • Gas may be evolved due to a chemical reaction between ingredients

  17. Breaking of structure of disperse systems • Gelling agents like carbomers , sodium cmc lose viscoisty by change in pH outside an optimum range • CarbomerpH< 5 and pH> 10 liquify • Alginic acid at pH< 3 precipitates sodium alginate to form sodium derivative

  18. Change in or development of color • Dyes – color -IONIZATION DEPENDING ON pH

  19. HYDROLYSIS DRUGS PRONE TO HYDROLYSIS : Procaine Sulphonamides Chlorothiazide Barbituric acid Aspirin Alkaloids Penicillin ADDITIVES PRONE TO HYDROLYSIS : GELATIN- SUCROSE FLAVORING OILS CHLOROBUTANOL Hydrolysis promoters : • Heat catalysts • Hydrogen ions • Hydroxyl ions Ex: ESTERS, AMIDES, METALS like Zn, Fe

  20. EXPLOSIVE COMBINATIONS

  21. Racemization • Conversion of optically active form of a drug substance to an optically inactive form without a change in chemical constitution associated with reduction in pharmacological activity Examples • Adrenaline • Ephedrine • Norephedrine • HYOSCYMINE – racemizes to atropine

  22. Complexation • The medicaments or excipients get bound to or trapped inside the macromolecules • The complexes are too large to penetrate cell membranes • Reversible complexation is useful • POVIDONE – IODINE Complex : useful to reduce the irritancy and stability of the drug

  23. Other changes • Cementation • Polymerization • Development of heat • Lowering of temperature • Double decomposition • Substitution • Addition

  24. PHYSICAL INCOMPATIBILITIES • They are easier to PREDICT, DETECT AND CORRECTby applying proper technique , mixing, selection of additives etc • They are manifested by • Non-uniform • Unsighty • Unpalatable products

  25. CLASSIFICATION • INSOLUBILITY • PRECIPITATION • SEPERATION OF IMMISCIBLE LIQUIDS • LIQUEFACTION OF SOLID • PHYSICAL COMPLEXATION • MISCELLANEOUS

  26. INSOLUBILITY • When a drug is insoluble in a solvent , it may create in proper administration of the dose • Ex: • Solubility enhancers • Alteration in the volume • Settling - suspending agents • Poor wettability – levigating agents

  27. Precipitation of the drug • A Solubilized substance may precipitate from its solution if a non – solvent for the substance is added to the solution • Poor solvent – order of mixing • Precipitation – suspension • Cap locking – co-solvents • Grainy semisolids – non uniform cooling EX: • HYDROCOLLOIDS +ALC addition --> PPTS • Aromatic waters + electrolytes addition -> VOLATILE OILS precipitates • ELECTROLYTES+ in SOAP EMULSIONS -> cracking

  28. Liquefaction Eutectic substance (LOW MELTING SOLIDS )such as camphor, menthol, thymol if mixed together undergo liquefaction ex: • Eutectic powders • Insufflations • Siedliz powder TO OVERCOME: • Mixtures dispensed separately • Triturate separately with adsorbent to give free flowing product • If already liquefaction occurred -> adsorbed on powder -> filled in capsules -> dispensed

  29. Example – Liquefaction • Menthol – 2g • Camphor -2g • Ammonium chloride – 20g • Make a powder • If the ingredients are triturated together , they shall liquefy due to the formation of eutectic mixture • Powder form is obtained by mixing them separately in suitable adsorbent like Mg Co3 • 3 mixtures dispensed separately to obtain a powder

  30. Adsorption and complexation Drug + excipient Physical complexes • Alter appearance • Alter medicament activity ex : Adsorption of cyanocobalamin by talc as tablet lubricant decrease the adsorption of this vitamin in GIT Adsorption of preservatives like parabens onto drugs lead to loss of antimicrobial activity

  31. INORGANIC INCOMPATIBILITIES • Incompatibilities of metals and their salts • Incompatibilities of acids • Incompatibilities of alkalies ORGANIC INCOMPATIBILITIES BY • Purine bases • Alkaloids • Pyrazolone derivatives • Amino acids • Quaternary ammonium compounds • Glycosides • Anesthetics

  32. INCOMPATIBILITIES OF THE METALS AND THEIR SALTS GROUP 1A ( Li,Na,K,Rb,Cs,Fr) • sodium salicylate + potassium bicarbonate – sodium bicarbonate ppt , darkening due to salicylates • K+ Tartaric acids- ppt , Sulfurated potash incompatible with acids and liberate H2S • Lithium carbonate – in alkaline or neutral solutions GROUP 1 B (CU,Ag,Au) • Copper salts ppts tannic acid ,arsenates , alkalis etc • Cupric salts – iodides, acetates • Silver salts decomposed by light and form metallic silver • Ago – powerful oxidizing agent and causes explosion when triturated with reducing agents • Gold salts +weak reducing agents - gold metal

  33. INCOMPATIBILITIES OF THE METALS AND THEIR SALTS • Group II- A ( Be,Mg,Ca,Ba,Ra) Mg- • Mg.trisilicate,adsorbs alkaloids , dyes, toxins • MgO – adsorbs moisture,co2 when exposed to air • Mg.sulfate– water soluble salt , but ppts on addition on soluble phosphates,carbonates ,salicylates • Mg.saltsreact with bromide reacts with ammonia –( ANTACIDS X Bromide preparations) Ca- Incompatible with hydroxides , citrates , carbonates , oxalates ,tartrates, phosphates ,forms precipitates except in acids

  34. INCOMPATIBILITIES OF THE METALS AND THEIR SALTS Group II – B: ( Zn, Cd , Hg) Zinc : • Soluble zinc salts incompatible with alkali hydroxides,carbonates, phosphates and converts into insoluble zinc compounds • They also precipitates fatty acids , acacia , proteins , tannins Mercury : Mercury salts reduced to free metals by light , moisture , trituration Mercurous saltsoxidizing agents Mercuric salts Hgcl2 + 4KI Hg + K2HgI4 +2KCl • Mercurous salts ppts alkaloids proteins tannins organic acids • Yellow HgO gets pptd from alkali hydroxide solutions • Combined use of ammoniated mercury + salicylic acid in ointments causes severe irritation due to the formation of mercuric salicylate • Calomel decomposes into mercuric chloride and free mercury when exposed to sunlight or triturated excessively

  35. INCOMPATIBILITIES OF THE METALS AND THEIR SALTS Group III –A ( B,Al , Ga, In Ti ) • Aluminium solutions are acidic • Incompatible to weak acids , borax • Produce effervescence with carbonates • Complexes the penicillin , sulphonamides when mixed with organic salts • Alum incompatible with soluble sulfates

  36. INCOMPATIBILITIES OF THE METALS AND THEIR SALTS Group VII – B( Mn ,Tc ,Re) • Mn hypophosphite ,Mn salts ppt out as Mn.hydroxide • These ppts darkens on standing due to absorption of oxygen • MnO2 is a strong oxidizing agent and causes explosion if triturated with reducing agents like phosphides , hypophosphites and organic substances

  37. INCOMPATIBILITIES OF THE METALS AND THEIR SALTS Group VIII ( Fe, Ru ,Os ,Co ,Rh, Ir ,Ni , Pd, Pt ) Ferrous salts in aqueous solutions are unstable They gets oxidized to ferric state by precipitation of a basic ferric salt 4FeSO4 + 2H2O+ O2 4Fe(OH)SO4 Oxidation reaction can be prevented by adding iodides and hypophosphites Incompatible with alkali hydroxides – white ppt of Fe(OH)2 – green – brown due to oxidation Ferric salts gets reduced to ferric state by iodides and hypophosphites 2Fe 3+ + 2I- 2 Fe 2+ + I2 Precipitation can be prevented by addition of organic hydroxy acids or their salts such as tartrates, citrates etc or polyhydric alcohols such as glycerin and sugars

  38. INCOMPATIBILITIES OF NON METALS • Most of the non-metallic elements form acids and exhibit acidic incompatibilities • Other non-metal incompatibilities include – • Carbon • Sulphur • Iodine

  39. INCOMPATIBILITIES OF NON METALS Carbon – • Charcoal gets easily oxidized , - so don't triturate with oxidizing agents • High adsorptive characteristics – so dispensed separately if potent drugs are present since they may get inactivated SULPHUR – Sulphur gets readily oxidized in presence of water On heating with fixed hydroxides – solubilizes forming metal thiosulphates 14S + 12 KOH K2S3+2K2S3O3+2K2S+K2S5+6H2O Iodine- • Iodine acts as an oxidizing agents in alkaline solution • Incompatible with reducing agents like hypophosphite's , arsenites I2+H3AsO3+H2O 3HI+H3AsO4 • Iodine + turpentine oil - gives explosive combination • Iodine + potassium iodide – precipitates alkaloids • Iodine + oxidizing agents – gives iodates

  40. INCOMPATIBILITIES OF ACIDS • ALL ACIDS EXHIBIT INCOMPATIBILITIES • Strong acids • Weak acids • Oxidizing acids • Reducing acids • Acidic preparations

  41. INCOMPATIBILITIES OF ACIDS • Strong acids highly ionize in aq.solutions • Sulphuric acid chars many organic substances , forming carbon , charring of sugar C6H1206 6C + 6H20 • Hot,concentratedsulphuric acid acts as a strong oxidizing agent for metals,non-metals Hg+ 2H2SO4 HgSO4 + SO2 + 2H20 • Orthophosphoric acid reacts with salts of lead and silver to give precipitates

  42. INCOMPATIBILITIES OF ACIDS • Weak acids slightly ionize in aq.solutions • All weak acids reacts with alkali carbonates to give CO2 Oxidising acids -incompatible with org.sub and give explosive combinations • Reducing acids - incompatible with oxidising agents and give explosive combinations • Ergot fluid extracts • Nuxvomica fluid extracts • Compound pepsin elixer • Ammonium acetate solution • Ferric chloride solution • Citric acid syrup DO N T C OMB I NE Carbonates Bicarbonates Chorates Hypochlorites nitrates

  43. INCOMPATIBILITIES OF ALKALIES • Metallic alkaloids precipitate due to solubility changes and salt formation • Strong alkali hydroxides – soluble in water • Weak alkali hydroxides – insoluble in water • Amphoteric alkali hydroxides-soluble in water by addition with acid • Fluid extract of senega • Ammonium valerateelixer • Calcium hydroxide solution • Aromatic spirit of ammonia INCOMPATIBLE WITH ALKALIES Neutralizes acids Precipitates alkaloids Precipitates heavy metals from salt solutions

  44. ORGANIC INCOMPATIBILITIES Some specific incompatibilities include : • Purine bases (xanthines) • Alkaloids • Pyrazolone derivatives • Amino acids • Quaternary ammonium compounds • Glycosides • Anaesthetics

  45. Xanthines • Weak basic properties • Scarcely available in the form of salts with acids • Salts so formed are weak mixtures

  46. Alkaloids

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