PHYSICOCHEMICAL INCOMPATIBILITIES

PHYSICOCHEMICAL INCOMPATIBILITIESDrug IncompatibilityProblems that arise during the dispensing and compounding of the Rx or administration of the drugIt affects the appearance, elegance, safety and therapeutic efficacy of drug

Drug Incompatibility refers to interactions between two or more substances which lead to changes in chemical, physical, therapeutic properties of the pharmaceutical dosage form.

2Types of IncompatibilitiesTherapeuticPhysicalChemicalTherapeutic Incompatibility1. Pharmacokinetics:ADME2. Pharmacodynamics synergism.antagonism, altered cellular transport, effect on the receptor involve the effect of a drug on another from the point of view that includes absorption ,distribution , metabolism and excretion.

Pdynamics are related to the pharmacological activity of the interacting drugs e.g 4Therapeutic IncompatibilityPharmacokinetic interactions1. Altered GIT absorption2. Displaced protein binding3. Altered metabolism4. Altered renal excretion

Altered pH b. Altered bacterial flora c. Formation of drug chelates or complexes d. Drug induced mucosal damage and altered GIT motility

Altered pH: The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does. Altered intestinal bacterial flora EX., In 10% 0f patients receive digoxin..40% or more of the administered dose is metabolized by the intestinal flora. Complexation or chelation: TCA + Iron

Displaced protein binding It depends on the affinity of the drug to plasma protein. The most likely bound drugs is capable to displace others. The free drug is increased by displacement by another drug with higher affinity.

5Therapeutic IncompatibilityPharmacodynamic interactionsa. Additive b. Synergismc. Potentiationd. AntagonismIt means alteration of the dug action without change in its serum concentration by pharmacokinetic factors.

. Additive effect-occurs when two or more drugs having the same effect are combined and the result is the sum of the individual effects relative to the doses used. This additive effect may be

Synergistic effect- occurs when two or more drugs, with or without the same overt effect, areused together to yield a combined effect that has an outcome greater than the sum of the singledrugsactive components alone

Potentiation-describes a particular type of synergistic effect-a drug interaction in which only oneof two drugs exerts the action that is made greater by the presence of the second drug.

-reactions have the opposite effect of synergism and result in a combined effect thatis less than either active component alone. (eg. Protamine administered as an antidote toanticoagulant action of heparin) Examples:- -adrenoceptor antagonists diminish the effectiveness of -receptor agonists, such as salbutamolOr terbutaline

6Therapeutic IncompatibilityProbenecid + PenicillinCaffeine + Ergotamine tartrate Antiparkinson drugs + Antipsychotic drugsUse of Probenecid to prolong the activity of penicillin

It is the modification of the therapeutic effect of one drug by the prior concomitant administration of another. (It is also called drug interactions) Intentional or Expected incompatibilitiesCaffeine decreases solubility of ergotamine (both are vasoconstrictors? For the treatment of HeadacheAntiparkinson + antipsychotic= extrapyramidal effect (bradyphrenia, tremors7Physical IncompatibilityInteraction between two or more substances which lead to change in color, odor, taste, viscosity Incomplete solution- production of non-homogenous product due to insolubility or immiscibilityEx: resins in H2O, oils+silicones+H2OResins- Remedy: adjust solvent system, add emulsifying agents or suspending agentsUnsightly, unpalatable, non-uniform mixtures, inaccurate dosagesEasiest to detectPredicted from physicochemical characteristics of the drug

Physical incompatibilities are often called pharmaceutical incompatibilities.Def.: Interaction between two or more substances which lead to change in color, odor, taste, viscosity andmorphology.Manifestations of physical incompatibility:The following list outlines the various ways incompatibility between or among drug agentsmay be manifested.1. Insolubility of prescribed agent in vehicle2. Immiscibility of two or more liquids3. Liquification of solids mixed in a dry state (called eutexia)

8Physical IncompatibilityPrecipitation= materials in solution forced out of solution due to dehydration or salting out, change in solvent system and temperaturesalting out- aqueous solutions of slightly soluble non-electrolyte + electrolyteex: hydroalcoholic solution + electrolytes; sugars + hydrophilic colloids; NaCl/KCl benzoic acid salting in- increased solubility of organic compounds + saltex: globulins + dilute salt solutionsSalting in Change in solvent system = tinctures or fluidextracts + syrup or other aq. SolutionTemperature= KI, H3BO3, Ca(OH)2 * substance endothermically dissolved results to pptn if stored below RTRemedy: change the order of mixing, temp, pH monitoring (decrease pH is preferred to prevent pptn)9Factors affecting solubility (for Ca/PO4 mixture)Concentration of CaSalt form of CaConcentration of amino acidsAmino acids decompositionConcentration of dextroseTemperature of solutionpH of solutionPresence of other additivesOrder of mixingPhysical IncompatibilitySalting-out- occurs when electrolyte is added to an aq. solution. The salt competes with the solute for water molecule to allow hydration reduced solubility of the dissolved material Liquefaction eutexia or formation of eutectic mixtureEx: phenol, menthol, salol, thymol, ASA + paracetamol; ibuprofen stearic acid; stearyl ROH,/Ca or Mg stearate Release of H2O of hydration (atropine SO4, FeSo4, citric acid and MgSO4) -- efflorescentAbsorbs water (hygroscopic) (NaOH,NH4Br,CaCl2.6H2O)Remedy: triturate separately, addition of inert diluents, dispense powders as separate sets (inert such as MgO or MgCO3) divided between the reacting ingredients)11Physical IncompatibilityIncorrect form prescribedEx: AtSO4liquid petrolatum*Alkaloidal salt is insoluble in liquid petrolatum free alkaloid is solubleVaporizationvolatilization (drug loss-volatile oils, NTG, alcohols)Remedy: dispersion of solid drug in macromolecule, packaging (NTG tablets)Physical IncompatibilityPolymorphism polymorphs with lowest free energy has the highest melting point and most stable and lowest dissolution rateEx: steroids, chloramphenicol palmitate, theobroma oil/cacao butter- 2 polymorphs ()Water loss- evaporation of H2O from liquid preparation - crystallizationEx: water loss from o/w creams - surface rubbery feel, cracking of emulsionRemedy: store in well-closed containers form = upon excessive heating is transformed to

13Chemical IncompatibilityReaction between two or more substances which lead to change in chemical properties of pharmaceutical dosage form.Unintended and undesirable chemical changes or reaction Change in color, evolution of gas, precipitation, therapeutic incompatibilityDetected by analytical methods

14Types:a. Immediate (precipitation, color change, effervescence)(DO NOT DISPENSE)b. Delayedmixtures react at a slower rate; may or may not result to a loss in therapeutic activitydispense if to be consumed before 10% of therapeutic activity is lostClassification:1. Oxidation- gain of O, removal of H, loss of e-Accelerated by light, trace metal ions, coinage metals, O2 from air, Ex: stannous salts -- stannic form (anticariogenic)Fe in Fe +3 --- OA in organic compoundsFe +2 --- RA

amines, many alkaloidal compounds, local anesthetics and tranquilizers*accelerated by excessive storage temp., overdilution, incorrect pH adjustment or presence of catalysts (Fe+3, Fe+2, cupine, or chromium, excess hydrogen or hydroxyl ions, bacterial or mold ednzymes

16Chemical Incompatibility2. HydrolysisA chemical reaction in which water is used to break down a compound; this is achieved by breaking a covalent bond in the compound by inserting a water molecule across the bond Chemical Incompatibility3. Polymerizationsmall repeating units called monomers are bonded to form a long chain polymer. Ex: Formaldehyde Paraformaldehyde (Polymer: white precipitate ) To avoid this formaldehyde must be stored in suitable temperature and addition of methanol 15%.

Ampicillin in high temperature forms polymers which cause allergy.

Factors induce Polymerization:1. Temperature 2. Light 3. Solvent 4. pH 5. Impurities 18Chemical Incompatibility4. Isomerization: Optical isomerization: Conversion of optical active drug into less active Ex: L-adrenaline to D-adrenaline

5. Decarboxylation: Ex.: NaHCO3 Na + CO2

Ex: a. L-Adrenaline is converted to d-adrenaline by change of pH or temperatureb. L-adrenaline is more therapeutically active than d-adrenaline, a although they have the same physical properties but different arrangement of atoms. c. This is not general for other drugs: d-tubocurarine is more active than l-type

It means conversion of drug to its isomer Isomers have: - Identical molecular formulas. - A different arrangement of atoms.

Factors affect optical isomerization : 1. Temperature 2. pH 3. Solvent 4. Impurities

19Chemical Incompatibility6. CO2 absorption: Ex: Ca(OH)2 + CO2 CaCO3 7. Combination: Ex.: Surfactants with positive and negative charges 8. Formation of insoluble complexes: Ex.: Tetracycline + heavy metals

When some pharmaceutical dosage forms contain CO2, precipitate is formed: Take place when the pharmaceutical dosage form contain substances with different charges

20