Dosage Forms I PDF

Dosage Forms I  Pharmaceutical Incompatibilities Prepared By Dr. Basma Nagy Abd El-Hamid  What is incompatibility? It occurs when two or more ingredients of a prescription mixed together, the undesired changes that may take place in the physical, chemical or therapeut...

Dosage Forms I  Pharmaceutical Incompatibilities Prepared By Dr. Basma Nagy Abd El-Hamid  What is incompatibility? It occurs when two or more ingredients of a prescription mixed together, the undesired changes that may take place in the physical, chemical or therapeutic properties of a medicament is termed incompatibilities. The undesired changes resulting in formation of undesirable product which may affect the safety, efficacy, appearance and stability of the pharmaceutical product.  Incompatibilities may occur during; Compounding Formulation Manufacturing In vitro Incompatibilities Packaging Dispensing Storage  Incompatibilities may occur during; After administration of In vivo drugs Incompatibilities  Types of incompatibilities Physical incompatibilities. Chemical incompatibilities. Therapeutic incompatibilities.  Physical Incompatibilities Interaction between two or more substances which may lead to change in color, odor, taste, viscosity and morphology. It is also called as pharmaceutical incompatibility.  Physical Incompatibilities The various ways of physical incompatibility may be manifested as: A.Insolubility Insolubility of prescribed agents in vehicle. B.Immiscibility Immiscibility of two or more liquids. C.Precipitation Solvent is insoluble when it is added to solution. D. Liquefaction Solids mixed in a dry state become liquid (called eutexia).  The following factors affect the solubility of prescribed agent in vehicle and may render it less soluble: - Change in pH - Surfactant - Complex formation - Co-solvent Any change in previous factors may lead to precipitation of drugs and change in their properties.  A. Insolubility Examples RX Chalk powder 2g Tincture catechu 2 mL Cinnamon water 2 mL Chalk powder is not soluble in water. It gets precipitated when added to aqueous medium. These precipitates are found indiffusible in nature which results in physical incompatibility.  Use of suspending agents is necessary to suspend the precipitated chalk particles. Generally, 2% W/V of compound tragacanth powder is recommended as suspending agent. The corrected prescription is RX Chalk powder 2g Tragacanth 0.6 g Tincture catechu 2 mL Cinnamon water up to 30 mL  Examples Rx Phenol 2% Sodium sulfate 5% Distilled water q.s 120 mL When phenol and sodium sulfate come together, turbidity and decomposition/separation are observed. Phenol is soluble in glycerin. First solve it. Incompabilities are not observed when phenol- glycerin solution mixed with sodium sulfate.  B. Immiscibility When two such ingredients are combined resulting in a non- homogenous product (separation in two phases ), such ingredients are called immiscible. This appears clearly in emulsions, creams, lotions, some types of ointments.  The following factors lead to immiscibility: 1. Incomplete mixing 2. Addition of surfactant with: Unsuitable concentration False time of addition Unsuitable for the type of emulsion 3. Presence of microorganisms Some bacteria grow on constituents of mixture. (e.g. Gelatin Arabic gum)  B. Immiscibility Examples Rx Castor oil 15 mL Distilled water up to 60 mL In this prescription castor oil is immiscible with water due to high interfacial tensions, which is a sign of incompatibility. To overcome this type of incompatibility, emulsification is necessary with the help of an emulsifying agent.  B. Immiscibility Examples Rx Castor oil 15 mL Gum Acacia 2% W/V (???) Distilled water up to 60 mL  C. Precipitation Solubilized substances may precipitate from its solution if a non-solvent for the substances is added to the solution. Resins are insoluble in water. Alcoholic solution of resins + water = precipitated resins. Aqueous dispersions of hydrophilic colloids are insoluble in alcohol. Polysaccharide mucilage + high concentration of alcohol or salts = precipitated colloids.  C. Precipitation Examples Rx Tincture benzoin compound 5g Glycerin 10 mL Rose water up to 100 mL Tincture benzoin compound contain resins. This change in solvent system results in an unavoidable precipitate. Solution: Addition of tincture with rapid stirring yields a fine colloidal dispersion. So there is no need of any suspending agents.  D. Liquefaction (Eutexia) When certain low melting point solids are mixed together, a liquid or soft mass know as eutectic mixture is produced. This occurs due to the lowering of the melting point of the mixture to below room temperature and liberation of hydrates. If such conditions take place, compounding such powders becomes difficult since the ultimate mixture turns to liquid. The medicaments showing this type of behavior are camphor, menthol, phenol, thymol, chloral hydrate, aspirin, sodium salicylates.  D. Liquefaction (Eutexia) Examples Rx Menthol 5g Camphor 5g Water up to 60 mL This mixture is a physical incompatibility because both the ingredients in the prescription are liquefiable of mixed together. Solution: These substances can be dispensed by any one of the following methods: a) Triturate together to form liquid and mixed with an absorbent (light kaolin, magnesium carbonate) to produce a powder. b) The individual medicaments is powdered separately and mixed with an absorbent and then combined together tightly and filled in a suitable container.  Chemical Incompatibilities Reaction between two or more substances which lead to a change in the chemical properties of the pharmaceutical dosage form. Chemical incompatibilities occur due to: pH change. Oxidation-reduction reactions. Acid-base hydrolysis. Double decomposition.  These reactions may be noticed by: Precipitation. Effervescence. Decomposition. Color change. Explosion.  A. Oxidation Air, storage temperature, light, pH value, yeast and bacterial enzymes are effective in this event, which creates a big problem especially in solutions. Adrenaline, phenylephrine, morphine, codeine, vitamin C (in aqueous medium), aspirin (in aqueous medium) are easily oxidized. Heat increases this reaction rate. To prevent oxidation-related incompatibility; Antioxidant should be added to the environment. –Antioxidants absorb the first energy in the environment and prevent oxidation of the substance. Packaging material can also prevent oxidation. –Light and heavy metals may accelerates oxidation  Examples of antioxidants Water soluble Fat soluble Na-sulfite Butyl hydroxy toluene Na- bisulfite Butyl hydroxy anisole Cysteine Amil gallat Ascorbic acid Propyl gallate Alpha tocopherol  B. Reduction It is less common than oxidation. It is found in preparations containing Au, Ag, Hg. Thus, metallic compounds are separated from their salt and released.  C. Racemization Without any change in the chemical structure of the compounds, the optically active form may change and its inactive form may occur. Ex: Adrenaline, ephedrine, noradrenaline...  D. Gas outlet If there is a CO2 reaction with chemical reaction, the mouth of the package should be closed after the gas discharge ends after the recipe is prepared. In aqueous environment, carbonates with acids give CO2 E.g. Magnesium citrate lemonade (MgCO2 is formed)  E. Color Change Color change occurs in most chemical reactions. Depending on pH, color change is observed in the preparations. E.g. Phenolphthalein: colorless in acidic medium, pink-purple in basic medium.  F. Hydrolytic Change An endothermic process is any process which requires or absorbs energy from its surroundings. An exothermic reaction gives off energy to the surroundings. Depending on whether the reaction is exothermic or endothermic, it is necessary to cool or heat the medium to slow down the reaction. If there is heat output in the environment, it is necessary to prevent the volatile substances in the prescription from evaporating and leaving the environment.  Hydrolysis of aspirin in aqueous medium can be given as an example. For this reason, aspirin does not exist in the form of solutions. Penicillin suspensions are prepared in lyophilized form and diluted when used. Because it is hydrolyzed in aqueous medium and is divided into penicilloic acid and penilic acid. The penicilloic acid has no therapeutic effect. Atropine hydrolysis in the form of tropic acid and apoatropin in aqueous medium. Apoatropin returns to belladonin form as a result of temperature increase, and this substance is toxic.  Therapeutic Incompatibilities It is also called drug interactions. It is the modification of the therapeutic effect of a drug by the prior concomitant administration of another. It occurs when a drug or excipient that are antagonists to each other are prescribed together.  Mechanism Pharmacokinetic Pharmacodynamics The effect of a drug Pharmacological on another in activity of the interacting drugs Absorption Synergism Distribution Antagonism Metabolism Altered cellular transport Excretion Effect on the receptor site  Therapeutic Incompatibilities Occur due to following reasons: A. Error in dosage. B. Wrong dose or dosage form. C. Contra-indicated drugs. D. Synergistic and antagonistic drugs i.e. Drug interactions.  A. 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.  Example Rx Atropine sulphate 0.005 g Phenobarbitone 0.015 g Aspirin 0.300 g The recommended dose of atropine for a single capsule is 0.25 to 2 mg. In this prescription, the quantity of the atropine sulphate in each capsule is more than its recommended dose. The prescription is referred back to the prescriber to correct the overdose of the atropine sulphate.  B. 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 Digitoxin. Many drugs are available in different dosage forms. 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 is to check the prescription intensively and if he finds these types of errors, he should immediately consult the prescriber for the clarification.  C. Prescribing contraindicated drugs Corticosteroids are contraindicated in the patients having peptic ulcers. The penicillin and Sulphur drugs are contraindicated in the patients who are allergic. Vasoconstrictors are contraindicated in hypertensive patients. Barbiturates and morphine should not be given to the asthmatic patients.  C. Prescribing contraindicated 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.  Example A combination of aspirin and paracetamol increases the analgesic activity. A combination of penicillin and streptomycin increases the antibacterial activity. Amphetamines show antagonistic effect with the barbiturates.  Midazolam and Ketamine particle Formation (formation of water-insoluble form) Precipitation of Midazolam according to pH change