Pharmaceutical Incompatibility PDF

# Ex-20 ## Pharmaceutical Incompatibilities **By:** Prof. F. C. Kenechukwu, PhD, MPSN, MNYA, Affiliate Fellow African Academy of Sciences **Department of Pharmaceutics, University of Nigeria, Nsukka.** ## Definition Incompatibility is defined as a change resulting when an undesirable product is fo...

# Ex-20 ## Pharmaceutical Incompatibilities **By:** Prof. F. C. Kenechukwu, PhD, MPSN, MNYA, Affiliate Fellow African Academy of Sciences **Department of Pharmaceutics, University of Nigeria, Nsukka.** ## Definition Incompatibility is defined as a change resulting when an undesirable product is formed, which may affect the safety, efficacy, appearance and stability of the pharmaceutical product. Incompatibilities occur when the components of a medicine interact in such a way that properties of that medicine are adversely affected. Incompatibilities occur during: - Compounding - Formulation - Manufacturing - Packaging - Dispensing - Storage - Administration of drugs ## Ways of detecting Incompatibility The incompatibilities may be detected by changes in the physical, chemical, and therapeutic qualities of the medicine. In other words, it may be detected by: - Physical change. - Chemical change. - Therapeutic change. ## Importance Of Determining Incompatibility Incompatible products may effect: - Safety of medicament. - Efficacy of product. - Appearance of a medicine. - Purpose of medication. ## Types of Pharmaceutical Incompatibilities 1. Physical incompatibilities 2. Chemical incompatibilities 3. Therapeutic incompatibilities. ### (A) Meaning, Manifestations, Correction and Prevention of Physical Incompatibilities This occurs when two or more substances are combined together and a physical change takes place leading to an incompatible product - change in color, odor, taste, viscosity and morphology. **Consequences include:** - Formation of unsighted product. - Non uniform dosage form. - Removal of Inaccurate dose. - Improper Therapeutic effects. **Manifestations of physical incompatibilities include:** 1. Insolubility - insolubility of prescribed agents in vehicle. 2. Immiscibility - immiscibility of two or more liquids. 3. Precipitation - occurs due to solvent is insoluble when it is added to solution. 4. Liquefaction - liquefaction of solids mixed in a dry state (called eutexia). ## Insolubility This is the inability of material to dissolve in a particular solvent system. The majority of incompatibilities is due to insolubility of the inorganic as well as organic compounds in particular solvents. ### Criteria for determining solubility | Condition | Amount Of Solvent Require to Dissolve 1 Part Of Solute | |---|---| | Very soluble | less than 1 part | | Freely soluble | 1-10 parts | | Soluble | 10-30 parts | | Sparingly soluble | 30-100 parts | | Slightly soluble | 100-1000 parts | | Very slightly soluble | 1000-10,000 parts | | Practically insoluble | More than 10,000 parts | The following factors affect the solubility of prescribed agent in vehicle and may render it less soluble: - Change in pH - Milling - Surfactant - Chemical reaction - Complex formation - Co-solvent - Any change in previous factors may lead to precipitation of drugs and change in their properties. - Substances like chalk, acetyl salicylic acid, succinyl sulphothiazole, zinc oxide, and calamine are the common examples of in diffusible solids. - Some tinctures containing resins or chlorophyll may provide precipitation when added to the aqueous system. **E.g.:-Mixture of prepared chalk** Rx - Chalk powder -2g - Tincture catechu - 2ml - Cinnamon water - 2ml **Causes:** Chalk powder is not soluble in water. It gets precipitated when added to aqueous medium, These precipitates are found in diffusible in nature which results in physical incompatibility. **Remedy (correction/prevention):** - 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:** **Mixture of prepared chalk** Rx - Chalk powder-2g- - Tragacanth - 0.4g - Tincture catechu - 2ml - Cinnamon water up to 30ml. **Examples Of Insoluble Combinations:** - Some indiffusible solids such as Chalk, Aspirin, Phenobarbitone, Succinyl sulphathiazole etc - Some Antibiotics like Cortisone Acetate, Hydrocortisone Acetate, Procaine benzyl penicillin. - Constituents of alcoholic vegetable drugs may precipitate when the solvent is changed (On addition of water). For e.g. tinctures of Belladonna and hyoscyamus. - Resindus tincture is precipitated when added to water. For e.g. Myrrh Tincture. ### Methods Of Rectifying Insolubility - Co solvency: for e.g. we may use alcohol, propylene glycol, syrups. - Complexation: for e.g. formation of tri-iodide complex, complexation of caffeine with Sodium Benzoate. - Hydrotrophy: for e.g. Hyoscamine with tween. - Solubilization; for e.g. Fats soluble vitamins, certain antibiotics. ## Immiscibility **Miscible solution:** The components of an Ideal solution are miscible in all proportions for e.g. water and ethanol, propylene glycol and water, propylene glycol and acetone etc. **When two ingredients are combined resulting in a non-homogenous product, such ingredients are called immiscible to each other and the phenomenon is called immiscibility.** This manifestation appears clearly in emulsions, creams, lotions, some types of ointments. **Separation in two phases is noticed in these pharmaceutical dosage forms. Storage must be at room temperature to prevent separation.** **Examples:** - Oil and water. For e.g. Castor oil, Olive oil. - Concentrated Hydro alcoholic solutions of volatile oils (spirits and concentrated water). The following factors can lead to immiscibility: - Incomplete mixing. - Addition of surfactant with, unsuitable concentration, false time of addition, unsuitable for the type of emulsion. - Presence of micro-organisms - Some bacteria grow on constituents of mixture. E.g.:- Gelatin, Arabic gum (acacia), while others produce enzymes which oxidize the surfactant. - Temperature - Oils and water are immiscible with each other which shows physical incompatibility. **E.g.:- Castor oil emulsion** Rx - Castor oil-15ml - Water-60ml **Causes:** In this prescription castor oil is immiscible with water due to high interfacial tensions, which is a sign of incompatibility. **Remedy (correction/prevention):** To overcome this type of incompatibility, emulsification is necessary with the help of an emulsifying agent. The corrected prescription is i - Castor oil-15ml - Acacia - 2% W/V - Water-up to 60ml. ### Methods Of Rectifying Immiscibility - Vigorous shaking / stirring. - Emulsification or solubilization for e.g. Fats soluble Vitamins, Certain antibiotics like Chloramphenicol, Amphotericin B, Analgesics like Aspirin, Acetanilide & phenacetin many alkaloids and glycosides etc are made soluble by the technique of solubilization. ## Precipitation Solubilized substances may precipitate from its solution if a non-solvent for the substances is added to the solution. **E.g.:- Resins are insoluble in water** - Alcoholic solution of resins + water =precipitated resins. - Aqueous dispersions of hydrophilic colloids (polysaccharide mucilage + high concentration of alcohol or salts) =precipitated colloids. - High concentration of electrolytes causes cracking of soap emulsion by salting out the emulsifying agents. Vehicles (one or more organic liquids) use to dissolve medicaments of low solubility; water soluble adjuvant practically inorganic salts may be precipitated in such vehicles. When tinctures containing resinous matter are added in water, resin agglomerates-forms in diffusible precipitates. This can be prevented by slowly adding the undiluted tincture with vigorous shaking. Suspension or by adding some suitable thickening agent or suspending agent. **E.g.- Lotion of compound tincture of benzoin.** Rx - Tincture benzoin compound - 5g - Glycerin - 10ml - Rose water up to 100ml **Causes:** Tincture benzoin compound contain resins, This change in solvent system results in an unavoidable precipitate. **Remedy:** Addition of tincture with rapid stirring yields a fine colloidal dispersion. So, there is no need of any suspending agents. ## 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 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, etc. **E.g.-Insufflations** Rx - Menthol - 5g - Camphor - 5g - Water-60ml **Causes:** This mixture is a physical incompatibility because both the ingredients in the prescription are liquefiable of mixed together. **Remedy:** These substances can be dispensed by any one of the following methods: (Method A) Triturate together to form liquid and mixed with an absorbent (light kaolin, magnesium carbonate) to produce the following powder. (Method B) The individual medicaments are powdered separately and mixed with an adsorbent and then combined together tightly and filled in a suitable container. **Hence the corrected prescription is** Rx - Menthol - 5g - Camphor - 5g - Light kaolin- 0.2g **Examples of substances that liquefy:** Camphor, menthol, phenol, thymol, chloral hydrate, sodium salicylate, Aspirin, phenazone. **Methods Of Rectifying Liquefaction:** By the use of absorbent like kaolin, light magnesium carbonate. ### (B) Meaning, Manifestations, Correction and Prevention of Chemical Incompatibilities Reaction between two or more substances which lead to change in chemical properties of pharmaceutical dosage form. As a result of this a toxic or inactive product may be formed. Chemical incompatibilities occur, due to the chemical properties of drugs and additive like: - pH change - Oxidation-reduction reactions - Acid-base hydrolysis - Double decomposition - Complex formation (formation of insoluble complexes) - Polymerization - Isomerization - Decarboxylation - Absorption of CO2 These reactions may be noticed by: - Precipitation - Effervescence - Decomposition - Color change - Explosion - Oxidation: Oxidation is defined as loss of electrons or gain of oxygen. - Auto-oxidation: It is a reaction with oxygen of air which occur spontaneously without other factors. - Pre-oxidants: are substances catalyze oxidation process i.e. metals, some impurities. - Hydrolysis: A 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. - Polymerization: In polymerization, small repeating units called monomers are bonded to form a long chain polymer. - CO2 – absorption: - When some pharmaceutical dosage forms contain CO2, precipitate is formed. ## Types of Chemical Incompatibilities **Based on chemical interactions:** - **Tolerated incompatibility:** - In this type incompatibility, the chemical interactions can be changing the order of mixing the solutions in dilute forms, without or by changing the order of mixing. - **Adjusted incompatibilities:** - In adjusted incompatibility change in the formulation is needed with a compound having equal therapeutic value. E.g.: substitution of caffeine citrate with caffeine in sodium salicylate and caffeine citrate mixture. **Based on nature of chemical reaction:** - **Immediate incompatibilities:** - If the chemical reaction takes place, immediately after combining the prescription ingredients, they are called immediate incompatibilities. Hence, they should be dispensed only after correction. - **Delayed incompatibility:** - When the chemical reaction proceeds at a very slow rate and no appreciable visible change occurs which may develop on keeping the product for a long time are called delayed incompatibility. **Based on the prescriber:** - **Intentional** - When the prescriber knowingly prescribes the incompatible drugs. - **Unidirectional (unitentional)** - When the prescriber prescribes the drugs without knowing that there is incompatibility between the prescribed drugs. **Generally, reaction between strong solution proceed at a faster rate and the precipitates formed are thick and do not diffuse readily. Reaction between the dilute solutions proceeds at a slow rate and the precipitates formed are light and diffuse readily in the solution. Hence, the reacting substances should be diluted as much as possible before mixing.** **Examples of chemical incompatibilities and their correction:** **Alkaloid incompatibility -** - Alkaloidal salts with alkaloid substances - Alkaloidal salts with soluble iodides - Alkaloidal salts with tannins - Alkaloid salts with salicylates - Alkaloid with soluble iodides and bromides. **Soluble salicylates incompatibility –** - Soluble salicylates with ferric salts - Soluble salicylates with alkali bicarbonates - Soluble salicylates and benzoates with acids. **Soluble iodides incompatibility –** - Oxidation of iodides with potassium chlorate - Oxidation of iodides with quinine sulphate. **Chemical incompatibility 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 incompatibilities** - Soluble barbiturates with ammonium bromide - Potassium chlorate with oxdisible substances - Incompatibility of emulsifying agent - Color stability of dyes - Incompatibilities of liquorices liquid extract. ## Precipitate yielding interactions The precipitates so formed may be diffusible or indiffusible (non-diffusible). The method A or B is followed in dispensing the prescription yielding diffusible and indiffusible precipitates, respectively. The preparation should contain a thickening agent if the precipitate is non-diffusible. **Method A:** This method is suitable for diffusible precipitates following steps are carried out. Divide the vehicle into two portions. Dissolve the reactants in separate portions and mix the two portions by slowly adding one into other with constant stirring. **Method B:** This method is suitable for in diffusible precipitates following steps are carried out. Divide the vehicle into two portions. Dissolve the one of the reacting substances in one portion. Place second portion of vehicle in mortar and incorporate suitable amount of compound tragacanth powder (2g/100ml of preparation) with constant trituration until a smooth mucilage is produced. Add and dissolve the other reacting substance to the mucilage. Add the solution of first reactant to the mucilage slowly with constant stirring. **A secondary label —SHAKE THE BOTTLE BEFORE USE should be fixed on the container whenever method A or method B is followed in dispensing the prescription.** **Eg-1: strychnine hydrochloride mixture** Rx - Strychnine hydrochloride solution -6ml - Aromatic spirit of ammonia -4ml - Water up to - 120ml **Causes:** The quantity of strychnine hydrochloride is more than its solubility in water (1:30). The aromatic spirit of ammonia contains negligible amount of alcohol. **Remedy:** Strychnine hydrochloride gets precipitated yielding diffusible precipitate, hence follow method A. **E.g-2: Quinine hydrochloride mixture** Rx - Quinine hydrochloride -0.12ml - Sodium salicylate -4g - Water-100ml **Causes:** When quinine hydrochloride combined with the sodium salicylates it forms quinine salicylates which is an indiffusible (non-diffusible) precipitate. **Remedy:** Hence follow method B for precipitate yielding interactions. ### (C) Meaning, Manifestations, Correction and Prevention of Therapeutic Incompatibilities It is the modification of the therapeutic effect of one drug by the prior concomitant administration of another. It may be the result of prescribing certain drugs to the patient with the intention to produce a specific degree of action but the nature or the intensity of the action produced is different from that intended by the prescriber. Therapeutic incompatibilities occur due to the following reasons: - Error in dosage - Wrong drug or dosage form - Prescribing contra-indicated drugs - Prescribing synergistic and antagonistic drugs - Drug-food interactions. ## 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. **Wrong drug 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. Sometimes, 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. ## Prescribing contraindicated drugs There are certain drugs which may be contra-indicated in a particular disease or a particular patient who is allergic to it: - Corticosteroids are contra-indicated in the patients having peptic ulcers. - Chloroquine, penicillin and sulphur 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. - NSAIDs should not be given to ulcer patients because it exacerbates the condition. **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. ## Prescribing synergistic or 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. **Examples:** - 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. ## Drug-food interactions The effect of one drug is altered by the prior or simultaneous administration of food. The 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. ## Mechanisms of therapeutic incompatibility These can be divided into two groups, viz - Pharmacokinetics: involve the effect of a drug on another from the point of view that includes absorption, distribution, metabolism and excretion. - Pharmacodynamics: are related to the pharmacological activity of the interacting drugs e.g. synergism, antagonism, altered cellular transport, effect on the receptor site. ## Pharmacokinetic interactions: 1. **Altered GIT absorption** - Altered pH - Altered bacterial flora - Formation of drug chelates or complexes - Drug induced mucosal damage and altered GIT motility 2. **Displaced protein binding** - It depends on the affinity of the drug to plasma protein. The most likely bound drugs are capable to displace others. The free drug is increased by displacement by another drug with higher affinity. 3. **Altered metabolism** - The effect of one drug on the metabolism of the other is well documented. The liver is the major site of drug metabolism but other organs can also do e.g., WBC, skin, lung, and GIT. 4. **Altered renal execration:** - Inhibition of renal tubular secretion It occurs in the proximal tubules (a portion of renal tubules). The drug combines with a specific protein to pass through the proximal tubules. When a drug has a competitive reactivity to the protein that is responsible for active transport of another drug. This will reduce such a drug excretion increasing its concentration and hence its toxicity. E.g., Probenecid decreases tubular secretion of methotrexate. ## Pharmacodynamic interactions - alteration of the dug action without change in its serum conc. 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 beneficial or harmful to the client. - **Synergistic effect- occurs** when two or more drugs, with or without the same overt effect, are used together to yield a combined effect that has an outcome greater than the sum of the single drugs active components alone. - **Potentiation-describes** a particular type of synergistic effect-a drug interaction in which only one of two drugs exerts the action that is made greater by the presence of the second drug. - **Antagonistic-reactions** result in a combined effect that is less than either active component alone. (e.g. Protamine administered as an antidote to anticoagulant action of heparin). **Rx** **Tetracycline Hydrochloride 250 gms** **Directions for Pharmacist:** Make Capsules. Send 10 such capsules. **Label:** Take 10 capsules every six hours with milk. **Comments:** Therapeutic incompatibility.