Module 2 Flashcards
Problems arise during the compounding, dispensing or administration of these products.
PHYSICAL INCOMPATIBILITIES
Result of prescribing or mixing two or more substances which are antagonist in nature.
PHYSICAL INCOMPATIBILITIES
Unintentional, occur in vitro between drugs and other components during preparation, storage or administration.
PHYSICAL INCOMPATIBILITIES
TYPES OF INCOMPATIBILITIES:
- Physicochemical
-Physical Incompatibility
-Chemical Incompatibility - Therapeutic
MANIFESTATIONS OF INCOMPATIBILITIES
- Insolubility
- Immiscibility
- Precipitation-(Physical Means) due to change in menstruum, change in solvent or changes in temperature
- Precipitation due to chemical Reaction
- Eutexia-quality of melting of a mixture of substances at a minimum
- Gelling, granulation, cementation of liquids
- Evolution of gas
- Change in color
- Explosive combination
MANIFESTATIONS OF INCOMPATIBILITIES - insolubility
Atropine Sulfate in Olive oil, ASA in syrup
MANIFESTATIONS OF INCOMPATIBILITIES - Precipitation-(Physical Means)
Alcohol extract plus water
Hydrophilic colloids in dehydrating medium
Saturated solutions of volatile oils in water plus salts
Supersaturated solutions at lowered temperature.
MANIFESTATIONS OF INCOMPATIBILITIES - Precipitation - chemical Reaction
Hydrolysis: Zinc chloride in water, Phenobarbital in water, Double composition –AgNO3+NaCl🡪AgCl+ NaNo3
MANIFESTATIONS OF INCOMPATIBILITIES - Eutexia-quality of melting of a mixture of substances at a minimum
Mixing of ketones, phenols or aldehydes
MANIFESTATIONS OF INCOMPATIBILITIES - gelling, granulation, cementation of liquids
Bismuth subnitrate plus acacia as suspending agent
Alcohol solutions and acacia
MANIFESTATIONS OF INCOMPATIBILITIES - Evolution of gas
Effervescence
Liberation of nitrous oxide from zinc and concentrated nitric acid
MANIFESTATIONS OF INCOMPATIBILITIES - Change in color
Antipyrine blue ethyl nitrite
Cherry syrup plus alkalis
Liberation of iodine from iodides in acid medium
Explosive combination
Oxidation-reduction
IMPORTANCE IN DETERMINING INCOMPATIBILITY:
Safety of Medicament
Efficacy of the product
Appearance of a medicine
Purpose of the medication
Results in a physicochemical change in the properties of drug or dosage form.
Production of a new chemical substance having different pharmacological action
PHYSICOCHEMICAL INCOMPATIBILITIES
occurs if incompatibility is prevented by addition, substitution or elimination of one or more ingredient
Adjusted Incompatibility
GENERAL METHODS TO PREVENT INCOMPATIBILITIES:
- Modify the order of mixing
- Dispense with labels like “Shake well before use”.
- Recommend storage condition.
- Add physical stabilizer. (Suspending & emulsifying agent)
- Add chemical stabilizer. (Antioxidant/Buffer)
- Add preservative.
- Select soluble, compatible or stable form dosage form.
Also called ________
Change in color odor, taste, viscosity and morphology.
A physical change takes place and unacceptable product is formed.
PHARMACEUTICAL INCOMPATIBILITY
physical incompatibilities may be corrected by using any one or more of the following methods:
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 sub. to help in compounding of the prescription.
EXAMPLES OF PHYSICAL INCOMPATIBILITIES:
- IMMISCIBILITY/ INSOLUBILITY
- PRECIPITATION
- LIQUEFACTION
- PHYSICAL COMPLEXATION
- SEPARATION OF IMMISCIBLE LIQUIDS
- INCORRECT FORM PRESCRIBED
- GELATINIZATION
CORRECTION OF IMMISCIBILITY/INSOLUBILITY
Adjusting the solvent system
Changing the order of mixing or suspending or emulsifying the material.
FACTORS THAT LEAD TO INSOLUBILITY/ IMMISCIBILITY:
- INCOMPLETE MIXING
- ADDITIONAL SURFACTANT WITH:
- UNSUITABLE CONCENTRATION
- FALSE TIME OF ADDITION
- UNSUITABLE FOR THE TYPE OF EMULSION
- PRESENCE OF MICROORGANISMS
- TEMPERATURE
Inability of a material to dissolve in a particular solvent
Chalk, aromatic chalk powder, ASA, Phenacetin, Zinc oxide and calamine.
IMMISCIBILITY/ INSOLUBILITY
Result of dehydration or salting out, change in solvent system or temperature change.
TWO MANIFESTATIONS:
dehydration or salting out of slightly soluble nonelectrolytes from aqueous media.
Stronger the ability of the electrolyte ions to hydrate (lyotropic numbers, hydration energies and charge-to-ionic-radius ratios), the greater the effects.
PRECIPITATION
EXAMPLES OF PRECIPITATION:
The separation of alcohol from a hydroalcoholic vehicle on the large amounts of an electrolyte.
Salting out of electrolytes from an aqueous solution by alcohol.
Sugar and hydrophilic hydrocolloids.
Camphor and volatile oils
Boric acid w/ tragacanth
MANIFESTATIONS OF PRECIPITATION:
- Change in solvent system
- Mixing of tinctures or fluidextracts with syrups or other aqueous solutions.
- Temperature change
- ENDOTHERMIC: KI, boric acid and common electrolyte and non-electrolyte stored below room temperature will precipitate.
- EXOTHERMIC: Calcium Hydroxide stored above room temperature.
result from eutexia of dry materials.
Due to release of water hydration or absorption of water.
LIQUEFACTION
A. EUTEXIA
B. WATER HYDRATION
a depression in the melting point of a solid in contact with certain other components in room temperature.
Phenol, menthol, thymol, salol
EUTEXIA
Chemicals that form HYDRATES, compounds with water of crystallization that are stable at room temperature and within range of humidity.
Compounds will tend to release under the influence of decreasing humidity.
Pasty solid-result product.
WATER HYDRATION
CORRECTION OF LIQUEFACTION:
- ADDITION OF INERT DILUENTS
- Magnesium carbonate, Light magnesium oxide, Starch, Kaolin, talc
- USE OF THE ADSORBENTS
- Placing of separate substance in separate capsules
- Absorb the liquid on sufficient kaolin or magnesium carbonate
- Should be placed in tightly stoppered containers.
Present in organic compounds due to formation of coordinate compounds or molecular complex that could decrease solubility bonded together by a coordinate bond, not ionic or covalent.
PHYSICAL COMPLEXATION
Oils dissolved in alcohol-separate in the addition of water.
Ethyl nitrite spirit-separates as a layer when potassium citrate is present in prescription.
SEPARATION OF IMMISCIBLE LIQUIDS
EXAMPLE: When a physician prescribe an alkaloid salt to dissolved in liquid petrolatum.
Alkaloidal salt are insoluble in liquid petrolatum.
Therefore, Free alkaloids should be prescribed because they are usually soluble in liquid petrolatum.
INCORRECT FORM PRESCRIBED
Form a gel when combined with certain substances.
EXAMPLE: Ferric salts gelatinize acacia solutions since acacia possesses carboxyl groups.
GELATINIZATION
Result of chemical interactions between the ingredients of a prescription and toxic or inactive product may be formed.
Oxidation-reduction, acid-base hydrolysis, or combination reactions.
Effervescence, decomposition, color change occurs.
CHEMICAL INCOMPATIBILITIES
TYPES OF CHEMICAL INCOMPATIBILITIES:
- PRECIPITATION
- REDOX REACTIONS
- HYDROLYSIS
- POLYMERIZATION
- ISOMERIZATION
- RACEMIZATION
- EFFERVESCENCE
- COLOR CHANGE
- INCOMPATIBLITY WITH CONTAINERS
pH change.
Chemical reaction between drug-drug or drug-additives.
PRECIPITATION
PRECIPITATION - pH CHANGE
EXAMPLES: MORPHINE HYDROCHLORIDE above 2.5%- insoluble & formation of diffusible precipitate under alkaline condition.
TREATMENT: PREPARING SUSPENSION OF DIFFUSIBLE PRECIPITATE USING ALCOHOL AS CO-SOLVENT
EXAMPLES: CAFFEINE CITRATE ABOVE 2.2%- under alkaline condition produces diffusible precipitate.
TREATMENT: USING ALCOHOL AS CO-SOLVENT- tolerates higher concentration of caffeine citrate without precipitation
N/A
PRECIPITATION - DRUG-DRUG INTERACTIONS:
EXAMPLE #1: CAFFEINE CITRATE
CAFFEINE CITRATE is a mixture of equal weight of caffeine & citric acid. The CITRIC ACID reacts with SODIUM SALICYLATE to liberate SALICYLIC ACID in the form of precipitate, which causes gastric irritation.
EXAMPLE #2: LIQUORICE
N/A
Some drugs or their dosage forms undergo oxidation when exposed to air, excessive temperature & due to over dilution of liquids, incorrect pH or presence of catalyst.
Metal ions, enzymes & bacteria.
Oxidation- gain of Oxygen or loss of hydrogen
Reduction-loss of oxygen or gain of hydrogen
REDOX REACTIONS
FACTORS LEAD TO OXIDATION:
Presence of Oxygen
Light
Temperature
pH
Pharmaceutical dosage forms
Presence of pre-oxidants as metals
Type of solvent used
Presence of Unsaturated bonds
REDOX REACTIONS
EXAMPLES OF REDOX REACTIONS:
AUTO-OXIDATION OF OILS, FATS, PHENOLIC SUBSTANCES, ALDEHYDES & VITAMINS
>PREVENTION: ADDITION OF PRIMARY ANTIOXIDANTS: Alpha-tocopherol, BHT
PARALDEHYDE, TANNINS,EPINEPHRINE, SULPHACETAMIDE & RELATED COMPUNDS UNDERGO OXIDATION ACTIVATED BY HEAT.
>PREVENTION:ADDITION OF ANTIOXIDANTS: Ascorbic Acid, Sodium Metabisulfite Or Complexing Agents (EDTA)
PREPARATIONS CONTAINING RIBOFLAVIN, FOLIC ACID AND ASCORBIC ACID- show incompatibility.
- Riboflavin- is light sensitive and easily degraded by heat and light.
Should be stored at its stable PH 6 to 6.5.
WHEN DRY POWDERS CONTAINS BOTH OXIDIZING & REDUCING AGENTS- the mixture may explode.
N/A
PROTECTION OF DRUGS FROM OXIDATION:
- Addition of Antioxidants: Vitamin E, Vit C and inorganic sulfur compounds: thiosulfate and polysulfide
- Addition of chemicals which form complexes with metals ie. EDTA, Benzalkonium chloride
- Protection from light
a. Using of dark container
b. Storage in dark places
c. Packaging with substances which absorbed light ie Oxybenzen - Choice of suitable solvent (rather than water)
- Storage in low temperature
- Protection from air by:
a. using good, closed containers
b. replacement of oxygen by nitrogen
CHEMICAL GROUPS WHICH UNDERGO OXIDATION:
Phenolic compounds: Phenylephrine
Catechol derivatives: adrenaline and noradrenaline
some antibiotics: tetracyclines
Oils (fixed oil and volatile)
Vitamins (lipids and water soluble)
HOW TO IDENTIFY OXIDATION IN PHARMACEUTICAL DOSAGE FORM?
Change in color, odor, viscosity of dosage form
For fixed and volatile oils: change of color, taste, odor and viscosity
A chemical reaction in which water is used to break down a compound.
Controlled by avoiding moisture contact or by changing pH.
HYDROLYSIS
TYPES OF HYDROLYSIS:
- IONIC HYDROLYSIS
- MOLECULAR HYDROLYSIS
->CHEMICAL GROUPS WHICH UNDERGO HYDROLYSIS:- Esters, amides, nitriles
FACTORS THAT MAY INDUCE HYDROLYSIS:
Presence of water
High temperature
PROTECTION FROM MOISTURE BY:
- Protection from moisture by:
a. Packaging with substances impermeable for moisture.
b. Addition of substances that absorb water (CaCO3)
c. Using of solvent rather than water. - Maintenance of pH by using buffer system
- Formation of complexes
- Using surfactants (micelle formation)
- Reducing of solubility of substance
Small repeating units (monomers) are bonded to form a long chain polymer.
EXAMPLE:
Formaldehyde paraformaldehyde (Polymer: white precipitate)
Must be stored in suitable temperature and addition of methanol 15%
AMPICILLIN
FACTORS INDUCE POLYMERIZATION: Temperature, light, solvent, pH and impurities
POLYMERIZATION
Conversion of drug to its isomers
Identical molecular formulas have a different arrangement of atoms
ISOMERIZATION
TWO TYPES of ISOMERIZATION:
- Optical isomerization
- Geometric Isomerization
- Cis: same direction
- Trans: opposite direction
FACTORS INDUCE ISOMERIZATION:
Temperature
Solvent
pH
Impurities
Conversion of an optically active form to an optically inactive form without changing chemical constitution usually results in reduced therapeutic activity.
RACEMIZATION
Two or more ingredients of formulation reacts to generate CO2.
To overcome such reactions either:
Mix the reacting ingredients in open container & allow to complete reaction before filling in to container before filling in to container.
Change the one or more reacting ingredients.
Dispense reacting substances separately.
EFFERVESCENCE
Visible incompatibility
Delayed color change in formulation creates confusion in the mind of patient
COLOR CHANGE
The product filled in a container may react chemically with the container or get absorbed by the container or the closure.
1. Glass containers alkali leaching.
2. Rubber closures may adsorb preservatives.
3. Metal containers catalyze rate of chemical reaction
INCOMPATIBLITY WITH CONTAINERS