Solutions Flashcards
How can mixtures be divided into two main groups?
Homogenous (uniform composition)
Heterogenous (non-uniform composition)
What is the only type of homogenous mixture?
Solutions (particles are small and evenly dispersed)
What are the types of heterogenous mixtures?
Colloid (particles are medium and dispersed, but do not settle)
Suspension (Particle are large and settle out)
What is the definition of a pharmaceutical solution?
A chemicaly and physically homogenous liquid preparations of two or more substances
What are some excipients added to solutions?
Flavouring, sweeteners, colourants, and preservatives are some examples
What solvents are used in pharmaceutical solutions?
Water is most commonly used and desirable, but other solvents are also used
Alcohol (94-96%)
Glycerin
Propylene glycol
Oils
For topical applications, are polar solvents better compared to non-polar solvents?
No, non-polar solvents are more liklely to absorb into the skin (lipid-based)
What is the utility of solutions as a dosage form?
Injectable drugs
Pediatric formulations
Opthalmic preparations
Some lotions
Sprays
Liquid dosage forms are prefered by children and people who have a hard time swallowing other oral dosage forms
What are the advantages of solutions in pharmacy?
Solutions skip disintegration and dissoultion, therefore the absorb the faster compared to solid dosage forms
Can be intended for multiple routes of administration
Flexible dosing, different volumes can be used depending on the circumstances
No shaking needed (solute is completely disolved into the solvent)
What are some disadvantages of solutions in pharmacy?
Increased sensitivity to environmental conditions
Reduced technical accuracy
Solubilty of drug must match excipients
Bulky storage and transport
What is the difference between solubility and dissolution?
Solubility: The quantity of solute to form a saturated solution (constant at a given temperature)
Dissolution: The transfer of molecules and ions from a solid phase into a solution (describes the process)
How can dissolution be enhanced?
Trituration can reduce particle size and decreases solution time
Heat
Vigourous shaking
What physiochemical factors affect solubility?
Molecular weight and volume
Precense of functional groups and their position (structure)
Acids or bases (pH dependent solubility)
Do aqueous solutions have different boiling and freezing points compared to pure water
Solutes increase boiling point and reduce freezing point
What are the different types of solutions?
Gases in Liquids (effervescent tablets)
Liquids in Liquids (elixirs)
Solids in Liquids (drug powders for injectable reconstitution)
Does pressure increase solubilty of gases in liquids?
Yes
Does temperature increase solubility of gases in liquids?
No, increased temperatures reduce the amount of solvent that can be dissolved into the solvent
What happens to gases in liquids when a different solute is added to the solution?
If the solute has a greater affinity for water than the dissolved gas, the solution will bubble of some gas
What is miscibility?
Expresses the mutual solubility of components in a liquid-liquid system (mixes without separating)
Are all liquids miscible with each other?
No, some are only miscible under certain conditons (proportion and temperature), while others are completely immiscible
How does temperature impact solubility?
With endothermic substances, solubility increases with temperature (disolution requires the input of energy)
With exothermic substances, solubility decreases with increases in temperature (dissolution results in the release of energy)
With Normothermic substances, solubility does not change with temperature (energy is neither absorbed or released during dissolution)
What is polarity?
It is the separation of electric charge leading to a molecule or its chemical groups having an electric dipole moment, with a negatively and positively charged ends
What are some non-polar solvents used in pharmceutical preparations?
Fixed oils (non-volatile): ex. vegetable oils
Hydrocarbons: ex. mineral oils
Non-polar solvents are used as a vehicle for injections and for external preparations (topical)
What is the most desirable polar solvent?
Distilled Water
What is potable water?
Water that is “fit to drink”
It may contain impurities and minerals:
Ions
Organic matter
Atmospheric gases
Suspended materials (clay, silt, etc)
How is water made potable from raw sources?
Removal of insoluble matter via settling and filtration
Destruction of pathogenic organisms by chlorination (boil and treat with chlorinating agent)
Once processed, potable water contains less than 0.1% of total solids
Is potable water an acceptable ingredient in pharmaceutical preparations?
No, potable water still contains many impurities. It serves as the starting point for further processing
What types of water are used in pharmaceutical preparations?
Purified water (dilutin for non-sterile preparations)
Water for injections (sterile, no particles or pyrogens)
Sterilized water
Bacteriostatic Water for Injection (used in multi-dose sterile preparations
Do formulations that use sterile water need preservatives?
Single dose formulations can sometimes go without preservatives, but multi-dose formulations need preservatives. Preservatives prevent contamination following each use
What are some semi-polar solvents commonly used in pharmaceutical preparations?
Alcohol (Ethanol) is the most common semi-polar solvent. It is often used to dissolve organic compounds.
The following are also used in pharmaceutical preparations:
Isopropyl alcohol
Glycerin
Propylene glycol
Polyethylene glycol 400
What is an elixir?
Alcohol+water=hydroalcoholic solution (elixir)
Elixirs can dissolve both alcohol and water soluble compounds
What are the advantages of semi-polar solvents?
Better solubility for many compunds
Better drug stability (reduced hydrolysis and bacterial growth)
Is alcohol (ethanol) miscible in a wide variety of other solvents?
Yes
ex. Caster oil (not other fixed or mineral oils), Water, other semi-polar solvents
What are the limits for alcohol content in OTC products?
Children under 6: below 0.5%
Children 6-12: below 5%
12+ (Teens and Adults): below 10%
What are the different types of alcohol?
Denatured alcohol (ketones or kerosene): not fit for internal use
Absolute alcohol (99.5% ethanol v/v): water-free ethanol
Diluted Alcohol NF (equal amounts of water and alcohol)
Rubbing Alcohol (70% alcohol): for external use only
Are mixed solvents more effective in their ability to dissolve solutes?
In some cases, water and alcohol mixed solutions have better solubility compared to either solvent on their own
How should solutes be added to a mixed solution?
It is important that each solute is first dissolved into the solvent it is most soluble. The two solutions are then blended into a mixed solution. Usually the solution without actual drug compound is poured into the drug containing solution (ensures the drug solution concentration remains well above near zero, prevents the drug from precipitating out)
What is complexation?
They are loose molecular associations that can either increase or decrease solubility
Ex. Tetracycline complexes with Ca2+ from mil/milk products to form an insoluble complex that decreases the drug’s dissolution and absorption
What types of drugs are susceptible to complexation with di/trivalent ions?
Certain antibiotics (tetracyclines, fluoroquinolones)
Certain osteoporosis drugs (risedronate)
Thyroid medications (levothyroxine)
What is the difference between molarity and morality?
Molarity: mol/L
Molality: mol/kg
What are some different ways drug concentration can be represented?
Molarity and Molality
Osmolarity: Osmol/L(# of moles contributing to osmotic pressure of the solution, moles of ions following dissolution into water)
Units of potency/unit volume: I.U/L
Weight/Unit Volume: g/L, mg/mL, etc.
Percentage: w/v, v/v, w/w, mg%, etc.
Parts per million (PPM): #of parts of substance/1 million units of solvent
What is the use of excipients in solutions?
Help increase storage stability, enhance solubility, taste, etc.
What are some conversion rates between metric and pharmacy units?
5mL = one tsp
10mL= two tsp
15mL=three tsp(one tbsp)
What are some requirements for an oral solution?
Physical stability
Chemical stability
Microbiological stability
Palatability
Pleasing appearance
What does physical stability in oral solutions look like?
No discolouration/cloudiness
No precipitation
No loss of elegance
No loss of taste
What does chemical stability look like in oral solutions?
There must not be changes to the molecular structure of the drug (maintain integrity and potency of drug)
pH must be controlled to ensure stability
Hydrolysis also needs to be limited, this can be done with the use of non-aqueous solvents like alcohol
Oxidation can be controlled through the use of antioxidants like ascorbic acid
What does microbiological stability mean in oral solutions?
Preservatives are commonly added to improve shelf life. Examples of preservatives include glycerin, alcohol, and anti microbial
What are some characteristics held by the “ideal” additive to an oral solution?
- Pharmacologically inactive and non-toxic
- Potent, therefore can be used in low concentrations
- No unpleasant odour or flavour
- Compatible with drug and other excipients
- pH stable and resistant to light energy
- Soluble in vehicle/solvent
What are some types of additives in oral solutions?
Flavouring agents
Sweeteners
Colouring agents
Antimicrobial preservatives
Antioxidants
Buffers
Viscosity-inducing agents
Surface active ingredients
How does the tongue detect taste?
The solution comes in contact with the taste cells on the tongue and initiates a nerve impulse. The impulse is transmitted via the cranial nerve to the brain, where it is interpreted as a specific taste.
*The drug must be dissolved in the mouth before it can be tasted
What are the four primary tastes?
Sweet: (low molecular weight poly-hydroxyl compounds, ex. sucrose, mannitol)
Sour: (H+ ions cause acidity, sour is sensed if acidic compounds are tasted)
Bitter (most common in pharmaceutical preparations): high molecular weight salts, free bases and nitrogen-containing compounds (ex. caffeine and codeine)
Salty: (low molecular weight salts and ionic compounds, ex. NaCl, ammonium chloride)
What are some flavouring techniques used in pharmaceutical preparations?
Physiological
Physical
Masking or overshadowing
Blending
Chemical
Describe the physiological flavouring technique
In this approach, the goal is to anesthetize the taste buds/receptors
ex. menthol and other mint flavours, carbonated beverages, cooled liquid
Describe the physical flavouring techniques
In this approach, the goal is to prevent dissolution of drug or preventing drug from coming in contact with taste buds/receptors.
Viscous liquids are employed to reduce the dissolution rate
Tablets can be coated to contain bitter compounds inside
Describe the overshadowing flavouring technique
Addition of a flavour whose intensity is longer and stronger than the taste of the drug
ex. Methyl salicylate
This technique uses the same concept of adding lemon juice to food to make it taste less salty because the lemon juice overpowers other flavours
Describe the blending flavouring technique
In this approach, the goal is to add flavours which complement the taste and modify the flavour perception. Add fruit flavours to drugs that are sour tasting and add salty or sweet and sour flavours to bitter tasting drugs
ex. Vanillin, benzaldehyde
Describe the chemical flavouring technique
A drug compound can be complexed or delivered as a prodrug, a new substance that has a better flavour profile. These modifications should not affect the overall therapeutic profile of the drug.
ex. Tetracycline dispensed as a HCl salt
What are some other factors besides flavouring that can affect taste?
Aroma is a strong determinant of taste perception (scent shoulkd be pleasant and correlate with flavour)
Texture is also iprtant for taste perception and acceptance
Viscosity of syrups have a positive effect on patient acceptance (les viscous: perception of watered down, and if a preparation is too viscous, it is seen as slimy or gooey
What are the two catagories of sweeteners?
Natural and artificial sweeteners
What are some desired properties in sweetners?
Colourless
Dodourless
Pleasant tasting
No aftertaste
Stable over a wide pH range
What compound is the gold-standard for sugar-based sweetening agents in pharmaceutical agents
Sucrose (cane sugar, beet sugar)
Other sweeteners are compared to sucralose
What are some examples of sugar-based sweeteners?
Sucrose
Lactose (usually used as an inert filler)
Dextrose (less sweet than sucrose)
What are some possible concerns for using sugar-based sweeteners in pharmaceutical formulations?
Sugar-based sweeteners have high water solubility, and this can salt out other solutes/drug
Poses concern for diabetics
They can crystalize on the bottle caps
Sugar can crystallize during heating
What are some examples of artificial polyol-based sweeteners?
Glycerine
Propylene Glycol
These sweetners are less sweet compared to sucrose
What are some examples of natural polyol-based sweeteners?
Sorbitol (less sweet compared to sucrose, can cause flatulence)
Mannitol (less sweet than sucrose, but has laxative effects at high doses)
Xylitol (similar sweetness as sucrose, but absorbed slower)
What are examples of artificial sweeteners?
Saccharin (300 times sweeter than sucrose):
Often used in its sodium salt form due to better water solubility. Moderate amounts of saccharin is safe for consumption
Cyclamate (30 times sweeter than sucrose): Used as either a sodium or calcium salt. Due to safety concerns, it is only used in drugs and not food
Aspartame (180 times sweeter than sucrose): most commonly used and unstable at high temperatures
Sucralose (600 times sweeter than sucrose): stable at high temperatures
Stevia (200 times sweeter than sucrose): plant source, but has some drug interactions
What are some problems associated with aspartame and heat?
Aspartame degrades into diketopiperazine when exposed to high temperatures (180*C).
Diketopiperazine has decreased sweetness, therefore aspartame shouldn’t be used in preparations that will involve high temperatures in their processing
What are some problems associated with aspartame and PKU (phenylketonuria)?
Patients with PKU have an intolerance for aspartame
When should sweeteners be added to a formulation in relation to flavoring agents?
When experimenting with formulations, always establish flavour concentration and then modify sweetener concentration
Most flavours are bitter, so they require sweetening to make taste more pleasant
Why are colours added to drug formulations?
To enhance the esthetic quality of the preparation (elegance, attractiveness). Can be done with natural or synthetic dyes
To act as a sensory adjunct to flavour
What colours are rejected by patients?
Dark colours such as dark purple, navy black, and brown because they are often associated with poisons
How can colours improve taste?
Some drug manufacturers resort to visual distraction by colouring bitter drugs with bright colours. This can enhance palatability by fooling the brain into not fully perceiving bitter taste
What situations make visual distraction ineffective as a way to mask taste?
Not practical in young children, because they do not yet associate colours, aromas, and taste
In drugs that need to be taken multiple times, visual distraction works the first few times, but that effect wears off
Are liquid stock colourants found in grocery stores safe to use in pharmaceutical preparations?
No, they lack stability and contain impurities that could potentially affect the safety and efficacy of a given drug
What is the difference between pigments and dyes?
Pigments are insoluble materials that give colours when dispersed in some liquid
What are some examples of natural colouring agents used in pharmaceutical preparations?
Mineral pigments (used for lotions, cosmetics, and other external preparations)
ex. yellow ferric oxide or white titanium oxide
Plant pigments
ex. green chlorophyll, orange b-carotene, yellow saffron
Animal pigments
ex. purple murex (sea snails)
What is the safety of colouring agents?
Colours used in foods, drugs, and cosmetics must be certified for such use:
FD&C: food, drugs, and cosmetics (safest)
D&C: drugs and cosmetics (no food)
External D&C: not allowed in products for lips, but can be applied on the skin
Colouring agents are safe for use in ophthalmic solutions. True or False
False. No colour is certified for use in ophthalmic solutions
Preservatives should never be added to opthalmic solutions. True or False
False. Preservatives are commonly added to opthalmic solutions especially if they are intended for multiple use
What are some concerns with synthetic colouring agents?
Carcinogenicity
Hypersensitivity (potential to develop allergic symptoms)
Hyperactivity in kids
Dyes can be affected by changes in pH
Are subject to oxidation/reduction reactions
They can be incompatible with large cationic compounds such as alkaloids
What is the concentration of colouring agents in pharmaceutical preparations?
For colour: use a concentration of between 0.0005-0.001%
For a tint: use a concentration of as low as 0.0001%
These low concentrations are achieved through repeated dilutions of stock solutions
When are preservatives added to pharmaceutical formulations
Added to non-sterile dosage forms to protect drug from microbial growth and proliferation of microorganisms
Preservatives are also added to sterile multiple-dose formulations
In what cases is a preservative not needed?
No water is present (tablets, powders, and hydrocarbon ointments)
If the formulation is acidic or basic (less than 3 or more than 9)
Other ingredients with antimicrobial properties (high sugar or alcohol content)
Large volume parenteral drugs are free of preservatives due to bulk exposure to preservatives (potential toxin)
In what products are preservatives contraindicated?
Drugs for neonates
Opthalmics
Parenteral solutions with volumes greater than 30mL
What are some strategies used to prolong shelf life without the addition of preservatives?
Prepare single sterile doses
Prepare smaller quantities
Refrigerate formulation
What requirements must an excipient meet to be officially classed as a preservative?
Actvity needs to be broad spectrum
Must reduce a microbial population significantly and prevent subsequent re-growth
How do antioxidants work in basic terms?
They divert the oxidative process by reacting with one or more compounds in the formulation to prevent a free radial mediated chain reaction
What antioxidants are used in pharmaceutical preparations?
For aqueous systems (ascorbic acid, sodium sulfite, and bisulfite)
For oil systems (BHA, Vitamin E)
What is the purpose of buffers?
They control the pH of a solution and therefore the stability of the product
They always contain a weak acid and its conjugate base
When are buffers used in pharmaceutical preparations?
Used in formulations applied to sensitive membranes, of eye or nasal passages or injected into muscles, blood, organs, tissues or lesions
What is the use of viscosity-inducing agents in pharmaceutical preparations?
They can change the consistency of a preparation. If used, they have a concentration of 2-10% w/v
The product becomes easier to pour vs. something that is less viscous
May improve appearance and palatability
Great for achieving desired smoothness and consistency, especially in topical solutions
Ease in the application of topical solutions
What are some examples of viscosity-inducing agents?
Methylcellulose
Carboxymethylcellulose
Acacia
Bentonite
Does viscosity affect dissolution?
Yes, higher viscosity liquids have more difficulties dissolving solutes thoroughly
This issue is solved by mixing solutes into solvents before adding viscosity-inducing agents
What are surface active agents (surfactants)?
Chemicals that contain both hydrophillic and hydrophobic regions. They are also called wetting agents.
Surfactants modulate solubility of ingredients in order to improve stability and sometimes bioavailability
ex. sodium lauryl sulfate
How can oral solutions be divided based on solvent type?
Aqueous solutions (syrups and aromatic waters)
Non-aqueous solutions (elixirs, spirits, and tinctures)
Describe aqueous solutions?
They are the most prevalent of the oral solutions
Dissolving any drug in distilled or purified water along with other excipients makes an aqueous solution
What are syrups?
Syrups are concentrated, viscous and sweetened aqueous solutions that contain less than 10% alcohol
What can syrups be sweetened with?
Sucrose, other natural sugars, non-sugar polyols, non-nutritice artifical sweeteners (aspartame, saccharin)
What are some common non-medicinal ingredients besides sweeteners?
Citric acid, glycerin, polyethylene glycol, sodium benzoate, sorbitol, sucralose, water
When do syrup not need antimicrobial preservatives?
If the sucrose content is above 80%
What is special about cherry syrup?
A sucrose-based syrup containing 47% by volume cherry juice
What is special about cocoa syrup?
It is flavoured with vanilla and is effective in administering bitter tasting drugs to children
What is a concern with flavoured syrups and drug stability?
Flavoured syrups can be acidic, neutral, or slightly basic
What is the definition of a simple syrup?
A saturated solution of sucrose in water (85% w/v or 65% w/w)
The sugar content is so high that a preservative is not needed.
What are the compounding methods for a drug within syrup-based formulations?
In formulas containing both drug and sucrose, each ingredient is usually dissolved separately and then mixed together in such a way to avoid precipitation
The drug is usually disolved in water or another solvent before mixing with the syrup vehicle
What are aromatic waters?
Used as flavouring or perfuming solutions
They are clear, saturated aqueous solutions of volatile oils or other aromatic solutions of volatile oils or other aromatic substances
Talc is also added to these formulations
What is the purpose of talc in aromatic water formulations?
It acts as a distribution agent. It increases the surface area of volatile substance to the water. This allows for better mixing of volatile substances and water
Talc is also a filter aid that helps remove excess volatile substance
What types of non-aqueous solvents can be used for topical solutions
Saturated aliphatic hydrcarbons, ether and glyceryl ester of aliphatic acids
Commonly used in elixers, spirits, and tinctures
What are elixirs?
Clear, sweetened hydroalcoholic (water and alcohol ) solution intended for oral use
Range: 3-44% (mostly between 5-10%)
At what concentration of alcohol do elixirs need preservatives?
In elixers, which contain less than 10-12% alcohol
They require the addition of an antimicrobial preservative
What are some properties that differentiate elixirs from syrups?
Compared to syrups, elixers are:
Less sweet
Less viscous
Less effective in masking bitter tasting drugs
More able to maintain water and alcohol soluble components in solution
More long-term stability
More strict storage conditions due to alcohol
Why is the aqueous solution added to the alcohol solution with constant stirring?
Order is important to maintain the highest possible alcoholic strength at all time so that minimal separation of the alcohol soluble components occur
What should a pharmacist do if an elixir shows preciptation?
Add glycerin, sorbitol, or propylene glycol aids in dissolution (synergistic solubility in mixed solvent solutions)
Allow elixir to stand for a few hours (gives time to ensure saturation and then remove the insoluble material by filtration)
What are spirits in terms of pharmacological preparations?
They are alcoholic or hydroalcoholic solutions of volatile substances
Alcohol content range: 62-85%
Used frequently as flavouring agents in small quantities (serve as a stock solutuion for flavouring oils)
What is the difference between aromatic waters and spirits?
Due to the higher alcohol content in spirits, they can contain a greater concentrations of volatile oils
What are tinctures?
Alcoholic or hydroalcholic solutions of non-volatile substances preprared from vegetable or chemical substances
Alcohol content: 15-80%
Cannot be exposed to high temperatures
How much potent drug can be dissolved into a tincture?
Up to a concentration of 10g of drug/100mL of tincture (10% tincture)
ex. Belladonna Tincture, opium tincture
How much non-potent drug can be dissolved into a tincture?
Up to a concentration of 20g of drug/100mL of tincture (20% tincture)
ex. Tolu Balsam Tincture
What are some disadvantages of tinctures?
Not prescribed any more due to high alcoholic content
TInctures are immiscible with liquids with very different solvent character without inducing precipitation of the solute
Light sensitive, therfore they need to be stored in light resistant containers
Unpleasant taste due to high alcohol content
What are some other pharmaceutical liquids not already covered?
Gargles/mouthwashes
Otic solutons
Opthalimic solutions
Lotions
Liniments
Enemas
Parenteral injectables (SQ, IV, and IM)
What is the advantage of reconstituted solutions?
By adding water/other solvent closer to time of administration, it greatly increaes shelf life and storage requirements
