PDD 03: Pharmaceutical Solutions Flashcards
1
Q
What are true solutions?
A
mixture of two or more components that form a homogeneous molecular dispersion
- transparent but not necessarily colourless
- one-phase
- solute are < 1 nm in diameter and not large enough to scatter light
- ie. sugar in water
2
Q
What are colloidal dispersions?
A
dispersion containing particles between 1-500 nm in diameter
- Tyndall effect
3
Q
What is the Tyndall effect?
A
particles scatter light and may appear visibly turbid (depending on concentration of drug)
4
Q
What are coarse dispersions?
A
dispersion containing particles > 500 nm in diameter
- particles scatter light and appear visibly cloudy
- solute can settle over time
5
Q
What are the 2 types of coarse dispersions?
A
- suspension
- emulsion
6
Q
What is a suspension?
A
solid in liquid coarse dispersion
7
Q
What is an emulsion?
A
liquid in liquid coarse dispersion
8
Q
What are the advantages of formulating a drug as a solution? (3)
A
- more easily administered orally to individuals who have difficulty swallowing (ie. geriatrics, pediatrics) compared to tablets, capsules, etc.
- drug is already dissolved in the formulation and is therefore immediately available for absorption – potentially enhanced bioavailability over oral solid dosage forms
- taste-masking is achievable
9
Q
What are the disadvantages of formulating a drug as a solution? (5)
A
- unsuitable for therapeutic agents that are chemically unstable in the presence of water
- poor solubility of some drugs can prohibit their formulation into pharmaceutical solutions (there are techniques to help improve solubility though)
- preservative is usually required to avoid growth of microorganisms
- expensive to ship and bulky
- inconvenient for the patient to carry and use
10
Q
What are the components of pharmaceutical solutions? (9)
A
- active pharmaceutical ingredient (API)
- solvent (or vehicle)
- buffers
- solubility enhancers (co-solvents, complexing agents, surfactants)
- taste-masking agents (sweeteners, flavoring agents, etc.)
- preservatives
- rheology (viscosity) enhancers
- antioxidants and chelators
- colorants
11
Q
Solvent/Vehicle
What are the 3 types?
A
- water
- aromatic water
- non-aqeuous solutions
12
Q
Solvent/Vehicle
What is the preferred and most commonly used vehicle in solutions for oral administration?
A
Purified Water USP (low cost, low toxicity)
- prepared by distillation, ion exchange or reverse osmosis
- solid residue is < 1 mg/100 mL
- not to be confused with water for injections
- should NEVER use tap/drinking water (ie. mineral/organic impurities, presence of particulates, etc.)
13
Q
Solvent/Vehicle
What is aromatic water?
A
saturated aqueous solutions of volatile oils
14
Q
Solvent/Vehicle
How is aromatic water prepared?
A
- volatile oil is triturated with powdered talc or pulped filter paper in mortar
- mixed with purified water 500x volume of oil
- by absorbing the oil to the large surface area of the talc/paper, oil quickly dissolves in the water
- solution is filtered to remove talc/paper (distributing agents)
15
Q
Solvent/Vehicle
What is an example of aromatic water?
A
peppermint water
16
Q
Solvent/Vehicle
Why might non-aqueous solutions be used?
A
sometimes it is not possible to ensure complete solution of the ingredients at all storage temperatures
- drug might be unstable in aqueous system
17
Q
Solvent/Vehicle
Name some alternative non-aqueous solvent systems. (3)
A
- alcohols: ethanol, isopropyl alcohol, glycerol
- non-volatile oils: peanut, corn, soybean, peppermint, etc. oil
- ketones: acetone
18
Q
Buffers
How does a buffer control the pH of a pharmaceutical solution? (2)
A
- maintains the solubility of the therapeutic agent (which can be compromised by small changes in pH since it is pH-dependent)
- increases the stability of the therapeutic agents as well as the other ingredients
19
Q
Buffers
What is a formulation method to enhance/optimize the aqueous solubility of therapeutic agents?
A
optimization of pH
- adjust and maintain pH with a buffer system so that API is in its more soluble ionized state
- APIs with ionizable groups within pH 2-8 are good candidates for improving solubility with pH optimization
- chosen pH does not conflict with other product requirements (stability of the drug or other ingredients – ie. colours, preservatives, flavours)
20
Q
Buffers
What does the choice of suitable buffer depend on? (3)
A
- pH
- buffering capacity required
- compatibility with the other excipients
21
Q
Buffers
What are some common buffers used in pharmaceutical solutions? (3)
A
- acetate (acetic acid + sodium acetate): pH 3.6 – 5.6
- citrate (citric acid + sodium citrate): pH 3.0 – 6.2
- phosphate (sodium phosphate + disodium phosphate): pH 5.8 – 8.0
22
Q
Solubility Enhancers
What are the 3 types?
A
- co-solvents
- complexing agents
- surfactants (surface-active agents)
23
Q
Solubility Enhancers
What is a co-solvent?
A
addition of a water miscible organic solvent in which the compound is also soluble
24
Q
Solubility Enhancers
What is the purpose of a co-solvent?
A
to alter (reduce) polarity of an aqueous system to help solubilize non-polar/non-ionized drugs and the un-ionized components of ionizable drug
25
Solubility Enhancers
What are some common co-solvents? (4)
- ethanol
- low molecular weight (200-400 g/mol) poly(ethylene) glycol (PEG) – also called poly(ethylene oxide) (PEO)
- propylene glycol
- glycerol
26
Solubility Enhancers
What are complexing agents?
complexation of a poorly soluble drug with a soluble material to form a soluble intermolecular complex
- after administration the complex should dissociate
27
Solubility Enhancers – Complexing Agents
What are cyclodextrins (CDs)?
family of cyclic oligosaccharides derived from starch
- form cup-like structure
- exterior contains large number of hydroxyl groups and is highly water-soluble
- interior is relatively non-polar and creates hydrophobic microenvironment
- hydrophobic regions of APIs can form non-covalent complexes with CDs to improve aqueous solubility
28
Solubility Enhancers – Complexing Agents
What are the 3 general classes of cyclodextrins (CDs)?
- αCD: 6 glucopyranoside units, 972 g/mol, 0.47-0.53 nm cavity
- βCD: 7 glucopyranoside units, 1135 g/mol, 0.60-0.65 nm cavity
- ƴCD: 8 glucopyranoside units, 1297 g/mol, 0.75-0.83 nm cavity
(thousands of different CD derivatives by attaching various –R- groups to α/β/ƴ backbone)
29
Solubility Enhancers – Complexing Agents
What do cyclodextrins (CDs) do in oral drug delivery?
- enhanced solubility of drugs
- enhanced bioavailability of drugs
- enhanced stability of drugs
- reduced gastric ulceration
30
Solubility Enhancers
What are surfactants (surface-active agents)?
possess both hydrophilic and hydrophobic regions (ie. amphiphilic molecules)
- at dilute concentrations, surfactants orient at interface between the two phases (ie. water/oil, water/air)
- above critical micelle concentration (CMC), surfactants form into colloidal structures called micelles
- in aqueous systems, non-polar drugs can partition into these micelles and be solubilized
31
Solubility Enhancers
What are some examples of surfactants (surface-active agents)?
- sodium dodecyl sulfate (anionic)
- trialkylammonium (cationic)
- glycine (zwitterionic)
32
Taste Masking Agents
What are some taste masking approaches? (5)
- numbing taste buds (taste blockade) – research
- obscuration of taste – viscosity, sweeteners/flavouring agents
- modification of API – solubility (salt, pH), prodrug
- create a molecular ‘barrier’ around API by complexation – cyclodextrins
- apply a physical ‘barrier’ on API or dosage form – polymeric and lipidic coatings
33
Taste Masking Agents
What are the 5 types?
- mixing with food/dilution
- sweeteners
- flavouring agents
- taste receptor blockers
- complexation
34
Taste Masking Agents
Why is mixing/diluting the API with food not ideal? (3)
- requires compatibility testing for each food/beverage
- entire dose may not be consumed if quantity/volume of food/beverage is too large or taste is not appropriately masked
- child may be put off by the food source – issue with breastfeeding infants
35
Taste Masking Agents
What are the 2 types of sweeteners?
- bulk sweeteners
- intense sweeteners
36
Taste Masking Agents
What are bulk sweeteners?
provides body and texture to the solution (ie. high viscosity sucrose syrup)
37
Taste Masking Agents
What are intense sweeteners?
provides sweet taste at very low concentration (ie. aspartame)
38
Taste Masking Agents
How are sweeteners chosen?
based on its processability (temperature/pH stability) and sensory qualities (texture, sweetness intensity over time, etc.)
39
Taste Masking Agents
What safety issues must be considered with sweeteners? (3)
- carcinogenicity
- effect on blood glucose
- caloric content
40
Taste Masking Agents
What are flavouring agents?
used to complement the taste profile of the API
41
Taste Masking Agents
What are the 2 types of flavouring agents?
- natural
- artificial
42
Taste Masking Agents
What are natural flavouring agents?
- complex mixtures – exact composition is often not known
- available as concentrated extracts, alcoholic or aqueous solutions, syrups or spirits
- fruit juices, aromatic oils (ie. peppermint and lemon), herbs, spices
43
Taste Masking Agents
What are artificial flavouring agents?
- less batch to batch variability in chemical composition
- greater chemical stability
44
Taste Masking Agents
What type of receptors are bitter taste receptors?
G-protein coupled
45
Taste Masking Agents – Taste Receptor Blockers
2 Steps
- bitter receptor antagonists (Step 1 in slides) (R&D stage)
- taste transduction cascade blockers (Steps 2-6 in slides) (R&D stage)
46
Taste Masking Agents – Taste Receptor Blockers
What are bitter receptor antagonists
- tasteless or sweet compounds derived from known bitter compounds
- competitively block binding site of one or more bitter receptors – block release of receptor-associated G-protein (Gustductin)
- ie. adenosine 5’monophosphate (AMP), neohesperidine dihydrochalacone (E959), caffeic acid, etc
47
Taste Masking Agents – Taste Receptor Blockers
What are taste transduction cascade blockers?
- block signal transduction from taste receptor
- potential for broader blockade of bitter taste receptors compared to receptor antagonists
- ie. TRPM5 ion channel blockers turn bitter tastes into a sweet/umami taste
48
Taste Masking Agents
What is complexation?
cyclodextrins complex with the API, impeding its interaction with the taste receptors
- ie. bitter taste of cetirizine dihydrochloride improved with ƴCD, ditto for oseltamivir phosphate with βCD
49
Colourants/Dyes
Is addition of a colourant required?
no – but often added for pharmaceutical elegance
50
Viscosity Enhancing Agents
Why must the viscosity of a formulation be controlled?
to ensure accurate measurement of dispensed volume/ease of handling
51
Viscosity Enhancing Agents
What are higher viscosity solutions better for?
taste-masking bitter APIs
52
Viscosity Enhancing Agents
How is viscosity increased?
by addition of non-ionic and ionic hydrophilic polymers:
- non-ionic polymers: polyvinylpyrrolidone, methylcellulose
- ionic polymers: sodium alginate (anionic), sodium carboxymethylcellulose (anionic)
53
Preservatives
What are preservatives used for?
to prevent or control microbial growth in the formulation
54
Preservatives
What are the properties of an ideal preservative? (4)
- broad spectrum antimicrobial activity against Gram-positive and negative bacteria as well as fungi
- adequate aqueous solubility and partitioning
- chemical and physical stability over the shelf-life of the product
- low toxicity to patients
55
Acidic Preservatives
What are the 2 common types of acidic preservatives?
- benzoic acid (pKa 4.2) and its salts (0.1-0.3% w/v)
- sorbic acid (pKa 4.8) and its salts (0.05-0.2% w/v)
56
Acidic Preservatives
What is the mechanism of action (MOA)?
1. unionized acidic preservatives partition across the membrane of a microorganism
2. within cytoplasm of microorganism where pH is ~neutral, acidic preservatives ionize
3. this leads to acidification of cytoplasm, denaturation of proteins, and inhibition of growth
57
Acidic Preservatives
Which form has preservative capability?
only the unionized form
- concentration of unionized preservative must be > minimum inhibitory concentration (MIC) of the preservative
- ionized form cannot penetrate into the microorganisms
58
Acidic Preservatives
What are the factors affecting preservative efficacy in oral solutions? (3)
- pH of formulation
- presence of micelles
- presence of hydrophilic polymers (ie. methycellulose and polyvinylpurrolidone)
59
Acidic Preservatives
What is the optimal pH of a formulation?
pH < 4.5
60
Acidic Preservatives
How does the presence of micelles affect preservative efficacy?
preservatives can partition and become sequestered in the lipophilic interior of micelles – reduced [preservative] that can partition into microbe
61
Acidic Preservatives
How does the presence of hydrophilic polymers affect preservative efficacy?
preservative can interact chemically or electrostatically with the dissolved polymer – reduces [preservative] that can partition into microbe
62
Preservatives
What are some other preservatives? (4)
- parabens
- quaternary ammonium compounds
- mercurials
- alcohols
63
Preservatives
Parabens
- MOA
- optimal pH
- example
- MOA: denatures proteins
- optimal pH: 4-8
- ie. alkyl esters of parahydroxybenzoic acid)
64
Preservatives
Quaternary Ammonium Compounds
- MOA
- optimal pH
- example
- MOA: lysis of cell membrane
- optimal pH: 4-10
- ie. benzalkonium chloride
65
Preservatives
Mercurials
- MOA
- optimal pH
- example
- MOA: disrupts function of enzymes by reacting with thiol groups
- optimal pH: <7
- ie. thiomersal
66
Preservatives
Alcohols
- MOA
- optimal pH
- example
- MOA: lysis of cell membrane and denatures protein
- ie. > 12% v/v EtOH
67
Antioxidants
What are antioxidants?
molecules that have a higher oxidative potential than the API or compounds that inhibit free radical-induced drug decomposition
68
Antioxidants
What do antioxidants do?
enhance stability of API (and excipients) that are prone to chemical degradation by oxidation
69
Antioxidants
What are the two types of antioxidants?
- water-soluble antioxidants: sodium sulphite, sodium metabisulphite, sodium formaldehyde sulphoxylate, ascorbic acid
- water-insoluble antioxidants: butylated hydroxytoluene (BHT), propyl gallate
70
Antioxidants
How do chelators act as antioxidants?
- heavy metals (like Pd) contribute to oxidative degradation of APIs – can catalyze degradation
- chelators form complexes (ie. coordinate) with heavy-metal to slow this form of oxidative degradation
- ie. ethylenediamine tetraacetic acid (EDTA), citric acid
71
What are the 3 methods to prepare pharmaceutical solutions?
- simple solutions
- solution by chemical reaction
- solution by extraction
72
What are simple solutions?
dissolve solute in suitable solvent
73
What are solutions by chemical reaction?
react two or more substances together in appropriate solvent to increase solubility
- esterification
- formation of aluminum subacetate solution USP
74
What are solutions by extraction?
used to isolate pharmaceutical products from vegetable or animal origin
75
What are the common solutions administered to the GI tract?
- syrups
- elixirs
- tinctures
- aromatic waters and spirits
- gargles and mouthwashes
- colonic lavages
- enemas
76
What are syrups?
concentrated aqueous preparations of a sugar/sugar substitute with or without flavouring agents and APIs
77
What are non-medicated syrups?
syrups containing flavouring agents but no API
- used for extemporaneous compounding of solutions, suspensions, and other DDSs
- ie. ora-sweet, SF alka
78
Why are syrups common with pediatric formulations? (2)
- excellent at masking disagreeable-tasting APIs
- contains little or no alcohol (< 10% v/v EtOH)
79
What sugar is the most frequently used in syrups?
sucrose
80
What is a commonly used alternative to sucrose in syrups?
sorbitol (64% w/v)
- high [sugar] (up to 85%) acts as a natural preservative since they are able to resist bacterial growth by osmotic effect – but many commercial preparations contain a preservative as a precaution
- inherent sweetness and high viscosity taste-mask APIs
81
What do sugar-free syrups contain?
contain an intense sweetener (aspartame or saccharin sodium), non-glycogenic viscosity modifier (ie. methylcellulose) and require a preservative (ie. paraben)
82
What are elixirs?
sweetened hydroalcoholic solution
- better able than aqueous syrups to maintain water-soluble or alcohol-soluble APIs in solution
- level of EtOH co-solvent depends on the API – generally, [EtOH] >10% v/v
- polyol co-solvents (i.e., propylene glycol, PEG) are often used to improve API/ excipient solubility or decrease the [EtOH] required
- natural or artificial sweetener
83
Compare elixirs to syrups.
elixirs are usually less sweet, less viscous, and less effective in masking unpleasant API taste
84
Are preservatives required in elixirs?
not required in elixirs that contain >12% v/v EtOH due to inherent anti-microbial properties of the co-solvent
85
How should elixirs be packaged/stored?
due to volatile nature of EtOH, elixirs should be packaged in air-tight containers and not stored at high temperatures
86
Is viscosity enhancement required for elixirs?
often required to optimize rheological properties of the formulation
87
What are tinctures?
hydroalcoholic solutions prepared via extraction from vegetable/animal materials or minerals
- contain ~15-90% alcohol
- do not require preservatives
- must be tightly stoppered and protected from high temperature
- ie. opium tincture USP
88
Are tinctures common?
no – more pleasant tasting elixirs or syrups with lower [EtOH] preferred
89
What are aromatic waters?
aqueous solution of volatile materials
- needs preservatives (ie. sodium methyl, ethyl and propyl hydroxybenzoates)
- ie. concentrated peppermint water BP (has anti-flatulent properties)
90
What are spirits?
alcoholic or hydroalcoholic solutions of volatile compounds
- [EtOH] usually > 60%
- do not require preservatives
- must be tightly stoppered and protected from high temperature
- because of the greater solubility of aromatic/volatile compounds in EtOH, spirits can contain a greater concentration of these materials than the corresponding aromatic waters
- can be used as flavouring agents and medicinally for the therapeutic value of the aromatic/volatile solute
91
What are gargles?
aqueous solutions designed for prevention/treatment of infection and inflammation of nasopharynx region (gargles)
92
What are mouthwashes?
aqueous solutions designed for prevention/treatment of infection and inflammation of oral cavity (mouthwash)
93
What are gargles and mouthwashes often formulated with?
these aqueous solutions are often formulated with ethanol as a co-solvent
- improve API solubility
- enhance antimicrobial properties of gargle/mouthwash
often formulated with colorants, flavouring agents, and non-cariogenic sweeteners
94
What are colonic lavages?
solution is iso-osmotic with a balanced electrolyte concentration – allows large amount of solution to be administered without significant change in water/electrolyte balance
- used to prepare the lower GI tract for procedures (ie. colonoscopy)
95
What is the formula for colonic lavages?
- 240.00 g PEG-3350
- 22.72 g sodium sulfate
- 6.72 g sodium bicarbonate
- 5.84 g sodium chloride
- 2.98 g potassium chloride
- qs to 4 L with Purified Water USP
96
What is colonic lavages used to replace?
replaces other strategies (ie. 24-48 h liquid diet + stimulating laxatives + evacuant enema) that suffer from compliance and malnutrition safety issues
97
What are enemas?
aqueous or oil-based solutions available for the rectal administration of medicaments for cleansing, diagnostic, or therapeutic reasons
98
What agents are often added to enemas?
viscosity enhancing agents are often added to aid retention of the solution within the rectum
99
What are the 2 types of enemas?
- retention enemas
- evacuation enemas
100
What are retention enemas?
medicated solution administered rectally for local effects or for systemic absorption
- ie. hydrocortisone for ulcerative colitis – local effects
- ie. aminophylline for asthma in pediatric patients) – systemic absorption
101
What are evacuation enemas?
solutions adminstered rectally to aid clearancew of the bowel by:
- softening and lubricating fecal matter (ie. mineral oil)
- promoting intestinal motility (ie. peanut oil)
- increase osmolality within rectum to increase water content of fecal matter (ie. glycerol, salts, PEG, etc.)
102
Syrups
- main solvent
- preservation
- examples
main solvent:
- water + sugar
preservation:
- sorbitol 64%
- sucrose 65-85%
examples:
- tylenol syrup
103
Aromatic Waters
- main solvent
- preservation
- examples
main solvent:
- water + etheric oils
preservation:
- needed (ie. benzoates)
examples:
- concentrated peppermint water
104
Colonic Lavages and Enemas
- main solvent
- preservation
- examples
main solvent:
- water
preservation:
- N/A (freshly made)
examples:
- PEG3350 lavage
105
Gargles and Mouthwashes
- main solvent
- preservation
- examples
main solvent:
- water + (maybe) alcohol
preservation:
- not needed if > 12% ethanol
examples:
- chlorhexidine antiseptic mouthwash
106
Elixirs
- main solvent
- preservation
- examples
main solvent:
- water + alcohol
preservation:
- not needed if > 12% ethanol
examples:
- theophyllin elixir
107
Tinctures
- main solvent
- preservation
- examples
main solvent:
- water + 15-90% alcohol
preservation:
- N/A
examples:
- opium tincture
- iodine tincture
108
Spirits
- main solvent
- preservation
- examples
main solvent:
- > 60% alcohol + water
preservation:
- N/A
examples:
- Klosterfrau Melissengeist
