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Solution Formulation Flashcards

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1
Q

How can the solubility of a drug be increased?

A

Use of surfactants to increase aqueous solubility

Use of chemical complexing agents to increase aqueous solubility

Use of physical complexing agents to increase aqueous solubility

Chemical modification to increase aqueous solubility

Use of co-solvents to increase aqueous solubility

Manipulation of pH to increase aqueous solubility

Salt formation to increase aqueous solubility

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2
Q

Discuss how surfactants can be used to increase aqueous solubility.

Include any issues with this process

Also include how surfactants work and then type of formulation they can be used with

A

Sodium lauryl sulphate (sodium dodecyl sulphate)
CMC= 0.23%

Polysorbate 80 (tween 80) 
CMC= 0.014%

Siri tan mono-oleate (span 80)

Issues with quantity and toxicity

Surfactant levels below cmc may help ‘wetting’
They can reduce the surface energy of a drug particle
Can be used for suspensions and tablet formulations

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3
Q

How can the use of a chemical complexing agent increase aqueous solubility?

State any issues with this method

A

Make a ‘complex’ between the drug and another material

Similar idea to a salt, but full ionisation is not achieved for either component

No covalent bonds so not a new drug molecule

It is held together by a range of molecular interactions

Sometimes called a ‘co-crystal’

Issues with stability of the complex
Issues with the release of the active drug
Issues with toxicity/dose of the complexing agent

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4
Q

How can the use of physical complexing agents be used to increase aqueous solubility?

State any issues with this method

Give an example

A

Cyclodextrins:
Cyclic glucose polymers
Arranged in aqueous solution as a truncated cone
Hydrophobic core provides a reservoir for poorly water-soluble drugs to increase the water solubility

Number of glucose residues: alpha= 6 beta= 7 gamma=8

Cyclodextrins:
Can have 1:1, 1:2 or 2:1 complexes
Can have modifications to basic glucose unit i.e. hydroxyl-beta-

Issues with acceptability/toxicity
Issues with the stability of the complex
Will the drug released from the complexing agent be effective?

Example:
Itraconazole
Solubility in water (neutral pH) = 1ng/ml
Solubility in 40% HP-beta-CD solution (neutral pH) = 10mg/ml
Used in the marketed products
Oral liquid and IV injections

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5
Q

How can chemical modification increase aqueous solubility?

A

Design in some hydrophilic character
This is now a new drug
Needs to be completely retested or biological activity and toxicity

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6
Q

What are non-aqueous solutions?

A

Oral formulations:
Oil soluble vitamins or very non-polar drugs
Fixed oils e.g. soybean oil, arachis oil, sesame oil
Volume of oil is important
Taste is important

Intramuscular depot injections:
Long acting
Fixed oils e.g. soybean oil, arachis oil, sesame oil
Volume 2 to 5ml

Enemas:
Fixed oils e.g. arachis

Topical lotions/ paints:
Ethanol’s/IM’s
Solvent volatile

Ear drops:
Olive oil to remove wax

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7
Q

What needs to be considered when selecting a vehicle for drugs:

A

Toxicity

Quality:
Chemical
Microbiological
Pharmaceutical grade

Flammability:
Ethanol (lotions/paints/collodions)

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8
Q

What are acceptable Ph ranges for oral medications?

A

PH 3 to 9 for routine dosing

PH 2 to 10 for occasional dosing

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9
Q

What is the acceptable pH range of intravenous drugs?

A

PH target = 7.4

Small volumes (<5) pH 5 to 9 
Large volumes (>5) ph 7 to 8

If the pH is far from 7.4 the drug needs to be administered via the central vein

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10
Q

What is the acceptable pH ranges of other injection routes?

A

PH target is 7.4; a very limited pH range is acceptable

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11
Q

What is the acceptable pH ranges of ocular preparations?

A

PH target is 7.4; very limited pH range available

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12
Q

What is the acceptable pH ranges of nebuliser solutions?

A

PH 6.5 target

PH 6.0 to 7.0 is acceptable

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13
Q

What is the acceptable pH ranges of nasal solutions?

A

Target pH is 6.8; very limited pH range is acceptable

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14
Q

What does sterility mean?

A

Sterility is an absolute concept, something cannot be half sterile

If the target site is sterile, the dosage form should be sterile such as parenterals, oculars and inhalation’s

If the target site is not sterile the dosage form should be micro biologically clean
E.g. orals and topicals

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15
Q

What are anti-microbial preservatives

A

All medications should be produced in a clean or sterile room

Preservatives are for in use protection

Single use sterile solutions do not require preservatives, for example, small volume injections, single use eye drops and nebuliser solutions

‘Multiple use’ solutions require preservatives, these included bottles of eye drops, nasal solutions, oral solutions, lotions

Preservative efficacy must be established case-by-case

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16
Q

What are five anti-microbials used in oral solutions?

What are their positive aspects and limitations

What strength is required

A

Sucrose:
Minimum 67% w/v for efficacy
Acts by hypertonicity and viscosity
To maintain preservative activity it should not be diluted
Has a sweet taste
Cariogenic (can cause tooth decay)
Used orally in extemporaneously produced products
Not generally used in proprietary products
Not used for other routes

Sordid acid: CH3CH=CHCH=CHCOOH
Approximately 0.1 to 0.2% w/v
In-ionised form effective
Best in weakly acidic solutions

Benzoic acid/ sodium benzoate 
C6H5-COOH / C6H5-COONa
Approximately 0.1 to 0.2% w/v 
Unionised form effective 
Best in weakly acidic solutions 
Cats are very sensitive to benzoic acid 
Parabens 
X para hydroxy benzoic acid 
X = methyl, propyl 
Approximately 0.1 to 0.2% w/v 
Often used with benzoic acid or sodium benzoate

Chloroform: CHCl3
0.25% v/v for oral use
Used in extemporaneously produced products

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17
Q

What are four anti-microbials used in injections ?

What strength is required

A

Benzoyl alcohol
Not to be used in neonates especially premature
Approximately 0.1 to 4% w/v

Parabens
Approximately 0.1 to 0.2% w/v

Phenol:
Approximately 0.2 to 0.5% w/v

Sodium bisulphite/ sodium metabisulphate
Approximately 0.1 to 1% w/v

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18
Q

What are seven anti-microbials used in topical preparations ?

What are their positive aspects and limitations

What strength is required

A

Phenoxyethanol
Approximately 1% w/v

Chlorocresol
Approximately 0.1% w/v

Chlorobutanol
Approximately 0.1% w/v

Parabens
Approximate 0.1 to 0.3% w/v

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19
Q

What is an anti-microbials used in ocular solutions?

What are their positive aspects and limitations

What strength is required

A

Benzalkonium chloride
Approximately 0.01 w/v
Long chain surfactant

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20
Q

What is the minimum shelf life of marketed products and extemporaneously prepared products

A

Marketed products: 2 years

Extemporaneously prepared products: 1 week

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21
Q

What is the initial specification for active drug contents?

A

General specification of 95.0 to 105.0% of stated

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22
Q

What does end of shelf life specification for active drug content mean?

A

Usually one indicative specified degradate at a maximum specified level e.g. 0.5%

Also specify total degradates allowed e.g. maximum 1.0%

Dependant on pharmacological activity and toxicity

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23
Q

How can drugs be degraded?

A

Oxidation

Reduction

Hydrolysis

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24
Q

What are catalysts for drug degradation?

A 
PH 
Oxygen 
Water 
Non-aqueous solvents 
Trace elements 
Heat 
Light
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25
How to prevent degradation by acid/base catalysis:
Use a buffer to maintain pH of maximum stability
26
How to prevent degradation by oxidation:
Use an antioxidant such as: Ascorbic acid 0.2% w/v Alpha-tocopherol 0.2% w/v Sodium metabisulphate 0.1& w/v Reduce O2 permeation into package e.g. glass not HDPE Replace air with nitrogen or CO2 in package headspace
27
How to prevent degradation by trace elements?
Use a chelator to absorb them e.g. EDTA
28
How to prevent degradation by temperature?
Refrigerate
29
How to prevent degradation by light?
Use amber glass
30
Why is toxicity needed?
Important for protecting cells
31
Discuss osmosis in an open system:
Individual solvent molecules diffuse across the semi-permeable membrane The level of liquid is the same on both sides Vapour pressure (and chemical potential) of the solvent is reduced in a solution Solvent will move across the semi-permeable membrane to equalise its chemical potential, i.e. from pure solvent into the solution The level of liquid is then higher on the solution side Applying pressure to the solution will reverse this movement of solvent molecules The amount of pressure required to return the system to its original state is the osmotic pressure of the solution In an open system, the changes in volume either side of the membrane is not too important
32
Describe osmosis in a closed system
In a closed system the changes in volume either side of the membrane are very important, as the membrane will move Applying pressure to the solution would reverse this movement of solvent molecules The amount of pressure required to return the system to its original state is the osmotic pressure of the solution
33
What is osmotic pressure?
Related to the number of molecules (or ions) in solution Colligative property Need a way of expressing the osmotic effect of materials Concept of osmolarity and osmolality 1 osmole = avogados number of osmotically active items Osmolarity = the number of osmotically active items in 1 litre of solution Osmolality = the number of osmotically active items associated with 1kg of solvent
34
What is 1 osmole?
Avogadro number of osmotically active items
35
What is osmolarity?
The number of osmotically active items in one litre of solution
36
What is osmolality?
The number of osmotically active items associated with 1kg of solvent
37
What is the osmotic pressure of 1 osmolar aqueous solution?
22.4 atmospheres at 0 degrees
38
What is the freezing point of 1 osmolar aqueous solution?
-1.86 degrees
39
What is the boiling point of 1 osmolar of aqueous solution?
100.52 degrees
40
What are iso-osmotic solutions?
Two solutions are iso-osmotic when there is no net movement of solvent between them Irrespective of the actual osmotic pressure of the solutions or of the composition of the solutions of the membrane
41
What are iso-tonic solutions?
The term iso-tonic is used when referring to biological systems Two solutions are iso-tonic when there is no net movement of solvent (water) between them - across a biological membrane e.g. rbc, cornea - matching the osmotic pressure of the biological system In a biological system, there is some limited solute movement across the membranes e.g. NaCl This is allowed for in calculations Should specify the membrane e.g. RBC
42
Why are iso-tonic solutions important?
They maintain integrity of plasma components after injection of a formulation Reduce pain after application of a formulation
43
Is an iso-tonic solution good?
Yes, Keeps red blood cells at a medium size
44
Is a hyper-tonic solution good?
No, it shrinks red blood cells
45
Is a hypo-tonic solution good for red blood cells?
No, it makes them swell and burst
46
What is the osmolarity of plasma?
325 mOsmolar
47
What is the osmolal of plasma?
291 mOsmolal
48
What is the osmolal of 0.9% w/v NaCl aqueous solution?
313 mOsmolal
49
What is the osmolarity of a 0.9% w/v NaCl aqueous solution?
308 mOsmolar
50
What is the aim of adjusting tonicity?
Aims to produce a formulation with the same osmolarity/osmolality as plasma components
51
What is the method to adjusting tonicity concentration?
Assume effects of all components are addictive Add up all components of osmolarity mode Subtract 325 mOsmolar Calculate quantity of NaCL/dextrose required
52
How to adjust tonicity using freezing point depression method?
All colligative properties work from the same basis Use fpd as a surrogate marker for osmotic pressure Assume effects of all components are addictive
53
What is the freezing point of water
0 degree
54
What is the freezing point of tears and plasma?
- 0.52 degrees
55
What is the freezing point depression of plasma a/tears compared to water?
0.52 degrees
56
What is the freezing point of 0.9% w/v NaCl aqueous solution?
- 0.52 degrees
57
What is the freezing point depression of 0.9% w/v NaCl aqueous solution compared to water?
0.52 degrees
58
What is the freezing point of 1% w/v NaCl aqueous solution?
- 0.58 degrees
59
What is the method of adjusting tonicity using the freezing point depression method?
Calculate or measure the fpd due to all components Substrate from a fpd of 0.52 degrees Calculate the quantity of NaCl/ dextrose required
60
Why is the sodium chloride equivalent method used to adjust tonicity?
Based on the fpd method NaCl equivalent = the amount of NaCl which has the same osmotic effect as 1g of the drug NaCl equivalents are additive
61
Explain the method of adjusting tonicity using the sodium chloride equivalent method:
Calculate the NaCl equivalent due to all components Subtract from a total NaCl requirement of 0.9% w/v Calculate the quantity of NaCl/ dextrose required
62
Which formulations should have a low viscosity?
Oral and parenteral solutions So that they can be easily poured and pain free
63
Which formulations should be more viscous?
Eye drops: Promotes retention on the surface of the eye Babies oral liquids: Reduces chances of dribble
64
How is viscosity increased?
Can be increased by adding a polymeric material such as Methylcellulose Polyvinylalcohol Hydroxypropy;methylcellulose (hypromellose)
65
What preparations must density be considered with?
Intra-thecal injections such as spinal anaesthesia e.g. epidurals
66
How can injection density be altered?
Using dextrose This will determine how it will mix with cerebrospinal-spinal fluid
67
What does isobaric mean?
Density is the same as CSF, will mix homogeneously
68
What does hypobaric mean?
Lower density than CSF, will rise
69
What does hyperbaric mean?
Higher density than CSF, will sink
70
What aesthetic aspects are considered?
Colour: Difficult issue Colourants may have a biological effect Children tend to like brightly coloured things Regulations are complex, variable and changeable, best to avoid colours if possible ``` Examples of colours: Amaranth (red) Tartrazine (yellow) FD+C Blue 2 (blue) Iron oxides (red,yellow) Titanium dioxide (white) ``` Flavour: Drugs tend to taste bitter Adults may accept but children probably wont Flavour perception: sweet, sour, salt, bitter, savoury Uncomplicated process Flavour masking: trying to compete directly with the drug Preference: Children prefer sweet and fruity flavours Adults prefer sharper tastes Flavour syrups: Syrup BP plus flavour extract e.g. orange syrup, wild cherry syrup Used at 10-20% v/v/ in extemporaneous preparation Solutions and syrups only, not suspensions ``` Concentrated flavours: Hydroalcoholic extracts e.g. concentrated cinnamon water Clear to cloudy white Best in suspensions Must be diluted 1 in 40 for use ``` Sweeteners: Syrup BP, sucrose, fructose, sorbitol, chloroform, aspartame Problems with dental caries and diabetics
71
What colour will amaranth turn a liquid
Red
72
What colour will tartazine turn a liquid
Yellow
73
What colour will iron oxides turn a liquid
Red and yellow
74
What colour will titanium dioxide turn a liquid
White
75
What flavourings should only be used in solutions and syrups and not suspensions?
Flavoured syrups Syrup BP plus flavour extract e.g. orange syrup or wild cherry syrup
76
What flavouring works best in suspensions?
Concentrated flavours e.g. hydroalcholic extracts such as cinnamon water
77
Why are solutions not a suitable formation?
Layering is possible so must be shaken well
78
What is the usual oral dosing?
5ml
79
What are the pros and cons of oral solutions?
Easy to administer Dose adjustment is easy Difficult to carry around
80
What are the pros and cons of injections?
Difficult to send administer Issues with needles and glass
81
What are the pros and cons of eye drops
Relatively easy to administer Convenient to carry around
82
What considerations should be taken in regards to manufacture and cost?
Manufacture: Easy process Bulky Need pharmaceutical-grade water Cost: Excipients are cheap The drug can potentially be expensive
83
Define solubility
The concentration of a solute in a saturated solution at a certain temperature
84
Define dissolution
The transfer of drug molecules or ions from its solid phase to the surrounding medium
85
What is the key difference between solubility and dissolution?
Key difference: Solubility is an intrinsic material property that can only be altered by chemical modification of the molecule while Dissolution is an extrinsic material property that can be modified by various physical and chemical properties such as particle size reduction and solubilisation enhancing strategies
86
What is a saturated solution?
A kind in which the solute is in equilibrium with the solid phase
87
What is a solution?
A mono-molecular dispersion of drugs in a liquid Each drug molecule is separate from all other drug molecules Each drug molecule behaves independently Optically clear (transparent) No lumps or visible particles
88
Where are solutions used medically?
``` Oral dosing: Especially in children and the elderly Issues with palatability Usually non sterile Wide pH range acceptable ``` Mouthwashes/gargles: Usually non sterile Wide pH rashness acceptable Topical solutions/paints Usually non sterile Can be non aqueous Nasal drops: Ideally should be isotonic Narrow range of pH acceptable Usually non-sterile Ear drops: Usually non sterile Eye drops: Need to be isotonic Need to be sterile Need to be pH controlled Nebulisation solutions: Need to be sterile Fairly narrow range of pH acceptable Irrigation: Needs to be sterile Narrow range of pH acceptable Injections: Need to be sterile Large volumes need to be isotonic Need to be pH controlled, especially large volumes
89
What are some formulation issues:
Solubility of the drug Vehicle acceptability PH Sterility and anti-microbial preservatives Chemical stability and stability enhancers Tonicity Viscosity and density Aesthetic considerations Reproducibility of dosing Ease of use Ease of manufacture and low cost
90
What is the main solvent used in most pharmaceutical solutions?
Water Can be: Purified water BP Water for irrigation BP Water for injection BP
91
Should desired drug concentration be close to the equilibrium solubility?
Desired drug concentrations should not be close to its equilibrium solubility A small reduction in temperate will cause precipitation So there will be a non-uniformity of dosing
92
What co-solvents can be used to increase aqueous solubility?
Ethanol CH3CH2OH Industrial methylated spirits (IMS) (do not ingest) Glycerin (glycerol) HOCH2CH(OH)CH2OH Propylene glycol CH£CH(OH)CH2OH Polyethylene glycol
93
What are the pros and cons of using co-solvents to increase aqueous solubility?
Limits on quantity Acceptability issue with ethanol Will change rheology of the product Will effect the taste
94
How can the pH be manipulated to increase aqueous solubility?
If the drug is ionisable, it solubility may vary with the pH Use the Henderson- hasselbalch equation to predict pH of maximum solubility Essentially adding/subtracting H+ to/from a drug
95
How can pH be manipulated to increase aqueous solubility? What should be added to what?
If the drug is a weak acid, dissolve it in a basic solution If the drug is a weak base, dissolve it in an acidic solution
96
What are the pros and cons of manipulating the pH to increase aqueous solubility?
Narrow range of pH acceptable for ocular, nasal and some injection formulations Wider ranges of pH for oral preparations May need a buffer to maintain the pH such as citrate, phosphate, acetate, bicarbonate, gluconate, lactate or tartrate Effect of buffer on stability and solubility of drug Effect of buffer on taste Absorption occurs only in the un-ionised form Varying pH may affect stability of the drug Varying pH mat affect action of other components
97
How is salt formation used to increase aqueous solubility?
Similar idea to the manipulation of the pH If the drug is a weak acid: React with a base and evaporate off the water to give a solid salt Then dissolve the solid salt in water to give a solution with pH>7 If the drug is a weak base: React with an acid and evaporate off the water to give a sold Dissolve the solid salt in water to give a solution with pH<7
98
What are acceptable cationic salts that can be used for salt formation;
Na+ K+ Ca2+
99
What are acceptable anionic salts that can be used for salt formation;
Cl- HCO3- SO4- HPO4 2- H2PO4 - Maleate, tartrate, citrate, lactate, succinate, mesylate
100
What is a surfactant and how do they behave in water?
Is amphiphilic i.e. it has a hydrophobic tail and a hydrophilic head In water, surfactants at low concentrations will form a layer on the surface of the water In water, surfactants at high concentrations will also form micelles in the bulk of the water Above the critical Micelle concentration (CMC) micelles are formed The centre of the micelle is hydrophic, so hydrophobic drugs can localise there Solubility of a drug will sharply increase at the CMC Need to get the drug out of the micelle for absorption

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