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1004 > Solution Formulation > Flashcards

Solution Formulation Flashcards

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
Q

How to prevent degradation by acid/base catalysis:

A

Use a buffer to maintain pH of maximum stability

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26
Q

How to prevent degradation by oxidation:

A

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

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27
Q

How to prevent degradation by trace elements?

A

Use a chelator to absorb them e.g. EDTA

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28
Q

How to prevent degradation by temperature?

A

Refrigerate

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29
Q

How to prevent degradation by light?

A

Use amber glass

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30
Q

Why is toxicity needed?

A

Important for protecting cells

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31
Q

Discuss osmosis in an open system:

A

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

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32
Q

Describe osmosis in a closed system

A

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

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33
Q

What is osmotic pressure?

A

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

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34
Q

What is 1 osmole?

A

Avogadro number of osmotically active items

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35
Q

What is osmolarity?

A

The number of osmotically active items in one litre of solution

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36
Q

What is osmolality?

A

The number of osmotically active items associated with 1kg of solvent

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37
Q

What is the osmotic pressure of 1 osmolar aqueous solution?

A

22.4 atmospheres at 0 degrees

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38
Q

What is the freezing point of 1 osmolar aqueous solution?

A

-1.86 degrees

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39
Q

What is the boiling point of 1 osmolar of aqueous solution?

A

100.52 degrees

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40
Q

What are iso-osmotic solutions?

A

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

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41
Q

What are iso-tonic solutions?

A

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
Q

Why are iso-tonic solutions important?

A

They maintain integrity of plasma components after injection of a formulation

Reduce pain after application of a formulation

43
Q

Is an iso-tonic solution good?

A

Yes, Keeps red blood cells at a medium size

44
Q

Is a hyper-tonic solution good?

A

No, it shrinks red blood cells

45
Q

Is a hypo-tonic solution good for red blood cells?

A

No, it makes them swell and burst

46
Q

What is the osmolarity of plasma?

A

325 mOsmolar

47
Q

What is the osmolal of plasma?

A

291 mOsmolal

48
Q

What is the osmolal of 0.9% w/v NaCl aqueous solution?

A

313 mOsmolal

49
Q

What is the osmolarity of a 0.9% w/v NaCl aqueous solution?

A

308 mOsmolar

50
Q

What is the aim of adjusting tonicity?

A

Aims to produce a formulation with the same osmolarity/osmolality as plasma components

51
Q

What is the method to adjusting tonicity concentration?

A

Assume effects of all components are addictive

Add up all components of osmolarity mode

Subtract 325 mOsmolar

Calculate quantity of NaCL/dextrose required

52
Q

How to adjust tonicity using freezing point depression method?

A

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
Q

What is the freezing point of water

A

0 degree

54
Q

What is the freezing point of tears and plasma?

A
  • 0.52 degrees
55
Q

What is the freezing point depression of plasma a/tears compared to water?

A

0.52 degrees

56
Q

What is the freezing point of 0.9% w/v NaCl aqueous solution?

A
  • 0.52 degrees
57
Q

What is the freezing point depression of 0.9% w/v NaCl aqueous solution compared to water?

A

0.52 degrees

58
Q

What is the freezing point of 1% w/v NaCl aqueous solution?

A
  • 0.58 degrees
59
Q

What is the method of adjusting tonicity using the freezing point depression method?

A

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
Q

Why is the sodium chloride equivalent method used to adjust tonicity?

A

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
Q

Explain the method of adjusting tonicity using the sodium chloride equivalent method:

A

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
Q

Which formulations should have a low viscosity?

A

Oral and parenteral solutions

So that they can be easily poured and pain free

63
Q

Which formulations should be more viscous?

A

Eye drops:
Promotes retention on the surface of the eye

Babies oral liquids:
Reduces chances of dribble

64
Q

How is viscosity increased?

A

Can be increased by adding a polymeric material such as

Methylcellulose
Polyvinylalcohol
Hydroxypropy;methylcellulose (hypromellose)

65
Q

What preparations must density be considered with?

A

Intra-thecal injections such as spinal anaesthesia e.g. epidurals

66
Q

How can injection density be altered?

A

Using dextrose

This will determine how it will mix with cerebrospinal-spinal fluid

67
Q

What does isobaric mean?

A

Density is the same as CSF, will mix homogeneously

68
Q

What does hypobaric mean?

A

Lower density than CSF, will rise

69
Q

What does hyperbaric mean?

A

Higher density than CSF, will sink

70
Q

What aesthetic aspects are considered?

A

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
Q

What colour will amaranth turn a liquid

A

Red

72
Q

What colour will tartazine turn a liquid

A

Yellow

73
Q

What colour will iron oxides turn a liquid

A

Red and yellow

74
Q

What colour will titanium dioxide turn a liquid

A

White

75
Q

What flavourings should only be used in solutions and syrups and not suspensions?

A

Flavoured syrups

Syrup BP plus flavour extract e.g. orange syrup or wild cherry syrup

76
Q

What flavouring works best in suspensions?

A

Concentrated flavours e.g. hydroalcholic extracts such as cinnamon water

77
Q

Why are solutions not a suitable formation?

A

Layering is possible so must be shaken well

78
Q

What is the usual oral dosing?

A

5ml

79
Q

What are the pros and cons of oral solutions?

A

Easy to administer
Dose adjustment is easy
Difficult to carry around

80
Q

What are the pros and cons of injections?

A

Difficult to send administer

Issues with needles and glass

81
Q

What are the pros and cons of eye drops

A

Relatively easy to administer

Convenient to carry around

82
Q

What considerations should be taken in regards to manufacture and cost?

A

Manufacture:
Easy process

Bulky

Need pharmaceutical-grade water

Cost:
Excipients are cheap

The drug can potentially be expensive

83
Q

Define solubility

A

The concentration of a solute in a saturated solution at a certain temperature

84
Q

Define dissolution

A

The transfer of drug molecules or ions from its solid phase to the surrounding medium

85
Q

What is the key difference between solubility and dissolution?

A

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
Q

What is a saturated solution?

A

A kind in which the solute is in equilibrium with the solid phase

87
Q

What is a solution?

A

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
Q

Where are solutions used medically?

A 
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
Q

What are some formulation issues:

A

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
Q

What is the main solvent used in most pharmaceutical solutions?

A

Water

Can be:

Purified water BP

Water for irrigation BP

Water for injection BP

91
Q

Should desired drug concentration be close to the equilibrium solubility?

A

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
Q

What co-solvents can be used to increase aqueous solubility?

A

Ethanol CH3CH2OH

Industrial methylated spirits (IMS) (do not ingest)

Glycerin (glycerol) HOCH2CH(OH)CH2OH

Propylene glycol CH£CH(OH)CH2OH

Polyethylene glycol

93
Q

What are the pros and cons of using co-solvents to increase aqueous solubility?

A

Limits on quantity

Acceptability issue with ethanol

Will change rheology of the product

Will effect the taste

94
Q

How can the pH be manipulated to increase aqueous solubility?

A

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
Q

How can pH be manipulated to increase aqueous solubility?

What should be added to what?

A

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
Q

What are the pros and cons of manipulating the pH to increase aqueous solubility?

A

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
Q

How is salt formation used to increase aqueous solubility?

A

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
Q

What are acceptable cationic salts that can be used for salt formation;

A

Na+

K+

Ca2+

99
Q

What are acceptable anionic salts that can be used for salt formation;

A

Cl-

HCO3-

SO4-

HPO4 2-

H2PO4 -

Maleate, tartrate, citrate, lactate, succinate, mesylate

100
Q

What is a surfactant and how do they behave in water?

A

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

1004 (3 decks)

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