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PY366 Drug discovery > Preformulation procedures for new drugs > Flashcards

Preformulation procedures for new drugs Flashcards

1
Q

what are the events in product development

A
  1. synthesis/isolation
  2. biological activity
  3. preformulation
  4. formulation development
  5. pre clinical and clinical testing
  6. IND/NDA application
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2
Q

what is the aim of a formulation scientist

A

to develop a pharmaceutical product for a drug suitable for administration to humans

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3
Q

what are the criteria for development

A
  • effective
  • ideal administration
  • stable
  • ideal for large scale manufacturing
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4
Q

what is preformulation

A

the first stage of formulation development process
- a collation of steps that are performed before actual formulation development is started
- logical sequence of events
- must be performed for all types of dosage forms

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5
Q

what are the pre-requisites for pre formulation

A
  1. synthesis- a small amount of the drug has been synthesised with suitable purity
  2. pharmacology- the drug has demonstrated the desired pharmacological effect in animal models or cell culture models
  3. toxicology- toxicity of the drug has been determined
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6
Q

what is the 1st step in preformulation

A

development of analytical techniques
- to determine identity
- to assay the drug

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7
Q

what can be used for identifying the drug substance

A

spectroscopy
- NMR
-MS
-UV/VIS
-IR
also give us the purity of the drug molecules and identification of any potential contaminants

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8
Q

why do we need accurate analytical data

A

to accurately determine the concentration of the drug in the dosage form and in biological samples

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9
Q

what methods are available to determine the concentration of a substance in a matrix formulation, biological sample or extraction sample

A
  1. traditional methods- TLC, UV/VIS, simple HPLC
  2. modern methods- HPLC-MS, UPLC-MS
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10
Q

What properties should an analytical method have for validation

A
  • sensitive
  • selective
  • reproducible
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11
Q

how do you validate an analytical method

A
  1. basic information
    - MW
    - purity
    - chemical structure
    - any info on synthetic impurities or degradation products
  2. physicochemical parameters
    - solubility
    - pKa
    - partition coefficient
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12
Q

how is data interpreted following method validation

A
  1. prepare a calibration plot or linear response graph for the drug
  2. extract the drug from the formulation into a solvent
  3. analyse the sample using the method
  4. calculate the concentration in the sample
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13
Q

give examples of physicochemical properties of a drug

A
  • particle size
  • crystal properties
  • solubility
  • pKa
  • log P
  • dissolution
  • organoleptic properties
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14
Q

what does particle size directly influence

A
  1. solubility and dissolution rate
  2. content uniformity in the final dosage form
  3. flow characteristics
  4. sedimentation rate
  5. bioavailability
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15
Q

what is the recommend particle size for inhalation

A

<5um in diameter
- eg corticosteroids and bronchodilators

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16
Q

what is the recommended particle size for suspensions

A

> 1um in diameter
- should have some degree of wettability

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17
Q

what can be the problems with crystal properties

A
  • uneven crystal shapes
  • difficult to formulate as crystal shape affects flow properties
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18
Q

what can be used to obtain uniform crystal shapes

A
  • crushing
  • spray drying
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19
Q

how do crystal properties affect melting point

A

require only a small amount of material to get information regarding stability and solubility

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20
Q

what can be used to measure crystals

A
  1. capillary melting point apparatus
  2. hot stage microscopy
  3. differential scanning calorimetry or thermal analysis
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21
Q

what is a polymorphism

A

where a solid material exists with at least 2 different molecular arrangements which give distinct crystal species

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22
Q

what are the types of crystals

A
  1. polymorphs
  2. solvates- contain trace amounts of solvent used for crystallising the drug
  3. hydrates- water bound to drug molecules
  4. amorphous
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23
Q

what can differential scanning calorimetry be used to identify

A
  1. how many polymorphs of the drug exists
  2. how stable each form is
  3. is there a glass transition state
  4. can the metastable form be stabilised
  5. how will processing and storage affect stability of the polymorph
  6. what is the solubility of each polymorph
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24
Q

what is meant by solubility

A

the maximum amount of drug that can be dissolved in a selected solvent at equilibrium conditions

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25
Q

what are the 2 types of solvents

A
  1. aqueous solvents- water, buffer solutions
  2. non aqueous solvents- oils, waxes
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26
Q

what measure of aqueous solubility represents good bioabsorption

A

aqueous solubility >10mg/ml

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27
Q

what temperature is intrinsic solubility measured at

A

measured at 4 degrees and 37 degrees

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28
Q

what are the 2 types of pH of solubilised drug

A

acidic or basic

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29
Q

what is a weak base

A

soluble in acidic solution but not in water

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30
Q

what is a weak acid

A

soluble in alkaline solution but not in water

31
Q

what does an aqueous solubility of free acid/base <1mg/ml indicate

A

indicates the need for a salt

32
Q

what are the factors involved in salt selection

A
  1. hygroscopic nature
  2. solubility and bioavailability
  3. physical and chemical stability
    - polymorphisms
    - incompatibilities
    - degradation
  4. each salt form is a different NCE
33
Q

what is the Henderson-hasselbach equation for weak acids

A

pH= pKa + log10[A-]/[HA]

34
Q

what is the Henderson-hasselbach equation for weak bases

A

pH= pKa + log10[B]/[BH+]

35
Q

what is the partition coefficient

A
  • solvent:water quotient for drug distribution
  • measure of relative lipophilicity (logP) of a drug between octane and water
  • indicates membrane penetration ability and absorption
36
Q

how is the partition coefficient determined

A

by shake flask method

37
Q

what is dissolution

A

a dynamic process by which a material is dissolved in a solvent and the rate is characterised
- amount of drug dissolved over a given time

38
Q

describe the dissolution rate in a weakly basic drug

A

will have a high dissolution rate and high solubility in stomach but not lower down the GIT

39
Q

describe the dissolution rate in a weakly acidic drug

A

has a lower dissolution rate and is less soluble in the stomach and more soluble down the GIT

40
Q

how is intrinsic dissolution rate of a compound reduced

A

due to common ion effect

41
Q

give examples of organoleptic modifiers for oral drug delivery

A
  1. natural sources
    - sweeteners (sorbitol)
    - fruit extracts (citrus)
    - natural colouring agents (b carotene)
  2. synthetic sources
    - artificial fruit flavours
    - colouring agents
42
Q

what potency is recommended at storage conditions

A

potency >95% at recommended storage conditions

43
Q

what are forced drug stability tests performed at preformulation

A

determines
1. stability of the drug in extreme conditions
2. identifies breakdown products
3. excipient incompatabilities
4. storage conditions
5. package conditions and incompatibilities

44
Q

what are the different types of drug degradation

A
  1. hydrolysis due to acid or base
  2. oxidation/reduction due to metal ions
  3. photolysis due to UV or visible light
  4. trace metal catalysis due to Fe2+, Cu2+
45
Q

describe the effect of temperature on stability

A
  1. 10 degree increase leads to a 5 fold increase in decay
  2. storage conditions
  3. moisture content
    - eg. if insulin is frozen, leads to inactivation
46
Q

give an example of an oxidation reaction

A

ascorbic acid– dehydroascorbic acid

47
Q

describe the effect of oxidation

A

oxygen or trace metals can lead to free radical production
- analyse compound using analytical method

48
Q

describe the effect of acid or base on drug stability

A
  1. drug stability usually between pH 4-8
  2. drug solubility at low or high pH can lead to drug instability
  3. to test stability, pH 1,3,5,7,9 and 11 at 37 degrees and in presence of 1M HCL and 1M NaOH
  4. Acid causes isomeric changes
    - eg conversion of cis isomer– trans isomer
49
Q

what are the effects of photodegradation

A
  1. UV catalysed
  2. often seen with storage instructions ‘keep away from direct sunlight’
  3. 300-400nm most damaging
  4. retinol and b carotene undergo oxidation
50
Q

what are the advantages in analysing the effect of UV light

A
  1. to understand the effect of light on the drug
  2. can be used for further drug development
  3. choice of suitable packaging containers
51
Q

what technique can be used to analyse molecular structure in solid state stability

52
Q

what technique can be used to analyse crystal structure in solid state stability

A

scanning electron microscopy

53
Q

what technique can be used to analyse particle size in solid state stability

A

laser diffraction, seiving

54
Q

what technique can be used to analyse polymorphism in solid state stability

55
Q

what technique can be used to analyse melting point in solid state stability

A

hot stage microscopy

56
Q

what are the 2 major applications of microscopy and macroscopy

A
  • crystal morphology
  • particle size analysis
57
Q

what is particle size critical for

A

critical for dosage forms

58
Q

what can storage cause

A
  1. aggregates
  2. size and shape can increase or decrease
  3. effect of other excipients on crystal structure
  4. change in bulk density
  5. change in angle of repose
59
Q

outline the different routes of administration

A
  • oral
  • topical
  • parenteral
  • nasal/pulmonary
  • eye
  • ear
  • rectal and vaginal
60
Q

give examples of oral dosage forms

A
  • solutions
  • syrups
  • suspensions
  • emulsions
  • tablets
  • capsules
61
Q

give examples of topical dosage forms

A
  • creams
  • ointments
  • pastes
  • gels
  • lotions
62
Q

give examples of parenteral dosage forms

A
  • injections
  • implants
  • dialysis solutions
63
Q

give examples of nasal/pulmonary dosage forms

A
  • solutions
  • inhalations
  • aerosols
  • sprays
64
Q

give examples of eye dosage forms

A
  • solutions
  • ointments
  • creams
65
Q

give examples of ear dosage forms

A
  • solutions
  • suspensions
  • ointments
  • creams
66
Q

give examples of rectal and vaginal dosage forms

A
  • suppositories/pessaries
  • powders
  • solutions
    -ointments
  • cream
67
Q

what are the factors involved in dosage form design

A
  1. biopharmaceutical considerations
    - drug absorption
    - route of administration
  2. physicochemical properties of drug
  3. therapeutic considerations
    - clinical indication
    - patient compliance
68
Q

give examples of drugs which have multiple dosage forms

A
  • metronidazole, prednisolone, paracetamol, lidocaine
69
Q

what is an excipient

A

an inert substance that is used as a diluent or vehicle for preparing a drug product

70
Q

what are the different types of excipients

A
  1. solvents- water
  2. flavours
  3. sweeteners (saccharin)
  4. preservatives (parabens)
  5. stabilisers (antioxidants)
  6. diluents or fillers (starch)
  7. binders (gelatin)
  8. anti adherents or lubricants (magnesium stearate)
  9. coating agent (sugar solution)
  10. disintegrating agents
  11. pharmaceutical bases (white soft paraffin)
71
Q

how do we know which excipients can be used

A

using the Handbook of pharmaceutical excipients and FDA guidelines

72
Q

what are the factors affecting excipient usage

A
  1. suitability for the dosage form
    - liquid paraffin not suitable for IV formulations
  2. recommended concentration
  3. compatibility with the drug
    - drug should be soluble/miscible
  4. drug stability in the presence of excipient
  5. effect on bioavailability
  6. pharmacokinetic considerations
73
Q

what are excipient incompatibilities

A

chemical incompatibilities
- interaction of preservatives with non ionic surfactants reduces its antimicrobial property
- interaction of carbomer with ionisable drugs leads to precipitation of gelling agent

74
Q

what must always be considered when performing formulation development

A

patient compliance

PY366 Drug discovery (15 decks)

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