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MDD > Preformulation > Flashcards

Preformulation Flashcards

1
Q

Drug molecules are categorised into 4 main classes

A

Class I - High permeability, High Solubility Class II - High permeability, Low Solubility Class III - Low permeability, High Solubility Class IV - Low permeability, Low Solubility

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2
Q

most drugs fall in either class..

A

2 or 4

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3
Q

describe Class I drugs characteristics and e.g

A

Cross the membrane relatively easily and do not require a lot of transporters. An example is paracetamol

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4
Q

describe Class II drugs characteristics and e.g

A

these drugs can go through the lipid membrane well, but not very soluble. The efflux transporters in the gut predominate. These drugs = cleared by metabolism. e.g Carbamazepine

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5
Q

describe Class IV drugs characteristics and e.g

A

These have poor permeability and poor solubility. Both efflux and absorptive transporters could be important. These drugs are also cleared Renally or by biliary elimination. e.g Methotrexate

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6
Q

describe Class III drugs characteristics and e.g

A

These have low permeability and high solubility. The absorptive transporters effect predominates. Cleared renally or by biliary elimination. e.g Acyclovir

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7
Q

how do we describe a highly soluble drug?

A

A drug that is fully soluble below 250mL, over pH range between 1-7.5.

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8
Q

what does ‘highly permeable’ refer to?

A

at least 90% of drugs absorbed in human

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9
Q

what do we refer to by ‘rapidly dissolving formulation’

A

one where > 85% is dissolved in 30 minutes

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10
Q

what is hygroscopicity

A

the term used to measure the amount of water being taken up by a drug/excipient at different relative humidities.

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11
Q

use an example to talk about a hygroscopic molecule

A

Starch - it is able to take in moisture well and return this moisture. This allows it to act as a disintegrant. When drying, the moisture is not lost in the same way. This is due to the amylase bonds returning the water. This phenomenon is known as moisture sorption hysteresis

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12
Q

starch is also able to acts as a

A

disintegrant

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13
Q

Polymorphs can all have different properties. This includes

A

Melting points, Hygroscopic properties, solubility and stability under different conditions

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14
Q

Because polymorphs have different properties, they must be identified. We can use techniques such as

A

Differential Scanning Calorimetry , Thermogravimetric analysis and X-ray powder diffraction. DSC involves heating the sample up to 300oC and monitoring any transitions. TAG involves heating a sample on a balance and measuring a loss of weight

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15
Q

what is the ICH and what does its guidelines state

A

the International Conference of the Harmonisation of Regulatory Requirements. It states that the drug should be tested under different stress conditions that will be indicative to the conditions to which the drug will be exposed to.

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16
Q

the ICH stress testing is thought to include the effects of:

A

pH - Temperature - Humidity - Light - Oxidising agents

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17
Q

compounds can degrade through a variety of processes:

A
  • hydrolysis (reaction with other molecules)
  • oxidation, by reacting with oxygen molecules
  • photolysis
  • trace metal catalysis
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18
Q

instability within drugs can be caused by

A

isomeration and polymerisation

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19
Q

why is stability testing important?

A

to provide feeback for the modification of labile groups to:

  • improve stability
  • help scientists determine how easily the compound can be developed
  • provide guidelines for product handling and storage
  • provide information to guide stabilitsation strategies
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20
Q

what is chemical testing?

A

a drug can be tested under acidic or basic conditions.

Under acidic conditions the drug is reluxed with 0.1mol HCl for 8-12hrs

Under basic conditions the drug is refluxed with 0.1mol NaOH for 8-12hrs

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21
Q

What is Solid State Testing

A

The solid-state stability testing assesses the effects of humidity and temperature on drug stability. This can also be used to assess the effect of the solid state form (amorphous vs crystalline)

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22
Q

How do i conduct a solid state stability test?

A

Pre - weighed samples places in stability cabinates for up to 8 weeks at:

  1. 40oC
  2. 60oC
  3. 20oC + 85oC relative humidity (open vials)
  4. 40oC + 70oC relative humidity (open vials)

At pre - determined time intervals, a sample is taken from each cabinet and dissolved in an appropriate solvent. This is then analysed under HPLC to identify if any degredation has occured. note: HPLC method is usually reverse phase HPLC

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23
Q

how do i conduct a photostability test?

A
  • Drug samples stored in high sensitivity light/UV conditions at 25oC in photostability cabinets
  • ICH guidelines (the drug should be exposed to 1.2 million lux hours and 200 W hour/m2 to UV)
  • Drug stored at different concentrations in various solvents.
  • The controls are protected from light, but ONE stored under the same conditions as the sample
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24
Q

how to conduct an oxidative stability test for unsaturated compounds?

A

steps include initiation, propagation and termination. This can be catalysed by heat, light, radicals, or the presentce of metals.

Note: degredation route may be dependent on high temperature, therefore the use of high temperatures may not accurately reflect what occurs at ambient temperatures.

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25
Q

how to conduct an oxidative stability test for electron-transfer reactions?

A

This is another type of oxidation stability test.

In the solid state, oxidation occurs where molecular oxygen

diffuses through the crystal lattice to the labile sites.

• Test in solution in the presence of 100-200 ppm hydrogen

peroxide or other free radical initiators such as 2,2’-azobis(2-

amidinopropane) dihydrochloride.

.

Excipient compatibility can be assessed using DSC. If they are any unexplained exothermic processes, it is due to excipient incompatibility.

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26
Q

what does DSC stand for, and what does it measure?

A

Differential Scanning Calorimetry. Measures Heat Flow (dQ/dt) into and out of a sample and a reference as a function of temperature, either heating or cooling

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27
Q

what are the fundamental physico-chemical properties of the solid state?

A

melting point, solubility, stability, taste, absolute density and hardness

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28
Q

what properties are based on the physical state of the solid?

A

particle size, flowability and compression characteristics

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29
Q

whats so important about impurities, and what kinds of impurities exist?

A

a small amount of impurity can influence a change in the melting point, so an impurity may influence the melting point of a drug product.

This in turn may influence the stability of the drug, therefore it is important to identify what effect the impurity has on stability. The different type of impurities are:

  1. moisture (water)
  2. organic and inorganic compound
30
Q

what is heat flow measured in?

A

Watts = J/s

31
Q

define pre-formulation

A

the process of gathering the parameters that influence the choice of formulation for a drug.

32
Q

pKa is important because

A

it determines the changes of the drug at various environments in the body.

33
Q

are weak bases absorbed in the stomach or the small intestine? and why

A

weak bases are ionised in the stomach so cannot be absorbed here. They’re non-ionised at the intestinem so can be absorbed at this site.

34
Q

state four fundamental properties that should be included in pre-formulation studies

A
  • solubility
  • acid dissociation constant
  • melting point
  • log D
35
Q

what is log D and what log D value is ideal?

A

2-3. Log D includes the ratio of ionised and the non ionised drug in octanol:water

36
Q

provide a brief overfiew of the formulation process to making a new drug

A
37
Q

State the different types of oxidation testing

A
  1. Free radical chain processes
  2. “Oxygen” electron-transfer reactions
38
Q

state the different ways to measure melting point

A
  1. Capillary melting, (tube in contact with metal plate)
  2. Hot stage microscopy ( controlled heating rate)
  3. DSC - Differential Scanning Calorimetry
39
Q

How does Heat Flux DSC work?

A

you have a sample and reference pan heated from the same source and the temperature differential between the pans is measured.

Equation dQ = ( Ts - Tr )/RT

40
Q

Sketch a schematic diagram of a heat flux DSC

A
41
Q

what does TGA stand for and what does it do?

A

Thermogravimetric analysis. The change in a sample’s mass is determined in a thermobalance as a function of temperature or time.

42
Q

what two physical features determins a particles character?

A

Their mean size and size distribution.

43
Q

what physical features determine density?

A
  • Particle density
  • Bulk density
  • Tap density
44
Q

why is assay method so important?

A

takes into account both specificity and selectivity.

  1. Specificity determines whether there is anything else but the drug
  2. Sensitivity refers to the level of detection (0.1% or 0.01% of drug)
45
Q

my drug has a chromophore, what techniue to i use?

A

UV Spectroscopy

46
Q

state Qualitiative factors and what they are used for

A

e. g smell - appearance - colour & taste can also be used to:
- Identify what the desired drug formulation shoulbe be like
- If the colour is significantly different to what it should be (it can be inferred that something had gone wrong)

47
Q

In solubility, a Solution can be a..

A

solid dissolved into another solid, a liquid or a gas. The same is true for liquids and gases

48
Q

solubility is affected by:

A

temperature and pH

49
Q

The solubility depends on the..

A

Solvation energy of the solute in the solvent overcoming both the crystal lattice energy of the solid and the energy to create space for the solute in the solvent.

50
Q

what can have an effect on high throughput screening assays?

A

poor solubility. Because if the drug is not going into well solution then drug may be disregarded and a potential hit may be lost.

51
Q

the rate of dissolution takes into account:

A
  1. the degree of agitation of the solid
  2. the formation of the saturated solution at the solid -liquid interphase
  3. the viscosity of that solution and the diffusion from the saturated solution through the stationary layer of the solvent surrounding the particle.
52
Q

The factors that influence dissolution are

A
  1. the intrinsic dissolution (the dissolution rate of a substance under constant surface area conditions)
  2. the volume of dissolution in medium
  3. the dose: solubility ratios,
  4. the surface area of the solid
  5. particle size distribution
53
Q

common solvents used in manufacturing

A

water, ethyl alcolol and polyethene glycol

54
Q

A solution is defined as a

A

mixture of two or three components to form a homogenous one phase molecular disersion

55
Q

consequences of poor dissolution

A

influence the ability to achieve efficacious results in animal studies

poor dissolution also affects bioavailability of the drug

56
Q

Tablets drug release process outline

A
57
Q

Factors that influence solubility of a drug include:

A
  • the solvent (amount, type)
  • The Temperature
  • pH
  • Hydrophobiity or hydrophilicity
  • Surface area of the drug
58
Q

what formulations are solvents currently used in?

A

oral formulation, external, IV/IM products, Manufacturing process

59
Q

state the relationship between solubility and temperature, if any

A

solubility increases with temperature, while for others, the solubility of i.e NaCl does not increase as the stability increases, or has little effect

60
Q

what may cause solubility in water of a compound to be poor?

A
  1. salts may be insoluble, drug may have a high logP value
  2. Molecular weight can be too high
  3. drug may not have an ionisable group
61
Q

The surface area of drug exposure to the solvent is defined by..

A

The surface area of drug exposure to the solvent is defined by the particle size distribution.

62
Q

If agitation and temperature are kept constant then the rate of solvation is..

A

the rate of solvation is proportional to the surface area of the solid in contact with the liquid. This means that rate of dissolution (solvation) decreases as surface area decreases

63
Q

How does solid-state modification improve drug solubility?

A

solid-state modification improve drug solubility by the addition of polar groups, such as carboxylic acid, ketones, amines which can increase hydrogen bonding between the drug and the water molecules, thus resulting in an increase in solubility.

64
Q

Can polymorphs influence solubility? why?

A

Yes, polymorphs can influence solubility! Because different polymorphs have different crystal lattice energy.

65
Q

state all methods to improve solubility of a product

A
  1. solid state modification (particle size/polymorph/new salt)
  2. Liquid systems (co-solvents, lipid based system, solutions, emulsions)
  3. Additives/ complexes (surfactants, cyclodextrins, polymers)
  4. Carrier mediated systems (liposomes, nanoparticles)
66
Q

what co solvents are used to improve stability

A

propylene glycol & ethanol (ethanol not always used in some countries because haram)

67
Q

how do surfactants improve solubility?

A

they are amphiphatic, with both hydrophilic and hydrophobic properties. When the surfactant is placed in water, it will form micelles.

68
Q

How many types of surfacts are there?

A

Three: Cationic Surfactant - Cetyl Trimethyl Aluminium Bromide

Anionic Surfactant - Sodium Lauryl Sulphate

Non-ionic surfactant - Tween 80

69
Q

What is complexation

A

what is complexation? it is a method to improve solubility of drugs. This relies on weak forces such as:

  • London forces
  • Hydrogen bonding
  • Hydrophobic interactions

As concentration of complexing agent is increasing, so is the solubility (up to a point). Polar groups can be incorporated into complexes

70
Q
A

MDD (29 decks)

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