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GI tract and liver > preformulation > Flashcards

preformulation Flashcards

1
Q

what does the design of a dosage form deal with?

A

the conversion of a new chemical entity into a deliverable medicine - the dosage form must facilitate the delivery of therapeutic durugs into the body safely, eficiently, reproducibly and conveniently.

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2
Q

whats preformulation?

A

the first step in the developement of dosage forms of a drug into a medicine. it inolves characterising the physical and chemical properties of the API to provide the formulation team with the critical information to develop a stable bioavailable dosage form that can be mass produced. it aims to produce a math based model for the drug behaviour of the proposed dosage form both in vitro and in vivo.

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3
Q

What are two controlling factors for the bioavailabilty of a medicine?

A

as most drugs are solids they must dissolve before they can permeate the gut epithelium. this is affected by the solubility and the dissolution rate controlling th rate of absorbtion and therefore the bioavailability.

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4
Q

what is optimal solubility?

A

an aquoes solubility greater than 10mg/ml is optimal.

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5
Q

what if the solubility is less than 1mg/ml?

A

a better alternative would be a salt form of the drug with increased bioavailability.

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6
Q

What is solubility?

A

solubility is the maximum concentration of a solute that can be attained in a given solvent under given conditions. solubility is a constant (where as dissolution rate is variable)

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7
Q

How can dissolution rate be expressed?

A

using the noyes whitney equation

dm/dt = DA(Cs - C)/H

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8
Q

What can be seen from the noyes whitney equation?

A

You can see that increasing the diffusion coefficient surface area of the drug or the solubility will increase the rate of dissolution.
Vice versa you can see that increasing the thickness of the boundary layer and the conc. in the bulk solvent will decrese the diffusion coefficent.

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9
Q

what are the 4 classes of oral dosage forms outlined by the BCS?

A 
1 = high solubility and high permeability
2= low solubility and high permeability
3= high solubility and low permeability
4= low solubility and low permeability
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10
Q

is there anything you can do to improve classes 2 3 and 4?

A

you can modify solubility for classes 2 qnd 4 however there is not much you can do about permeability.

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11
Q

what would the bcs class a highly soluble drug?

A

a drug is highly soluble if it can dissolve in 250ml in its dosage form at a range of pH values.

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12
Q

What can be done to improve drug solubility?

A

To improve drug solubility you can add cosolvents, surfactants, cyclodextrins, lipid based systems, cocrystals, amorphous solid dispersion, particle size reduction, salts, polymorphs?

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13
Q

What are cosolvents?

A

cosolvents - add a water miscible solvent in which the drug has good solubility - this will help hydrophobic drugs to mix in aqueous solution.

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14
Q

what are surfactants?

A

you can add amphoteric molecules to improve solubility as they will aggregate into micelles with the drug hence it can mix in aqueous solution.

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15
Q

what are cyclodextrins?

A

cyclodextrins form an inclusion complex with the drug.

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16
Q

what are lipid based systems?

A

dissolve drugs in lipids within an aquos system - surfactants can be added to help the aquoes solution aggregate round by forming a micelle around the lipid solution.

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17
Q

What are co crystals?

A

crystalline materials comprised of an API and a cocrystal former.

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18
Q

what is amorphous solid dispersion?

A

dissolve a hydrophobic drug in a polymer matrix although as it has no structured order it is less stable.

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19
Q

whats particle size reduction?

A

decreasing the size of the particle will imrove the solubility.

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20
Q

what are salts?

A

by ionising th drug into a salt you improve the solubility.

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21
Q

what are polymorphs?

A

you can alter the crystalline structure of the drug to form a different polymorph of the drug that may have lower stability hence increasing the solubility.

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22
Q

name a few physicochemical tests…

A

spectroscopy, hplc, pka, logp and solution stability.

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23
Q

what happens if the drug has an ionisable group?

A

the solubility of the drug will change as a function of pH.

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24
Q

whats the henderson hasselbach equation?

A

pKa = pH + log HA/A-

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25
Q

many drugs being discovered are lipophilic and water insoluble compounds henec it is useful to turn it into a salt. wht requirement is there to turn it into a salt and how may this affect the drug?

A

drugs with poor aqeuous solubility can be converted into a salt if they are a weak acid or base. this may change the physicochemical properties of the drug and can affect the quality safety and efficacy of a medicine. it is therefore important to choose a salt early in preformulation.

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26
Q

what does salt formation require?

A

a sufficient difference in pKanbetween the acid and base - ideal is pka difference of 3.

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27
Q

what are some pros of using pharmaceutical salts?

A

using the salt form of the drug enhances the solubility and dissolution rate, improves photostability and increases bioavailability and melting point.

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28
Q

what are some of the cons of using pharmaceutical salts?

A

using a salt form means theres a decreased percentage of the drug, increased hygroscopicity, increased toxicity and additional manufacturing steps, decreased chemical stability.

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29
Q

what does a microcrystallisation system do?

A

vapour diffusion - a reservoir undergoes vapour diffusion so a crystallisation drop forms on the lid leaving a reservoir with lower precipitant concentration.

30
Q

what must you consider when choosing a target salt?

A

the structure of the drug, the pKa of the drug, physical and chemical stability of the drug, ease of large scale preparation of the drug.

31
Q

what are the steps involved with salt selection?

A

crystallinity - hygroscopicity - solubility - stability - polymorphism - control - final salt.

32
Q

whats the biggest factor affecting the performance, developability, patentability, manufacturability and profitability of a compound?

A

the physical form of the drug in a solid state - these forms can include chiral habits amorphous and crystalline.

33
Q

highly important pharmaceutical parameters change with crystalline behaviour. what are some of the properties of a given compound that are determined primarily by the nature of the crystal structure?

A

solubility and dissolution rates, crystal hardness (this will affect the compressability of tablets) and chemical stability which is affected by enthalpy of solution and transition, hygroscopicity, and melting and sublimation temperatures.

34
Q

whats the crystal habit?

A

the external shape of the crystal - its associated with the way solute molecules orientate themselves when growing.

35
Q

what determines the general shape of a crystal?

A

the growth of individual crystal faces - the slowest growing face will dominate.

36
Q

what does the crystal habit influence?

A

flow, compaction, stability and solubility.

37
Q

Each crystal face has a designated index plane - what are thes known as?

A

miller indices - miller index provides information about the molecular ordering of the surface of a crystal face.

38
Q

how does the crystal habit affect injectables?

A

plate like crystals will pass through needles better than long needle like crystals.

39
Q

how does the crystal habit affect tabletting?

A

plate like tolbutamol crystals do not flow and have poor compressability.

40
Q

how does the crystal habit affect dry powder inhalers?

A

needle like crystals usually have better fine particle fraction.

41
Q

how does crystal habit affect paracetamol?

A

needle shaped paracetamol crystal powder shows poorest compression properties, showing greater capping and lamination than the plate or cube shaped crystals.

42
Q

What are unit cells?

A

these are the aligned building blocks that compose the crystals - they reveal the crystal structure and symmetry specific for each substance - this requires x ray diffraction to elucidate.

43
Q

there are 7 types of crystal structures, what are they and how are they defined?

A

the crystal structures are defined by the lengths and angles between each side of the unit cell. the 7 structures are: cubic, tetragonal, orthorhombic, trigonal, monoclinic, triclinic and hexagonal.

44
Q

What unit cells are typically formed by drug molecules?

A

triclinic, monoclinic and orthorhombic.

45
Q

What are bravais lattices?

A

molecules can arrange themselves into 14 different configurations known as bravais lattices.

46
Q

what are the two polymorphic forms of paracetamol? which one is used more frequently and why?

A

paracetmol exists in two polymorphic forms: monoclinic and orthorhombic. form 1 (monoclinic) is used commercially as its thermodynamically stable at RTP. however its not suitable for direct compression and therefore has to be mixed with binfing agents before tabletting.

47
Q

what is crystal form?

A

crystal form is the ordering of atoms and molecules to form a crystal structure.

48
Q

what is polymorphism?

A

when the same chemical compound exists in different crystal forms we call it polymorphism.

49
Q

what are special cases of polymorphs?

A

pseudopolymorphs - these include solvates (solvent molecules in crystal lattice) or hydrates (water molecules in crystal lattice)

50
Q

what is enantiomorphism?

A

chiral molecules can crystallise as mirror images of each other - a mixture of D and L crystal forms are known as a racemic mixture.

51
Q

what are solid phase transitions which transform reversibly without passing through the liquid or gaseous phases called?

A

enantiotropic

52
Q

what makes it monotropic rather than enantiotropic?

A

if the solid phase transition is not achieved prior to a phase change it is called monotropic.

53
Q

what makes polymorph transformations irreversible?

A

any transformation from one polymorph to another below melting point is irreversible.

54
Q

what are the properties of form 1 polymorphs (adjacent molecules)

A

lower density, lower lattice energy, lower melting point, faster dissolution rate, possible fracture line.

55
Q

What are the properties of form 2 polymorphs (overlapping molecules)

A

higher density, higher lattice energy, higher melting point, slower dissolution rate, lower bioavailability.

56
Q

what properties may change with polymorphism?

A

melting point, dissolution rate, compressability, density, flowability, surface proteins, habit and crystal shape, hygroscopicity, hardness and stability.

57
Q

what transformation can occur from one polymorph to another during processing and storage?

A

moisture mediated and solid state phase transformation.

58
Q

Chloramphenical-3-palmitate (a broad spectrum antibiotic) exists in 3 polymorphic crystalline forms - what danger does this pose?

A

A is the most thermodynamically stable but B is 8 times more bioavailable than A - this can create the danger of fatal doses if the unwanted polymorph is administered due to an alteration in the manufacture process or storage conditions (ie polynorph A may undergo interconversion into polymorph B which means the drug will be at a much higher concentration due to the 8 times higher bioavailability).

59
Q

why do organic compounds often form hydrates?

A

in the presence of water, organic compounds often form hydrates due to the small molecular size of water and the multidirectional hydrogen bonding capability of water.

60
Q

whats the hydration number?

A

the ratio of water molecules to API molecules.

61
Q

why are anhydrous solid forms usually favoured over hydrates?

A

although a hydrate is the most stable form in water, it is the least soluble form in the GI environment. however stable hydrates with acceptable bioavailability can be developed, these may have better physicochemical properties or be the only crystalline form of the API.
an example is that the plasma profile for thephylline anhydrate is much bigger than that of thephylline monohydrate.

62
Q

why must aripiprazole be packaged into blister packs?

A

aripiprazole is formulated as an anhydrate but will form a monohydrate on exposure to humidity hence changing the bioavailability. it must therefore be packaged into blister packs to prevent exposure to moisture. it should not be open until use and therefore cannot be repackaged into a monitored dosage system e.g. a dosette box.

63
Q

whats an amorphous solid?

A

a solid in which there is no long range order of the positions of molecules/atoms.

64
Q

what are the properties of amorphous solids?

A

amorphous solids have higher free energy than the corresponding crystalline solid and therefore have higher apparent solubility and dissolution rate.

65
Q

what are the 3 main formulations of amorphous solids?

A

solid amorphous dispersions, lyophilized powders, oral fast dissolving tablets.

66
Q

what is an amorphous solid dispersion?

A

the dug is dissolved in a polymeric matrix. molecular dispersion is a solid solution whilst particulate dispersion is a solid suspension - this can either be 2 components in 2 phases or 2 components in one phase.

67
Q

evaluate the stability of an amorphous solid dispersion.

A
  • matrix is unlikely to crystallise in totality but may become crystalline in parts.
  • a major concern is a form change of the drug in solid suspension or diffusion and crystallisation in solid solution.
  • the polymer matrix often acts to inhibit drug diffusion
  • can add cross linking stabilisers to the polymer matrix to preventcrystallisation.
68
Q

how is the low solubility of itraconazole overcome?

A

during manufacture the drug and HPMC in ethanol and dichloromethane are sprayed onto a sugar core. this creates a solid solution on the surface then granules are put in hard capsules. sporanox granules carry the drug to its location in the body.

69
Q

oral fast dissolving tablets are freeze dried tablets that melt in the nouth without need for water - they are useful for patients with dysphagia. How are they formulated?

A

drug coformulated with a sugar (usually mannitol) for strength and taste masking is a bonus. a collapse protectant like glycine is also added. the solution is then freeze dried directly into a blister pack - the tablet forms a suspension in the mouth that is easily swallowed.
the pure drug is not freeze dried alone as mechanical strength is usually an issue.

70
Q

what are lyophilized powders? when are they used?

A

a freeze dried powder in a sealed vial. lyophilized powders are used when an IV solution is required but the API is unstable in solution. for example drugs that hydrolyse like penicillin or biologics like vaccines.

71
Q

how are lyophilized powders prepared for injection?

A

they must be reconstituted with either saline BP or reconstitution solution - water cant be used as it is not isotonic with blood.

GI tract and liver (16 decks)

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