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Medicine Sem 2 > Pre Formulation and Formulation > Flashcards

Pre Formulation and Formulation Flashcards

1
Q

What is pre-formulation?

A

Pre-formulation is the stage in drug an dosage form development before formulation proper

It aims at optimising the drug candidate into a drug product.

The physicochemical properties of all drug candidates are determined and each showing activity towards to the biological target: the best one will be developed in a drug product

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2
Q

Pre-formulation data is used to:

A
  • Decide which drug candidate will be the easiest to formulate
  • Determine the most appropriate dosage form
  • Highlight issues with processing
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3
Q

Physicochemical properties are divided in two categories:

A
  • Intrinsic/molecular properties i.e. inherent properties of the molecule and can only be modified by chemical modification (e.g. solubility)
  • Derived/macroscopic properties are related to the bulk behaviour e.g. intermolecular interactions.
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4
Q

Intrinsic property examples:

A
  • Solubility
  • pKa
  • logP
  • Hygroscopicity
  • Stability
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5
Q

Technique and sample requirement for solubility:

A
  • UV Vis spectrophotometry

- chromophore

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6
Q

Technique and sample requirement for pKa:

A

Technique :

  • UV Vis spectrophotometry
  • Potentiometric titrations

Sample requirement:
- Acid or base group

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7
Q

Technique and sample requirement for log P:

A

Technique :

  • UV Vis spectrophotometry
  • TLC, HPLC

Sample requirement:
- chromophore

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8
Q

Technique and sample requirement for hygroscopicity:

A

Technique :

  • Dynamic vapour sorption
  • Thermogravimetric analysis

Sample requirement: n/a

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9
Q

Technique and sample requirement for stability:

A

Technique :
- HPLC, and suitable storage conditions

Sample requirement: n/a

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10
Q

Examples of derived/macroscopic properties:

A
  • Melting point
  • Enthalpy of fusion
  • Physical forms (e.g. polymorphs)
  • Particles size, shape, morphology
  • Density bulk, tapped, true
  • Flow
  • Compressibility
  • Excipients compatibility
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11
Q

Melting point technique assay:

A

DSC or melting point apparatus

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12
Q

Enthalpy of fusion technique assay:

A

DSC

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13
Q

Physical forms (e.g. polymorphs) technique assay:

A

DSC, XRPD, microscopy

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14
Q

Particles size, shape, morphology technique assay:

A

Microscopy, particle sizing

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15
Q

Density technique assay:

A

Densitometer

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16
Q

Flow assay technique:

A

Angle of repose

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17
Q

Compressibility assay technique:

A

Carr’s index

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18
Q

Excipients compatibility assay technique:

A

HPLC, DSC

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19
Q

Toxicity and bioavailability data in animal models require what solubility?

A

a solubility > 1mg/mL.

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20
Q

In all solubility determinations:

A
  • The solvent and solute must be pure
  • A saturated solution must be obtained before analysis
  • Separation of sample of saturated solution from undissolved material must be satisfactory
  • Temperature must be adequately controlled
  • Method for analysing the solution must be accurate and reliable
  • Solute concentration can be determined by UV spectrometry, chromatography (e.g. HPLC) or gravimetric analysis
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21
Q

Determination of log P techniques:

A
  • Shake flask method

- Chromatographic methods e.g. reversed phase TLC or reversed phase HPLC

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22
Q

Ways of modifying the solubility:

A

Molecular structure of the solute:
- Small change in structure e.g. introduction of a hydrophilic group, may improve the solubility by up to 100 fold

  • Reduction of aqueous solubility of a parent drug by esterification
  • Masking the taste
  • Protection form extensive degradation in the GI tract

Nature of the solvent:

  • Use of co-solvents (e.g. ethanol, PEG)
  • Using co-solvent for metronidazole make it suitable for parental administration
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23
Q

Most common counter ions for salt selection:

A

Cation: potassium, sodium, zinc, calcium

Anion: hydrochloride, sulfate, chloride, phosphate

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24
Q

Disadvantages of salt form?

A
  • Decreased percentage of active ingredient
  • Increased hygroscopicity
  • Decreased chemical stability
  • Increased number of polymorphs
  • Reduced dissolution in gastric media
  • No change in solubility in buffers
  • Corrosiveness
  • Possible disproportionation
  • Additional manufacturing step
  • Increased toxicity
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25
Q

How does a weakly basic drug modified into a salt work?

A

When the salt dissolves in water, it dissociates, donating its proton, lowering the pH of the solution and increasing the drug solubility.

Drugs are often formed in organic solvents

The increased solubility of a salt is only a result of the change of pH upon dissolution

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26
Q

Definition of hygroscopicity?

A

Hygroscopicity: tendency of a substance to attract water from its immediate environment either by absorption or by adsorption.

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27
Q

Appropriate steps need to be taken to protect hygroscopic formulations in humid conditions:

A
  • Suitable packaging

- Advising correct storage conditions

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28
Q

Problems of water content during formulation?

A

During formulation increased water content leads to wet powder, increased cohesion and reduced flowability.

Water can mediate solid state reactions:

  • Increase rate of degradation or interaction with excipients
  • If substance is amorphous, absorption of water results in plasticisation of the matrix
  • If amorphous matrix is a freeze dried product absorption causes the structure to collapse
  • Absorption of water may result in the crystallisation of the compound.
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29
Q

What is enthalpy of fusion?

A

The enthalpy of fusion, , is the change in enthalpy resulting from heating a given substance to change its state from solid to liquid

The temperature at which fusion occur is the melting point (50%).

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30
Q

How is size and shape of particle determined?

A

Size and shape of particle will be determined by light microscopy (unless it is spray-dried or micronised in which case SEM is used).

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31
Q 
The compressibility (or compaction) is calculated by measuring the bulk density and tapped density (Carr’s index). 
What is bulk density and what is tapped density?
A

Bulk density is obtained by adding a known mass of powder to a graduated cylinder. The density is calculated as mass/volume

Tapped density is obtained by mechanically tapping the graduated cylinder to see whether further volume change is observed

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32
Q

What is polymorphism?

A

when a compound exists in at least two different molecular arrangements in the solid state.
Stable polymorphic form and metastable forms
Each polymorph is different in crystal structure but identical in the liquid and vapour state.

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33
Q

What are amorphous materials?

A
  • Macroscopic property
    Amorphous materials are not characterised by a repeating unit arrangement - the matrix they form is termed amorphous
    High molecular weight molecules (polymers, biological materials) can have difficulty orientating themselves uniformly.
    As they have no lattice energy, they are unstable and over time they will convert to a crystalline form.
    Amorphous compounds are less stable but more soluble, so often exhibit faster absorption and enhanced bioavailability
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34
Q

What is wettability?

A

Wettability (wetting) describes the ability of a liquid to maintain contact with a solid surface

Poor wetting results in limited ability to dissolve
Adhesive forces between the liquid and solid cause the liquid to spread.

Cohesive forces with the liquid cause the liquid to drop and limit its contact with the solid

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35
Q

What can be used to reduce the surface tension and improve wetting?

A

Surfactants

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36
Q

What is rheology?

A

Rheology is the science of flow and deformation of matter.
The viscosity of a fluid is its resistance to flow or movement
Simple fluids such as water are said to be Newtonian: the rate of flow is proportional to the applied stress

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37
Q

Example of plastic flow?

A

(e. g. ketchup)
- No flow until a certain force is applied
- At lower stress behaves like an elastic solid
- Observed for concentrated suspensions, especially if the continuous phase is highly viscous or if particles are flocculated.

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38
Q

Example of pseudoplastic flow?

A

e.g. quicksand)
Material flows as soon as pressure is applied and flow rate increases with increasing pressure but not linearly
Hydrocolloids such as methylcellulose or carmellose, wynthetic polymers sias polyvinylpyrollidone
High molecular weigh polymers become entangle in immobilised solvent i.e. w/o force

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39
Q

What is Dilatant flow (e.g. starch and water)?

A

Viscosity increases with shear rate (force frequency)

Occurs in dispersion containing at least 50% small deflocculated particles

Without shear particles are closely packed

When shear is applied particles are displaced and form clumps
Creates larger voids into which the vehicle drains, so resistance to flow is increased
Behaviour I reversible with removal of stress.

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40
Q

What are disperse systems?

A
  • Disperse systems are made of a disperse/internal phase (particles or droplets) dispersed in another component (continuous phase).
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41
Q

Colloidal dispersion definition?

A

is used between 1nm-1mm and coarse dispersion above 1 mm.

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42
Q

What is a solution?

A

a colloidal dispersion of solid particles in a liquid

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43
Q

What is an emulsion?

A

is a mixture of two immiscible liquids

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44
Q

How is a foam formed?

A

formed when gas particles are trapped in a liquid or a solid

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45
Q

What is an aerosol?

A

contains solid or liquid dispersed in a gas

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46
Q

What does lyophilic mean?

A

Solvent loving.

47
Q

What does lyophobic mean?

A

Solvent hating.

48
Q

Lyophobic sol characteristics?

A
  • Very sensitive to electrolytes leading to irreversible aggregation
  • Stability controlled by charge of particles
  • Formation –> Usually metals, inorganic crystals . Never formed spontaneously. Particles remain dispersed due to electric repulsion.
  • Viscosity –> Low viscosity, particles unsolvated and usually symmetric
49
Q

Lyophilic sol characteristics?

A
  • Generally stable in presence of electrolytes except at high concentration of electrolytes
  • Stability is controlled by charge and salvation of particles
  • Viscosity: Usually high. At sufficiently high concentration of disperse phase, a gel can form. Particles are solvated and usually asymmetric.
50
Q

Purification of colloidal systems?

A

Dialysis
- Colloidal are not able to cross membranes (cut off size) whilst small ones can cross by diffusion.

Ultrafiltration
- By applying pressure on the solvent, solute may cross membrane; however colloids don’t.

Electrodialysis
- Electric potential is applied to increase the movement of ionic species (still colloids cannot cross); it speeds up purification.

51
Q

What are surfactants?

A
  • Amphipathic molecules
  • They are surface active and move at the interface between 2 phases; allowing one of the parts to evade contact with the solvent.
  • Above a certain concentration (cmc) when all interface have been covered they start to form micelles.
52
Q

What are the four type of surfactants?

A

1) anionic (SLS)
2) cationic (benzalkonium chloride)
3) non-ionic (polysorbates)
4) zwiterionic (CHAPS, phosphatidylcholine).

53
Q

What are the two types of micelles?

A
  • Micelles
  • Inverted micelles

Typical micelle is spherical, composed of 50-100 surfactant molecules and about 3nm in diameter

54
Q

are emulsions stable?

A

Emulsions have droplets from 0.1 to 100 mm and are inherently unstable

55
Q

What makes emulsions stable?

A

If globules retain initial character and remain uniformly distributed throughout the continuous phase

Emulsifiers form an interfacial film around the droplets

Any agent that destroy this film will crack the emulsion.

  • Chemicals incompatible with the emulsifier
  • Bacterial growth
  • Temperature change
56
Q

Stability can be increased in emulsions by:

A
  • Reducing the droplet size
  • Decreasing the density differences
  • Increasing the viscosity of the continuous phase

Stability is assessed by

  • Visualisation
  • Monitor particle size over time
57
Q

What is coalescence?

A

Small droplets combine to form larger ones – any electric charge on the particles will repulse this

58
Q

What is flocculation?

A

Droplets form clusters – the combined result of attractive and repulsive forces

59
Q

What is creaming?

A

the disperse phase rises to the top (or sinks to the bottom) – the result of density differences between phases. It can be redistributed, but may result in inappropriate dosage

60
Q

What oils are used In oral emulsions?

A

castor oil or

liquid paraffin

61
Q

What oils are used In parenteral emulsions?

A

Limited choice. Purified mineral oil used in some depot for i.m. injections; vegetable oils containing long chain triglycerides have been used.

62
Q

What type of emulsions are creams?

A

Oil in water

63
Q

How do creams maintain long term stability?

A

The formation of a viscoelastic gel network phases trapping oil droplets and preventing their movement/interaction

64
Q

What is the gel network theory of emulsion stability?

A
  • Coherent explanation how fatty amphiphiles and surfactants combined as emulsifiers not only stabilize these creams but also control their consistencies
  • Structure and stability of o/w creams are dominated by swelling properties of an a-crystalline gel network phase
65
Q

What are aerosols?

A
  • Aerosols are colloidal dispersions of liquids or solids in gases.
66
Q

Aerosol particle size?

A

Particle size usually within colloidal range; however if particle larger then 1mm, life of product is short.

67
Q

What is a foam ?

A
  • A foam is a coarse dispersion of a gas in a liquid which is present as thin films or lamellae of colloidal dimensions when the gas bubbles.
68
Q

Are foams stable?

A

Due to their vast interfacial area foams are thermodynamically unstable:
- Stability depends on their ability drain and become thinner, and their tendency to rupture in presence of stress (shaking, heat).

  • Gas diffuses from small bubbles to larger ones (reduces the surface area)
69
Q

How are gels formed?

A
  • Majority of gels are formed by aggregation of colloidal sol particles
  • The solid or semi solid system formed is interpenetrated by a liquid. Only a small percentage of disperse phase is needed.
  • If liquid is removed and structure remains: xerogel
70
Q

What is a lyophobic gel?

A
  • Flocculated lyophobic sols can be regarded as continuous floccule (example: aluminium hydroxide and magnesium hydroxide gels
  • Forces holding particles are weak (vdW and secondary minimum, electrostatic interactions) → thixotropy
    Used for pharmaceutical suspensions e.g. bentonite in calamine lotion
71
Q

What is a lyophilic gel?

A

Two types: type I and type II

  • Type I (or chemical) gels are held together by covalent bonds between macromolecules. An example are the poly(HEMA) crosslinked with EGDMA. They swells in water and are used for expandable implants to imbibe body fluids. They can also be used for controlled release of drugs especially antibiotics.
Type II (or physical) gels
Held together by weaker interaction bonds such a H bonds
Reversible
72
Q

What two mechanisms can aerosols be prepared by?

A

Dispersion:

  • Achieved by the use of a pressurised container, with a liquefied gas used as a propellant
  • The solution or suspension of active ingredients is contained within the liquefied propellant, or within an additional solvent
  • When the container is opened or deployed, the vapour pressure of the propellant forces the liquid out of the container, producing a dispersion in the air

Condensation:

  • A sample of vapour-saturated gas is subjected to rapid volume expansion (supercooling)
  • This lowers the temperature and causes supersaturation
  • The vapour condenses on any ions or particles present forming colloidal particles and is packaged for delivery
73
Q

What are metered dose inhalers?

A

Generate an aerosol when deployed.

74
Q

What are dry powder inhalers?

A

Contain capsules or blisters loaded with drug particles

75
Q

What does a nebuliser do?

A
  • A nebuliser convertsliquid into aerosol droplets, which are inhaled through a face mask or mouth piece
  • It can be driven by compressed gas or by an ultrasonically vibrating crystal
76
Q

How long is the nasal cavity?

A

The nasal cavity is 12–14cm long, with a total surface area of ~160 cm2

77
Q

What is the name of the region that is filled with folded projections of tissue from the nasal septum, is composed of mucus-secreting goblet cells, ciliated and non-ciliated cells?

A

The turbinate region.

78
Q

Particle size that deposits on the mucus lining?

A

Particles 5–10 μm in size

79
Q

What is the main drug absorption site?

A

Epithelium of the nasal turbinates

80
Q

How thick is the mucus layer?

A

1-10um thick

81
Q

Advantages of rectal delivery?

A
  • The avoids the oral route (patient vomiting, unconscious, GI problem)
  • Very young, very old or mentally ill patients may more easily be treated
  • Avoids adverse GI effects, problems with instability at low pH, high first-pass metabolism, unacceptable taste
  • Small and large doses can be administered
  • No protease activity is present in the rectum
  • Skilled health practitioner not needed
82
Q

Disadvantages of rectal delivery?

A
  • Route is generally disliked by patients – UK/USA versus Europe
  • Slow and sometimes incomplete drug absorption, variability between patients
  • Development of proctitis with long-term rectal delivery
    Problems with leakage and insertion
  • Short shelf life
  • Market size of rectal and vaginal formulations is less than 1% of the total pharmaceuticals market
83
Q

How long is the rectum ?

A

Final 15-20cm of the colon prior to the anus, a circular muscle.

84
Q

Does the rectum contain villi?

A

No

85
Q

What are the 3 separate veins that serve the rectum?

A

The inferior and middle haemorrhoidal veins drain into the inferior vena cava

The superior haemorrhoidal vein drains into the portal vein

86
Q

Two mechanisms of how a suppository dissolves:

A
  • dissolve in the rectal fluid or - melt on the mucous layer
87
Q

Usual weight of suppositories?

A

Rectal suppositories are usually 1 - 4g in weight

88
Q

What are the two suppository bases?

A

either glyceride-type fatty bases or water-soluble bases

89
Q

A suppository base should:

A
  • have a melting range small enough to give rapid solidification after preparation, preventing sedimentation of suspended drug particles
  • exhibit enough volume contraction to permit removal from the mould following solidification
  • melt, dissolve or disperse at body temperature
  • dissolve in the available volume of rectal fluid
  • be chemically and physically stable during storage
  • be non-irritant
  • have an appropriate viscosity to minimise leakage
90
Q

Desired particle size for suppositories?

A

To prevent sedimentation during manufacture the drug particle size must be <150µm
Particles < 50 μm will not cause irritation to the patient

The smaller the particles, the higher the dissolution rate

91
Q

What mechanisms are suppositories formed by?

A
  • Hand rolling (small scale, 6-50 at a time)
  • Compression moulding (semi-automated, 20,000/hour)
  • Fusion moulding (semi-automated, 20,000/hour)
92
Q

Why are rectal tablets not a good ideal dosage form?

A

due to the low amount of water present in the rectum, which limits dissolution
(rectal tablets that release CO2 after insertion can be used to stimulate defecation)

93
Q

What are rectal solutions, emulsion and suspensions (enemas)

A

Liquid preparations applied rectally to evacuate, cleanse or treat the lower parts of the GI tract

94
Q

What and how long is the vagina?

A

A fibro-muscular tube 4-6 inches long

95
Q

Healthy pH of a vagina in women?

A

3.5-4.5

This is due to the conversion of glycogen from the mucosal epithelium to lactic acid by lactobacillus

96
Q

Ideal vaginal dosage forms should:

A
  • be long acting, reducing the frequency of administration
  • be stable in a range of climatic conditions
  • be of appropriate viscosity to minimise leakage
  • not lead to any irritation
  • be easy to insert and/or apply
97
Q

What are pessaries?

A

Vaginal suppositories - they are solid, single-dose preparations for vaginal insertion.

98
Q

A vaginal suppository should be made:

A
  • of a shape, volume and consistency suitable for insertion (weight ~1g)
  • containing drug particles < 50 μm in size, to avoid irritation and sedimentation during manufacture
  • of a base that is soluble or dispersible in water, or melts at body temperature
  • of a base with melting range that gives rapid solidification after preparation, preventing sedimentation of suspended drug particles
  • from glycerol-gelatin bases, which are well tolerated
99
Q

What are vaginal tablets?

A

Solid, single-dose preparations similar to oral tablets

100
Q

What are biopharmaceuticals?

A

= biologics

  • Monoclonal antibodies (often IgG1),
  • ADC,
  • Interleukins,
  • Peptides,
  • Virus like particles…
101
Q

Classification of protein therapeutics?

A
  • Protein therapeutics with enzymatic or regulatory activity e.g. augmenting an existing pathway
  • Protein therapeutics with special targeting
  • Protein vaccines
102
Q

What is bioprocess?

A

‘Biological process”

103
Q

Naming of mAb?

A
  1. unique prefix
  2. Prefix letters related to type of target
  3. Prefix reflects source of the variable chain e.g. rat, human, mouse
  4. suffix = mab
104
Q

Formulation of biologics?

A
  • Biologics are either formulated as a liquid formulation or lyophilised (to be reconstituted before use)
  • Administration is either subcutaneous or i.v.
  • Issues often linked to frequency of administration
  • Adverse effects
105
Q

Biologics excipients:

A

Buffers–>

  • Acetate, citrate, succinate, histidine or phosphate
  • Formulations pH range often 5-6.5 (IgG pI approx. 8)
  • Buffer concentration kept low to adapt to physiological pH upon administration

Salt and Tonicity modifiers–>
- Colloidal stability
- i.v. injection requires isotonic preparation
- i.m. or s.c. injections may be able to handle hypertonic or hypotonic conditions
Common excipient is NaCl

Surface active agents–>
mAbs flexible molecules with hydrophobic and hydrophilic regions
- Unfolding leads to aggregation
- Surfactants cover interfaces (air/liquid and solid/liquid) thus limit unfolding.
- Polysorbates 20 and 80 most common
- PS Degradation may contribute to aggregation

Antioxidants–>

  • Oxidation reaction catalysed by metals
  • Use of EDTA to chelate metals contributes to control oxidation
  • Reducing agents such as glutathione can reverse oxidation

Protein stabilizers–>
- Stabilisers are preferentially excluded from the protein’s surface leading to preferential hydration of protein
- Sugars e.g. sucrose
Amino acids such as Arg

Lyophilisation development –>

  • Use of PEG
  • Same mechanism as aforementioned stabilisers: exclusion by steric hindrance and maintained upon freezing

Caveats to use of sugars as lyoprotectants–>

  • Disaccharides susceptible to hydrolysis at low pH
  • Hydrolysis of sucrose to glucose and fructose at pH5
106
Q

Most common routes of chemical degradation in biologics?

A

Oxidation, de amidation, asp isomerisation and cross linking. (oxidation most common)

107
Q

Physical degradation in biologics?

A
  • Conformational changes, aggregation and surface adsorption
  • Conformation changes = denaturation = unfolding

(all information to maintain proteins conformation is contained in the AA sequence)

108
Q

Sources of conformational changes in biologics?

A

Temperature changes, ice formation due to freeze thaw, shear forces, changes in ions in solution, changes in protein-protein interactions

109
Q

Protein aggregation is function of protein-protein interactions. True or false?

A

True

110
Q

IgG1 more prone to aggregation than others IgGs (IgG2, IgG3 and IgG4). True or false?

A

FALSE, IgG2 is

111
Q

Name some challenges for iv formulations:

A
  • Leachables = are compounds released from container closure system when in stress conditions - solvent include metals, organics, volatile compounds
  • Extractables = a subset of compounds eluting during normal storage or use conditions e.g. infusion bag, tubing i.v. bags prepared with different polymers
  • Dilution of the protective surfactant can lead to noticeable degradation of the product and that the generation of an air–water interface on agitation was responsible for the aggregate formation.
112
Q

What are SC formulations and their challenges?

A 
SC formulations: 
small volume (1.5 mL) high concentrations (50, 100 and more mg/ml)

Increase protein protein interactions and risks of aggregation

Impact on flow (syringeability), viscosity: internal diameter of needle is small (0.2mm)

113
Q

Who imposes control on stability of these medicines? (biologics)

A

WHO

114
Q

What property In biopharmaceuticals are an inherent source of instability?

A

The amphipathic nature.

Medicine Sem 2 (8 decks)

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