Pre Formulation and Formulation Flashcards

Question

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

Answer 1

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

Answer 2

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

Answer 3

- Suitable packaging | - Advising correct storage conditions

Answer 4

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.

Answer 5

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%).

Answer 6

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

Answer 7

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

Answer 8

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.

Answer 9

- 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

Answer 10

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

Answer 11

Surfactants

Answer 12

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

Answer 13

(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.

Answer 14

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

Answer 15

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.

Answer 16

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

Answer 17

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

Answer 18

a colloidal dispersion of solid particles in a liquid

Answer 19

is a mixture of two immiscible liquids

Answer 20

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

Answer 21

contains solid or liquid dispersed in a gas

Answer 22

Solvent loving.

Answer 23

Solvent hating.

Answer 24

- 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

Answer 25

- 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.

Answer 26

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.

Answer 27

- 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.

Answer 28

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

Answer 29

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

Answer 30

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

Answer 31

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

Answer 32

- 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

Answer 33

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

Answer 34

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

Answer 35

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

Answer 36

castor oil or | liquid paraffin

Answer 37

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

Answer 38

Oil in water

Answer 39

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

Answer 40

- 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

Answer 41

- Aerosols are colloidal dispersions of liquids or solids in gases.

Answer 42

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

Answer 43

- 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.

Answer 44

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)

Answer 45

- 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

Answer 46

- 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

Answer 47

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 ```

Answer 48

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

Answer 49

Generate an aerosol when deployed.

Answer 50

Contain capsules or blisters loaded with drug particles

Answer 51

- A nebuliser converts liquid 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

Answer 52

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

Answer 53

The turbinate region.

Answer 54

Particles 5–10 μm in size

Answer 55

Epithelium of the nasal turbinates

Answer 56

1-10um thick

Answer 57

- 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

Answer 58

- 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

Answer 59

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

Answer 60

The inferior and middle haemorrhoidal veins drain into the inferior vena cava The superior haemorrhoidal vein drains into the portal vein

Answer 61

- dissolve in the rectal fluid or - melt on the mucous layer

Answer 62

Rectal suppositories are usually 1 - 4g in weight

Answer 63

either glyceride-type fatty bases or water-soluble bases

Answer 64

- 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

Answer 65

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

Answer 66

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

Answer 67

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)

Answer 68

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

Answer 69

A fibro-muscular tube 4-6 inches long

Answer 70

3.5-4.5 | This is due to the conversion of glycogen from the mucosal epithelium to lactic acid by lactobacillus

Answer 71

- 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

Answer 72

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

Answer 73

- 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

Answer 74

Solid, single-dose preparations similar to oral tablets

Answer 75

= biologics - Monoclonal antibodies (often IgG1), - ADC, - Interleukins, - Peptides, - Virus like particles…

Answer 76

- Protein therapeutics with enzymatic or regulatory activity e.g. augmenting an existing pathway - Protein therapeutics with special targeting - Protein vaccines

Answer 77

'Biological process"

Answer 78

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

Answer 79

- 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

Answer 80

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

Answer 81

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

Answer 82

- Conformational changes, aggregation and surface adsorption - Conformation changes = denaturation = unfolding (all information to maintain proteins conformation is contained in the AA sequence)

Answer 83

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

Answer 84

FALSE, IgG2 is

Answer 85

- 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.

Answer 86

``` 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)

Answer 87

The amphipathic nature.

Pre Formulation and Formulation Flashcards

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