Solubility Enhancement Strategies

Question 1

How does solubility impact drug in body

Answer 1

Liberation from dosage form. Risk: Low absorption

Question 2

Relationship between molecule size and solubility

Answer 2

The bigger and more complex the molecule, the lower the chance of solubility

Question 3

Relationship between dosage and solubility

Answer 3

Solubility is the amount of drug dissolves /mg. The higher the solubility the less drug required for drug action

Question 4

Brick Dust Def

Answer 4

Hydrophobic. Substance that has strong intermolecular bonds in a solid state (crystal lattice). Tends to have poor solubility in both aqueous and non solvents. Made more soluble via polymorphism (forming an amorphous solid)

Question 5

Grease Ball Def

Answer 5

Hydrophobic, lipophilic. Doesn’t contain strong crystal lattice (intermolecular bonds don’t cause poor solubility). Is soluble in non-aqueous solvents

Question 6

Manipulation of pH Outline

Answer 6

Ionising/deionising weak acids and bases by changing pH of solvent. High pH (steps above pKa, low H+ in solvent) acids are ionised (negatively charged). Low pH (steps below pKa, high H+ in solvent) bases are ionised (positively charged). Ionised = more soluble

Question 7

Pharmacuetical Salting

Answer 7

pH changes in solids by adding oppositely harged counter ions to solid weak acids and bases. Results in sustained release and better flowability

Question 8

Salting of a weak acid outline

Answer 8

pH is raised 3 steps above pKa (99.9% ionised, loss of proton). Add positive counter ion. Counter ion embeds in crystal lattice structure weakening bonds (forming salt). Water pulls apart salt (salt = electrolyte), seperating counter ion from conjugate base. Conjugate base excepts a proton from water, increasing solvent pH (better dissolution)

Question 9

Salting of a weak base outline

Answer 9

pH lowered 3 steps below pKa (99.9% is ionised, accepted proton). Negative counter io is added. Binds to structure, weakening intermolecular bonds forming salt (electrolyte). Water separates electrolyte out into counter ion and conjugate acid. Conjugate acid donates it’s proton to solvent, increasing solvent pH (better dissolution)

Question 10

Exceptions in salt solubility rules

Answer 10

Weak acid sometimes contain micro-pH-enviorments that enable them to be soluble eve in stomach’s low pH, hydrochloride salts are less soluble in stomach due to pre-exisiing high conc of Chloride ions, sodium salts don’t dissolve well in circulation due to preexisting high conc of Na ions

Question 11

Common Ion Effect Def

Answer 11

Displacement of salt’s ionic equilibium as due to abundance more then 1 counterion was added. Results in percipitation

Question 12

Salt forms

Answer 12

Crystalline, crystalline solvates, liquid crystals and irregular amorphous states. Crystalline are more stable but less soluble (less hydroscopicity), high boiling point helps wiyh flow and manufacturing uniformity

Question 13

Crystal engineering Outline

Answer 13

Control over how molecules are packed in a crystal, changing strength of crystal lattice eg converting to amorphous form in brick-dust via polymorphism, salt, solvate, co crystals or particle engineering

Question 14

Relationship between bond energy, bond strength, energy state of substance, stability and solubility

Answer 14

Strong bond energy = high bond strength = low substance energy state = high stability = lower solubility

Question 15

Polymorphism

Answer 15

Different patterns of molecules appearing in the same crystal. Polymorphs can have different properties from eachother

Question 16

Amorphous Form in Body

Answer 16

Substance is very soluble but unstable. As time passes substance recrystallizes, causing percipitation. Not a problem in vivi as drug is absorbed very quickly

Question 17

Co crystals Def

Answer 17

2+ crystals mixed and held together by H bonds (non-ionic, non-covalent). Co-crystals bnd to amorphous form and increase stability without decreasing solubility.

Question 18

Co -formers Def

Answer 18

Co-formers bind to lattice weakening structure, increasing solubility (enables supersaturation). Will precipitate if left too long (absorbed quickly in vivo). Can only be used with ionisable drugs in neutral form

Question 19

Co -solvents Outline

Answer 19

Water miscible organic solvents, alter the polarity (by altering dielectric constant) of water allowing more lipophilic substances to dissolve. eg water and ethanol

Question 20

Problems with cosolvents

Answer 20

Phlebitis (irritation at injection site due to cosolvent diluting away caiusing percipitation, haemolysis, embolism

Question 21

Elixir Def

Answer 21

Oral cosolvents (not a suspension)

Question 22

Dielectric Constant notation

Answer 22

Epsilon.

Question 23

Surfactants Outline

Answer 23

Possess hydrophobic and hydrophilic properties place themselves between water and organic solute removing hydrophobic-hydrophilic interaction. Removes surface tension

Question 24

Micelle Formation

Answer 24

In nano-colloidal dispersions surfactant fold in on themselves forming a hydrophilic outer region and a lipophilic inner one. Lipophilic drugs dissolve at core. Non-ionic micelles cause less damage to cells

Question 25

Surfactant Safety Risk

Answer 25

Phlebitis, silution leads to percipitation, use non-ionic for oral formulations and non-ionic for external (eg creams)

Question 26

Inclusion Complexes eg Cyclodextrins

Answer 26

Macrocyclic oligosaccharides (bottomless flower pot shape). Externally hydrophilic, internally lipophilic. Host (complex) - Guest (drug) system (1:1). Drug binds (moderatly) inside cavity. Bonding too strong = drug won’t leave, bonding too weak = drug percipitates out. Used in oral and paraenteral delivery. Attach subteal-butul-etehr to incraese solubility

Question 27

Cyclodextrins examples

Answer 27

Alpha cavity = glucose 0.6, Beta cavity = glucose 0.7, gama- cavity = glucose 0.9. Most drugs bing in beta cavity

Question 28

What size particles dissolve instead of aggregate under high surface tension

Answer 28

Nano

Question 29

Particle Size Reduction

Answer 29

Increases, surface area, decreases lattice strength, increases solubility

Question 30

Particle Size Reduction Bottomup

Answer 30

Yielding nano-particles through recrystallisation

Question 31

Particle Size Reduction Topdown

Answer 31

Micro-ionisation via hammer, ball or jet mills

Question 32

Pearl Milling Def

Answer 32

Shattering the structure of hard solids

Question 33

Wet milling

Answer 33

Seperating out of soft solids and liquids by mixing

Question 34

Dispersion Outline

Answer 34

Dispersing 1 solid in another (non-homogenous) increases solubility. Cystalographers can promote super saturation state due to reduced particle size, improved wetting and reduced lattice energy

Question 35

Eutectic Mix (solid dispersion) outline

Answer 35

Crystalline drug, crystalline carrier

Question 36

Solid Suspension

Answer 36

Amorphous drug, crystalline carrier

Question 37

Solid solution

Answer 37

Molecular solution drug, crystalline carrier

Question 38

Glass Suspension

Answer 38

Crystalline drug, amorphous carrier

Question 39

Glass Amorphous Suspension

Answer 39

Amorphous carrier and amorphous suspension

Question 40

Glass solution

Answer 40

molecular dispersion drug, amorphous suspension

Question 41

Eutectic Mix Outline

Answer 41

Solid particles dispersed in another solid. Has the lowest melting point = the most soluble.

Question 42

Solid Carriers Outline

Answer 42

Act as spring pushing dispersion into blood. Subcarriers prevent percipitation

Question 43

Lipid Based Formulations Outline

Answer 43

Dispersion that take paths in body specificllly for absorption of fats soluble nutrients (eg vitamins). Used to be administered with food but now have emulsifying agents. Coarse dispersions are not thermodynamically stable and microemulsions are thermodynamically stable. The more lipophilic a drug is the bigger role lipid digestion plays

Question 44

Drug Derisvation Outline

Answer 44

Adding of functional groups, forming a prodrug, increasing solubility

Question 45

Prodrug Def

Answer 45

Inactive form of a drug. Activated by the cleavage of a functional group (usually an ester bond by esterase enzyme)