Solubility Enhancement Strategies Flashcards
How does solubility impact drug in body
Liberation from dosage form. Risk: Low absorption
Relationship between molecule size and solubility
The bigger and more complex the molecule, the lower the chance of solubility
Relationship between dosage and solubility
Solubility is the amount of drug dissolves /mg. The higher the solubility the less drug required for drug action
Brick Dust Def
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)
Grease Ball Def
Hydrophobic, lipophilic. Doesn’t contain strong crystal lattice (intermolecular bonds don’t cause poor solubility). Is soluble in non-aqueous solvents
Manipulation of pH Outline
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
Pharmacuetical Salting
pH changes in solids by adding oppositely harged counter ions to solid weak acids and bases. Results in sustained release and better flowability
Salting of a weak acid outline
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)
Salting of a weak base outline
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)
Exceptions in salt solubility rules
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
Common Ion Effect Def
Displacement of salt’s ionic equilibium as due to abundance more then 1 counterion was added. Results in percipitation
Salt forms
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
Crystal engineering Outline
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
Relationship between bond energy, bond strength, energy state of substance, stability and solubility
Strong bond energy = high bond strength = low substance energy state = high stability = lower solubility
Polymorphism
Different patterns of molecules appearing in the same crystal. Polymorphs can have different properties from eachother
Amorphous Form in Body
Substance is very soluble but unstable. As time passes substance recrystallizes, causing percipitation. Not a problem in vivi as drug is absorbed very quickly
Co crystals Def
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.
Co -formers Def
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
Co -solvents Outline
Water miscible organic solvents, alter the polarity (by altering dielectric constant) of water allowing more lipophilic substances to dissolve. eg water and ethanol
Problems with cosolvents
Phlebitis (irritation at injection site due to cosolvent diluting away caiusing percipitation, haemolysis, embolism
Elixir Def
Oral cosolvents (not a suspension)
Dielectric Constant notation
Epsilon.
Surfactants Outline
Possess hydrophobic and hydrophilic properties place themselves between water and organic solute removing hydrophobic-hydrophilic interaction. Removes surface tension
Micelle Formation
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
Surfactant Safety Risk
Phlebitis, silution leads to percipitation, use non-ionic for oral formulations and non-ionic for external (eg creams)
Inclusion Complexes eg Cyclodextrins
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
Cyclodextrins examples
Alpha cavity = glucose 0.6, Beta cavity = glucose 0.7, gama- cavity = glucose 0.9. Most drugs bing in beta cavity
What size particles dissolve instead of aggregate under high surface tension
Nano
Particle Size Reduction
Increases, surface area, decreases lattice strength, increases solubility
Particle Size Reduction Bottomup
Yielding nano-particles through recrystallisation
Particle Size Reduction Topdown
Micro-ionisation via hammer, ball or jet mills
Pearl Milling Def
Shattering the structure of hard solids
Wet milling
Seperating out of soft solids and liquids by mixing
Dispersion Outline
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
Eutectic Mix (solid dispersion) outline
Crystalline drug, crystalline carrier
Solid Suspension
Amorphous drug, crystalline carrier
Solid solution
Molecular solution drug, crystalline carrier
Glass Suspension
Crystalline drug, amorphous carrier
Glass Amorphous Suspension
Amorphous carrier and amorphous suspension
Glass solution
molecular dispersion drug, amorphous suspension
Eutectic Mix Outline
Solid particles dispersed in another solid. Has the lowest melting point = the most soluble.
Solid Carriers Outline
Act as spring pushing dispersion into blood. Subcarriers prevent percipitation
Lipid Based Formulations Outline
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
Drug Derisvation Outline
Adding of functional groups, forming a prodrug, increasing solubility
Prodrug Def
Inactive form of a drug. Activated by the cleavage of a functional group (usually an ester bond by esterase enzyme)
