solubility, solubilisation and Solutions. CH Flashcards
Solution definition:
A homogenous distribution of individual molecules of a substance dispersed in a solvent
A solvent:
The phase in which dispersion occurs. A liquid solvent is called a Vehicle, whereas a solid or semi-solid solvent is referred to as a base.
A solute:
The component that is dissolved as molecules or ions in the solvent.
Drugs are produced into large solid structures. Can either be:
Crystalline or Amorphous
How do we describe the shape of a Crydtalline solid?
Has a regular, defined molecular structure arranged in a regular, periodic mannor
How do we describe the shape of an Amorphous solid?
Looks like a crystal, but lacks any defined structure - there is no arrangement of molecules e.g. glass
The large solids are then reduced to fine powder particles. Particles that are less than what size are then called PARTICULATES?
less than 1 micron in size = particulates
Dissolving is also known as
Dissolution
What is the process of Dissolving/dissolution?
This is when the molecules at the exterior of the interface of the solute (in the case of a solid) are no longer bound or associated with the molecules inside the particle
It is a kinetic process and is characterised by a dissolution rate.
What affects the dissolution rate?
Association constant, temperature, and free energy of solvation.
What does ‘like dissolve like’ mean?
The more similar in polarity the solute and the solvent, the greater the tendancy to dissolve. The forces that bind two adjacent molecules together are overcome by attractive forces between molecules of the solvent.
What happens to a solute molecule once it is freed from its crystal?
The free solute molecule becomes solvated within a SOLVATION CELL.
Solvent molecules orientate towards the solute in a complementaary manner i.e. solvent with delta-ive orientates towards delta+ive
What happens when more solvent is added to the solution?
An outer, less strong, outer shell will be formed as the ‘sea’ of free solvent surrounding the solute molecule increases i.e. the solvation shell increases but becomes weaker towards the outside.
What happens in the cases when the associateion between the solvent is very strong?
The solute molecule will become permanently bound to the solvent and the bonds can only be broken by breaking down the molecule.
Dissociation Constant Kd:
Is a specific type of equilibrium constant that measures the propensity (tendancy) of a larger object to dissociate reversibly into smaller components e.g. salt formation.
How to accelerate Dissolution of a low Kd?
1) Heat
2) Shear
3) Sonication
How does heat accelerate Dissolution of a low Kd?
Higher temp increases Brownian motion causeing greater collisions between solvent molecules and molecules at the crystal solute surface
How does Shear accelerate Dissolution of a low Kd?
Using a Vortex mixture, shear increases the interaction between solvent molecules and molecules at the crystal solute surface.
How does Sonication accelerate Dissolution of a low Kd?
Ultrasonic waves are transmitted through water and pass through the crystal, physically causing them to shake apart and interact with the solvent faster.
What are the 2 types of non-solutions?
A colloid: a mixture in which one substance of microscopically (1nm - 1micron) dispersed insoluble particels are suspended throughout another substance. They are much less likely to be affected by gravity
Suspension: A mixture in which small (>1 micron) insoluble particelsa are dispersed throughout a liquid continuous phase. Will be affected by gravity.
What is solubility?
This is the amount of a substance (in mass or moles) that will dissolve in a specific volume of solvent (Csol)
How do we determine solubility of a drug?
- Excess drug is added to a solvent until no more dissolves at a certain temperature.
- Seperate the excess through centrifugation
- Analyse the supernantant (the liquid lying above the solid after centrifugation) by UV or HPLC.
- Often very large supernantant is necessary (e.g. x1000)
- Do the experiment again at least 3 times
- Use SD or SEM for precision purposes
What is solubility highly depensant on?
Highly dependany on Temperature.
Higher temperature = Higher Brownian motion = higher solubility.
What is a saturated solution?
This is the pint immediately before precipitation of drug (becomes clowdy) where no more drug can me solvated.
Why is the solubility so important?
Drugs in the solid phase cannot penetrate the biological membrane so the drug must be in solution to be absorbed.
The higher the concentration of the solution:
The quicker the transfer accross the biological membrane becasue of teh incresaed mass transfer from a high to low concnetration.
If the drug solution is saturated, the concentraiton is
Maximal. Higher the saturation, higher the concentration, higher the mass transfter accross a membrane.
Water as a solvent: Water is a:
non-ionic, polar molecules, and a good solvent for other polar or charged compounds.
What dissolves well in water?
salts, sugars, acids, some gasses (oxygen and carbon dioxide)
What is the most widely used solvent for use as a vehicle in pharmaceuticals?
Water due to its lack of toxicity and its physiological compatibility
What are the grades of water?
- Portable water: fresh, drinkable
- Purified water BP: Prepared by distillation or deionisation of dinkable water that is freshly boiled and cooled before use.
- Water for injections BP; for parenteral solutions, prepared by sterilisation of pyrogen-free distilled water
- Water for injections without CO2 or air BP: for injections with drugs that are unsteble in gasses i.e. liable to oxidation.
If a drug has low water solubility, what is the next common solvent used?
Alcohols with short hydrocarbon chains are good solvents e.g. Ethanol which is miscible with water and other organic fluids.
Why not use methanol or propanol?
Have the same properties as ethanol but is more toxic.
What about alcholos with longer chains so from Butanol (4C) and above?
Less hydrophilicity therefore not as good solvents.
What are the other 2 widely used solvents?
- Propylene glycol
2. Glycerol (glycerine)
When is glycerol used?
Used in laxatives as it irritates the anal mucose.
Also used topically as an ‘active exipient’- good for psoriasis, bites, rashes and cuts
Has some antibacterial properties as it draws water out of bacteria
When is Polythene glycol (PEG) used?
It has the longest chain that remains a liquid. They are the basis of many laxatives, also used for soft capsules, eye drops, and as a base in suppositoreis
What is PEGylation?
When PEG’s are added to various protein medications. PEGs allow slowed clearance of the carried protein from the blood, making the drug longer acting, less toxic and allows for longer dosing intervals.
What are fixed oils and fats?
lipophilic solvents
1 glycerol and 2-3 free-fatty acids
Polarity of solvents: hexane ethanol water HCL
Purely organic - no polarity
partly organic - partly polar
inorganic - polar
inorganic - very polar
What does the ionic state of an ionisable functional group have effect on a molecule?
greatly affects the hydrophilicity or lipophilicity
Can charged drugs exist on their own?
NO -must exist as salts
Lidocaine is lipophilic as a free base, but hydrophilic as a salt. which form is used topically and which form is used in injections?
free base form as it is lipophilic to penetrate the skin
salt in injections - needs to be polar to be absorbed.
What is a salt?
An ion and a counterion.
Why is it important to carefully select a counter ion during drug manufacture?
Because counter-ions can affect:
- Ion pair assoiation constant
- The toxicity levels of a counterion in the formulation
- interaction with exipients or packaging
- Making into a salt can affect the active drug.
What is crystalisation?
This is the opposite of solubilisation where the solvent is removed, and the molecules coalesce as a crysttal lattice or amphorous particels if no crystallinity.
When is the material known as being Polymorphic?
If there is more than one crystal lattice forming simultaneouslt
What is done after crystallisation?
The crystals are milled to fine powders and the purity can be altered using shear forces.
What are the issues with polymorphic dissolutions as formulations?
It can lead to fatal dosage irregularitires: if one polymorph dissolves slowly, but the other fast then this will affect the rates of GI absorption.
It can also affect the shelf life, formulation properties and processing properties.
How can polymorphism be rectified?
Can be rectified by heat, then look at IR spectra to see if worked: one peak = has worked. More than 1 peak = not worked because there is a peak for each crystal lattice.
P = Partition COefficient is a measure of
drug lipophilicity and hydrophilicity.
WHat is the equation for P
Concentration dissolved in non-aqueous (octanol) divided by concentration dissolved in aqueous (water)
If P is less than 1, then the drug is
hydrophilic
If P is More than 1 then the drug is
Hydrophobic / lipophilic
An ionic compound is a
molecule with a charge either due to the:
- loss of electrons - acidic
- gain of electrons - basic
What is a Zwitterion?
A molecule with both charges
What does the precense of a charge do to the solubility?
MAkes the molceule more soluble in polar solvents but less solvent in organic solvents
What is the distribution coefficient D?
This is the ratio of the sum of the concentrations of all forms of the compound - un-ionized, and ionized in each of the two phases
Is D pH dependant?
Yes - the aqueous phase is buffered before introducing a compound to get a specific pH value
FOr un-ionixable compounds, what si true about the LogP and the LogD?
LogP = LogD at all pH
What is pKa?
Acid dissociation constant
What is Pkb?
The base dissociation constant
What can the Pka and pKb tell us?
They can tell us the pH at which 50% of the drug is ionised.
%ionised = 100/1+ (10 to the power of (pKa - pH))
Modulating drug stability: why would some drugs be resistent to solubilisation to the point where therapeutic concns cannot be obtained?
- Insoluble in the vehicle of choice
- Tight crystalline structure
- Tightly bound ion-counterion salts
What is MAC?
This is the Maximum added concentration: the highest amount of the drug that can be incorporated into the solution. Can be worked out by measuring optical density i.e. the point where the solution is no longer clear.
Changing pKa or pKb can affect solubility. WHy must molarity of the acid or base added to change the pH be carefully considered?
DILUTE acids or bases will get the desired pH
STRONG acids or bases will degrade the drug or excipient
WHat can be added to maintain the preferred pH?
Add a buffer solution which is an aqueous solution with a mixture of weak acid and its conjucate base or vice-versa
What is the buffer solution often used to mimic the blood?
Phosphate Buffer SAline (PBS)
pH of 7.4
WHat is co-solvency?
this is improving the solubility of a weak elctrolyte or a non-polar compound by addition of a water miscible solvent - usually water/ethanol.
FIrst solution is made in the primary solvent - the one in which the drug is most soluble in, then a secondary solvent is added, but to below the level at which the drug preticipates.
WHat are surfactants?
Solubilisers - increase solubility. They are amphiphilic organic compounds consisting of hydrophobic tails and hydrophilic heads which can be either non-ionic or ionic.
Why are surfactants also called Surface active agents?
Becuase they are compounds that lower the surface tension of a liquid, and the interfacial tension between two liquids or between one liquid and a solid.
What else can surfactants act as?
Detergents, wetting agents, emulsifiers, foaming agents, dispersants
What is an emulsion?
A dispersion of two or more immiscible LIQUIDS e.g. oil and water. with a dispersed phase and a continuous phase.
Emulsions may be semi-solids or liquids depending on their:
oil/water proportions and their route of administration.
What is the diameter of a micro and nano emulsion?
400-600nm
WHich emuslion is used to kill microbes, blood and serum? mico or nano
Micro unless the nano emulsion of soy-bean oil is used.
What is the process of antimicrobial by micro emulsions?
NOT chemical, but MECHANICAL - the smaller the droplet, the greater the surface tension and the greater the force to merge.
WHat is a micelle?
A spherical aggregate. around 150nm of surfactant molecules can be dispersed in a liquid colloid. Normally, the hydrophobic tails will be inside the micelle, and thye hydrophilic heads on the outside.
What is an inverse micelle?
This is when the hydrophilic heads are in the centre, and the tails extending out - a water in oil micelle.
What is the CMC?
The critical micelle concentration. - the concentration at which the compound will dissolve to form micelles
When do surfactants act as emulsifiers?
Surfactants act as emulsifiers when they are present above the CMC
What is MAC?
This is the MAximum concnetration of active added.
What is the relationship between the concnetraation of surfactant and MAC?
As the concnetration of surfactant increases, the MAC that can be added also increases
What are Liposomes?
Spherical vesicles comprimised of one or more phospoholipid bilayer encapsulating a droplet of aqueous solution inside a hydrophobic core. Dissolved hydrophilic solutes cannot readily pass through the lipids.
WHat are the three types of Liposomes?
MLV - multilamellar vesicles
SUV - small unimlamellar vesicles
LUV - large unilamellar vesicles.
Can lysosomes carry both hydrophilic and hydrophobic molecules?
yes: hydrophobic dissolved in the membrane, and hydrophilic in the encapsulated droplet.
What are the advantages of Liposomes?
A way of protecting the compounds in the core from materials outside the liposome.
A way of delivering drugs that would normally be unable to diffuse across membrane.
What is Complexation?
The interaction of a poorly soluble drug with a soluble material to form a complex that is overall soluble.
These complexes are macromolecular.
Association is complex formation
Dissociation is drug release.
What is a supersaturated solution?
A solution with a thermodynamic activity of more than 1 (range from 2 - 4)
How is it possible to form supersaturated solutions?
- crystals grow when molecules coalesce
- The presence of polysaccharides sterically prevent the molecules of solute from interacting with each other to form crystals.
- so greater amounts of dissolved drug can be dissolved in solvent.
What are the advantages of Oral solutions?
Solid particles dissolved in liquid
- Easier to swallow
- No dissolution stage - drug immediately available for absorption therefore faster onset of action
- Homogenous system so drug will be uniformly distributed
- Irritation of gastric mucosa is reduced as it is already diluted
- 5ml dosing is manegable
whAT ARE THE disadvantages of oral solutions?
Difficult to mask the tase
What is an oral suspension?
solid drug particles suspended in an aqueous phase in which the drug is saturated.
Easier to mask the taste. MAy sediment over time but easuly redisperded on shaking
What is a mixture?
The same as a suspension. Usually cough mediciens, manufactured on a small scale and allocated a shelf life of a few weeks before dispensing.
WHat is a Draught?
A mixture of which only one or two large doses are given - 50ml
What is a syrup?
A liquid preparation in which the vehivle is a concentrated aqueous solution of sucrose and other sugars. Syrups have high osmotic pressures preventing the growth of bacteria, fungi and moulds
What is ELixir?
Clear, hydro-alcoholic oral formulation of potent or nauseaous drugs e.g. antibiotics, sedatives. Palatable, coloured and very stable. Alcohol is used to solubilize the active ingredient, stop crystallization of sugar and preserve the product. The lowest amount possible of alcohol is used.
Used when a potent medication with low solubility is required e.g. phenobarbitone.
What is a linctus?
A viscous oral syrup containing a high proportion of sucrose, other sugars and a suitable alcohol.
WHat is a mouthwash?
- An aqueous solution containing 1 or more actives
- May contain antiseptics, analgesics and astringents e.g. chlorhexidine (corsodyl) and may contain excipients e.g. antimicrobial preservatives
What are otic preparations?
Ear preparations:
1. Low volume, simple solutions of drug in water, glycerol, proplylene glycol or alcohol/water for local use
WHat are nasal preparations?
- Low volume aqueous preparations
2. Buffering capacity of nasal mucosa is low, isotonic pH 6.8 is used
What is a lotion?
- Low to medium viscosity
- Intended for application to unbroken skin
- Most are oil in water with an alcohol to keep the emulsion together
Lotion vs creams:
Creams are easier to handle
Lotions have much lower viscosity and so appropriate for hairy skin and scalp
Lotions are easier to spread
What is a Liniment?
Also known as a balm is a medicated topical preparation for application on the skin
Of similar viscosity to lotions but is applied with friction through rubbing or massaging.
typically used to relieve pain and stiffness
formulated from alcohol, acetone or similar quickly evaporating solvents and certain counterirritant aromatic chemicals
What are the disadvantages of liquids and suspensions?
Bulky thereofre inconvenient to transport and store
Stability much poorer than tab or caps therfore shorter shelf life
Solutions often provide media for growth of microorganisms so may need preservative.
Accurate dosing depends on patient’s ability to use a 5ml spoonsful
Difficult to mask taste of solutions
