“Dissolution” is the processin which a substance goes from a solid state to a solution in a solvent.
“Solubility” refers to the amount of solute (drug) that dissolves in a given volume of solvent at a given temperature and pressure.
According to USP a solution that dissolves 3.3% (1/30) or more of solute is considered soluble
Drug in the body, including in GIT, is considered to be in an aqueous environment.
Drug dissolution is a 2 steps process:
Drug dissolves at the surface of particles to form a layer ofsaturated solution (stagnant layer)
Drug diffuse from stagnant layer to the bulk of solvent(i.e. the release medium in vitro, and GI fluid in vivo).
Rate of drug dissolution=dC/dt=[𝑫𝑨/𝒉] [(𝑪𝒔−𝑪)]
D = diffusion coefficient (cm2/s)
A = surface area of the particles
CS = concentration of drug in the stagnant layer
C = concentration of drug in the bulk solvent (or release medium)
h = thickness of the stagnant layer.
Diffusion Coefficient-a constnat for a molecule in the given solvent (relates to how fast the molecules of that particular drug will move away and be released). It willincrease with temperature.
When we increase the speed ofstirring, the thickness of staganant layer will decreaseand better release to the bulk solvent (because the drug particle will travel a smaller distance).
The amount of agitation and nature of stirrer affect hydrodynamics of the system, thereby affecting the dissolution rate.
Low stirring rates (50–75 rpm) are more discriminating of formulationfactors. However, a higher dissolution rate may be needed for some special formulations (eg, suspensions) in order to obtain reproducible dissolution rates.
The size and shape of the dissolution vesselmay affect the rate and extent of dissolution.
A surfactant (SLS, Triton X-100) may be added to the dissolution medium for water-insoluble drugs.
Volume of dissolution medium used should not be less than 3 times to that required to form a saturated solution of drug.
In addition to routine quality control tests, comparative dissolution tests have been used to waive bioequivalence requirements (biowaivers) for lower strengths of a dosage form.
For highly water soluble (BCS classes 1 and 3) immediate release products using currently available excipients and manufacturing technology, an IVIVC may not be possible. For poorly water soluble products, BCS class 2, an IVIVC may be possible.
BCS Class 3 drugs have high solubility and low permeability, drug absorption is the rate limiting step and will not necessarily correlate with the rate of drug dissolution henceno IVIVC correlation possible.
It makes sense for BCS Class 2 drugs(low solublity but high permeability) that a correlation is presentbecause as soon as we’ve for instance increased the rate of solubilization of the drug, the rate of absorption will increase too(as permeation across the membrane will occur readily as long as we’ve solubilized the drug).A dissolution profile in multiple media is recommended for drug products in this category (BCS Class 2).
IVIVC is mantained but NOT at high drug concentrationsif the drug needs atransporters in absorption(because the transporters are saturable and hence the in-vivo plasma concnetration of the drug will plateau).
BCS takes into account three major factors that govern the rate and extent of absorption from IR solid oral dosage forms:
– Highly soluble: Highest dose soluble in 250 ml in pH 1.2,pH 6.8
– Highly permeable: extent of absorption greater than 85%
Predictive Mathematical treatment.
Relation betweenin vitro property (% dissolution or % drug release) and in vivo response (% drug absorbed or plasma concentration)
Fraction drug released (in vitro) vs Fraction drug absorbed/released (in vivo).
For controlled/extended-release formulation, the dissolution or drug release from the formulation is the rate-limiting step in the appearance of drug into the systemic circulation, it is possible to establish a relationship between the in vitro drug release and in vivo drug release (or its absorption into the systemic circulation) .
IVIVC Vs IVIVR
An IVIVC describes a quantitative (generally linear) relationship between in vivo and in vitro release characteristics while an IVIVR reflects a relationship that can be described by something other than that of a straight-line.
Center for Veterinary Medicine (CVM) recommends that at the very least, sponsors demonstrate an IVIVR to support the biological relevance of the in vitro release method.
Convolution: determining output function (plasma concentrations), if input function (% drug absorbed or dissolution results) is available.
Deconvolution–obtaining input function (absorption/dissolution results) if output function(plasma concentration) is provided. To obtain % or fraction drug absorbed (or in vivo dissolution profile) from plasma concentration.
In vivo release- mainly determined by measuring free drug concentration in blood, plasma and/or serum. It can also be ascertained by imaging methods like MRI & PET(quantitative specific organ uptake).
Convolution is a model independent method.
Superposition principle-total response caused by several inputs applied at various times is sum of all partial responses considering the time shifts.
Model dependent-Wagner Nelson (one compartment absorption), Loo Riegelman (two compartment absorption)
Model independent-Numerical absorption (No compartment assumptions. More flexibility on absorption function; can be set as 1st order absorption or general input function for non-standard/unknown formulations.)
Applicability of Numerical method to ivivc-not affected by absorption rate.
Applicability of Wagner nelson method to ivivc falls when absorption (not the dissolution) becomes rate determining step (RDS), i.e, when absorption rate<<release rate.
However, for highly absorbed formulations the ivivc plots & their correlation coefficients are comparable for both methods.