Drug properties relevant to sustained release formulationThe design of sustained release delivery system is subjected to several variables and each of variables are inter-relatedFor the purpose of discussion it is convenient to describe the properties of the drugs as being either physico-chemical or biological ,these may be divided in two types.1. Physicochemical properties2. Biological properties
1.Physicochemical propertiesA. Aqueous solubility and pKaB. Partition coefficientC. Drug stabilityD. Protein binding
A. Aqueous solubility and pKaThese are the most important to influence its absorptive behavior and its aqueous solubility ( if it’s a weak acid or base) and its pKaThe aqueous solubility of the drug influences its dissolution rate which in turn establishes its concentration in solution and hence the driving force for diffusion across the membranes as shown by Noye’s Whitney’s equation which under sink condition that is dc/dt= Kd.A.CsWhere dc/dt = dissolution rate Kd= dissolution rate constant A = total surface area of the drug particles Cs= aqueous solubility of the drug
Dissolution rate (dc/dt) is constant only when SurfaceArea A .isThe initial rate is directly proportional to the Aqueoussolubility (Cs) hence Drug with low aqueous solubilityhave low dissolution rate and its suffer low bioavailabilityproblemThe aqueous solubility of weak acid and bases arecontrolled by pKa of the compound and pH the mediumFor weak acidsSt= So(1+Ka/H+) = So (1+10pH-pKa )Where St = total solubility of weak acid.So = solubility of unionized formKa= Acid dissociation constantH+= H ion concentration
Similarly for Weak BasesSt = So (1+H+/Ka) = So (1+10pKa-pH )if a poorly soluble drug was consider as a suitable candidatefor formulation into sustained release system.Since weakly acidic drugs will exist in the stomach pH 1-2 ,primarily in the unionized form their absorption will befavored from this acidic environment on the other handsweakly basic drugs will be exist primarily in the ionized form(Conjugate Acids) at the same site, their absorption will bepoor.in the upper portion of the small intestine the pH is morealkalinepH 5-7 and the reverse will be expected for weak acids
B. Partition coefficientWhen the drug is administered to the GIT ,it must cross avariety of biological membranes to produce therapeuticeffects in another area of the body.It is common to consider that these membranes are lipidic,therefore the Partition coefficient of oil soluble drugsbecomes important in determining the effectiveness ofmembranes barrier penetration.Partition coefficient is defined as the ratio of the fraction ofthe drug in an oil phase to that of an aqueous phase.Accordingly compounds with a relatively higher partitioncoefficient are predominantly lipid soluble and have very lowaqueous solubility.
Furthermore , these compound can usually persist in thebody for long periods , because they can localize in the lipidmembranesPhenothiazines are representative of this type of compoundCompounds with very low partition coefficients will havedifficulty penetrating membranes , resulting in poor bioavailability
C. Drug stabilityOrally administered drugs can be subjected to both acid-base hydrolysis and enzymatic degradation . Degradation will proceed at a reduced rate for drugs in thesolid state therefore this is preferred composition of deliveryfor problem cases .Drugs that are unstable in the stomach can be placed inslowly soluble form or have their release delayed until theyreach small intestine.However for some drugs which are unstable in smallintestine are under go extensive Gut –Wall metabolism havedecreased the bio availability .
When these drugs are administered from a sustaineddosage form to achieve better bio availability, at differentroutes of the drugs administered should be chosenEg. NitroglycerineThe presence of metabolizing enzymes at the site or pathwaycan be utilized.
D. Protein bindingThe binding of the drugs to plasma proteins(eg.Albumin) results in retention of the drug into the vascular spacethe drug protein complex can serves as reservoir in thevascular space for sustained drug release to extravascular tissue but only for those drugs that exhibited ahigh degree of binding.The main force of attraction are Wander-vals forces ,hydrogen binding, electrostatic binding.In general charged compound have a greater tendency tobind a protein then uncharged compound, due toelectrostatic effect.
The presence of hydrophobic groups on drugmolecule also increases its binding potential.Eg amitryptline, cumarin, diazepam, digoxide,dicaumarol, novobiocin.