Sustained release property

Sustained release property

• 1.
  Drug properties relevantto sustained release formulation The design of sustained release delivery system is subjected to several variables and each of variables are inter-related For 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 properties 2. Biological properties
• 2.
  1.Physicochemical properties A. Aqueoussolubility and pKa B. Partition coefficient C. Drug stability D. Protein binding
• 3.
  A. Aqueous solubilityand pKa These are the most important to influence its absorptive behavior and its aqueous solubility ( if it’s a weak acid or base) and its pKa The 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.Cs Where dc/dt = dissolution rate Kd= dissolution rate constant A = total surface area of the drug particles Cs= aqueous solubility of the drug
• 4.
  Dissolution rate (dc/dt)is constant only when Surface Area A .is The initial rate is directly proportional to the Aqueous solubility (Cs) hence Drug with low aqueous solubility have low dissolution rate and its suffer low bioavailability problem The aqueous solubility of weak acid and bases are controlled by pKa of the compound and pH the medium For weak acids St= So(1+Ka/H+) = So (1+10pH-pKa ) Where St = total solubility of weak acid. So = solubility of unionized form Ka= Acid dissociation constant H+= H ion concentration
• 5.
  Similarly for WeakBases St = So (1+H+/Ka) = So (1+10pKa-pH ) if a poorly soluble drug was consider as a suitable candidate for 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 be favored from this acidic environment on the other hands weakly basic drugs will be exist primarily in the ionized form (Conjugate Acids) at the same site, their absorption will be poor. in the upper portion of the small intestine the pH is more alkaline pH 5-7 and the reverse will be expected for weak acids
• 6.
  B. Partition coefficient Whenthe drug is administered to the GIT ,it must cross a variety of biological membranes to produce therapeutic effects in another area of the body. It is common to consider that these membranes are lipidic, therefore the Partition coefficient of oil soluble drugs becomes important in determining the effectiveness of membranes barrier penetration. Partition coefficient is defined as the ratio of the fraction of the drug in an oil phase to that of an aqueous phase. Accordingly compounds with a relatively higher partition coefficient are predominantly lipid soluble and have very low aqueous solubility.
• 7.
  Furthermore , thesecompound can usually persist in the body for long periods , because they can localize in the lipid membranes Phenothiazines are representative of this type of compound Compounds with very low partition coefficients will have difficulty penetrating membranes , resulting in poor bio availability
• 8.
  C. Drug stability Orallyadministered drugs can be subjected to both acid- base hydrolysis and enzymatic degradation .  Degradation will proceed at a reduced rate for drugs in the solid state therefore this is preferred composition of delivery for problem cases . Drugs that are unstable in the stomach can be placed in slowly soluble form or have their release delayed until they reach small intestine. However for some drugs which are unstable in small intestine are under go extensive Gut –Wall metabolism have decreased the bio availability .
• 9.
  When these drugsare administered from a sustained dosage form to achieve better bio availability, at different routes of the drugs administered should be chosen Eg. Nitroglycerine The presence of metabolizing enzymes at the site or pathway can be utilized.
• 10.
  D. Protein binding Thebinding of the drugs to plasma proteins(eg.Albumin) results in retention of the drug into the vascular space the drug protein complex can serves as reservoir in the vascular space for sustained drug release to extra vascular tissue but only for those drugs that exhibited a high degree of binding. The main force of attraction are Wander-vals forces , hydrogen binding, electrostatic binding. In general charged compound have a greater tendency to bind a protein then uncharged compound, due to electrostatic effect.
• 11.
  The presence ofhydrophobic groups on drug molecule also increases its binding potential. Eg amitryptline, cumarin, diazepam, digoxide, dicaumarol, novobiocin.