Pharmaceutical factors affecting drug absorption

Definitions

Pharmacokinetics

o   Evaluate the way in which a drug interacts with various barriers within a biological system

Pharmacodynamics

o   Study of the relationship between systemic exposure of a drug and it’s biological effects on tissue

o   Absorption can be defined as the movement of active drug (or prodrug) from the site of administration across biologic barriers into a site where it is measured in the blood. This site of measurement is not specified.

o   Bioavailability can be defined as the fraction of administered drug that reaches the systemic circulation.

o   Note the difference in endpoint measurement sites 

 

PHARMACEUTICAL FACTORS:

It include factors relating to the-

A.    Chemical Factors

o   A variety of chemical options can be used to improve the stability and systemic availability of drugs.

o   For example, esters can be prepared of both acids and bases to produce more stable derivatives, which hydrolyse to the active parent once absorbed. The stability and solubility of both acids and bases tend to increase when they are in the form of salts. 

o   Typically, administration of soluble salts of penicillin give rise to higher circulating antibiotic levels than the free acid. When the salt of a weak acid dissolves in the stomach, it generates a diffusion layer of relatively high pH which,in turn, promotes further dissolution. The same argument could theoretically be used for basic drugs.

o   However, the pH effect in this case is swamped by the very low pH present in stomach fluids.

o   Thus, salts of basic drugs are used primarily for handling and solubility rather than for improved dissolution.

B.     Physicochemical properties of drug substances

1.      Drug solubility and dissolution rate:

o The rate determining steps in absorption of orally administered drugs are:

§  Rate of dissolution

§  Rate of drug permeation through the biomembrane.

o Imp prerequisite for the absorption of a drug is that it must be present in aq solution & this is depends on drug‘s aq solubility &its dissolution rate.

2.      Particle size and effective surface area:

o Smaller the particle size (by micronization) greater is the effective surface area more intimate contact b/w solid surface and aq solvent higher is the dissolution rate increase in absorption efficiency

o E.g. poorly aqsoluble nonhydrophobic drugs like Griseofulvin, chloramphenicol whose dissolution is rate limited.

o Particle size reduction has been used to increase the absorption of a large number of poorly soluble drugs, such as bishydroxycoumarin, digoxin, griseofulvin, nitrofurantoin,and tolbutamide.

o Griseofulvin has extremely low aqueous solubility, and material of normal particle size gave rise to poor and erratic absorption.

o Microsize particles improve absorption, but it is improved even more when it is formulated in ultramicrosize particles as a monomolecular dispersion in polyethylene glycol.

3.      Polymorphism and amorphism:

o When sub exist in different crystalline form i.e. in polymorphic form then diff forms are many compounds form crystals with different molecular arrangements, or polymorphs. These polymorphs may have different physical properties, such as dissolution rate and solubility.

o Stable form

§  Lowest energy state - Highest m.pt.

§  Least aq solubility

§  Dissolution rate limited

o Metastable form

§  Less stable form  - Highest energy state - Lowest m.pt.

§  Higher aq solubility

§  Better absorption and Bioavailability

o E.g The vitamin riboflavin exists in several polymorphic forms, and these have a 20-fold range in aqueous solubility.

o Polymorphs that have no crystal structure, or amorphic forms, have different physical properties from the crystalline forms.

o Absorption of many orally administered drugs is controlled by dissolution rate.

o Amorphous forms generally dissolve faster than crystalline forms because no energy is needed to break up the crystal lattice. For this reason, the amorphous form is often preferred over the crystalline form and several drugs, including hydrocortisone and prednisolone, are marketed in the amorphic form. E.g. novobiocin

o Amorphous form

§  More soluble

§  Rapidly dissolving

§  Readily absorbed

o Crystalline form

§  Less soluble

§  Slower dissolving

§  Not absorbed to significant extent

4.      Solvates/hydrates:

o During their preparation, drug crystals may incorporate one or more solvent molecules to form solvates.

o The most common solvate is water. If water molecules are already present in a crystal structure, the tendency of the crystal to attract additional water to initiate the dissolution process is reduced, and solvated (hydrated) crystals tend to dissolve more slowly than anhydrous forms.

o Significant differences have been reported in the dissolution rate of hydrated and anhydrous forms of ampicillin, caffeine, theophylline, glutethimide, and mercaptopurine.

o The clinical significance of these differences has not been examined but is likely to be slight.

o Solvates have greater solubility than their nonsolvates.e.g. chloroform solvates of Griseofulvin, n-pentanol solvate of fludrocortisone.

5.      Salt form of drug:

o At given pH, the solubility of drug, whether acidic/basic or its salt, is a constant.

o While considering the salt form of drug, pH of the diffusion layer is imp not the pH of the bulk of the solution.

o E.g. of salt of weak acid. ---Which increases the pH of the diffusion layer, which promotes the solubility and dissolution of a weak acid and absorption is bound to be rapid.

o Reverse in the case of salts of weak bases, it lowers the pH of diffusion layer and the promoted the absorption of basic drugs.

o Other approach to enhance the dissolution and absorption rate of certain drugs is by formation of in – situ salt formation i.e. increasing in pH of microenvironment of drug by incorporating buffer agent.e.g. aspirin, penicillin

But sometimes more soluble salt form of drug may result in poor absorption.e.g. sodium salt of phenobarbitone and phenobarbitone, tablet of salt of phenobarbitone swelled, it did not get disintegrate thus dissolved slowly and results in poor absorption.

6.      Ionization state:

o Unionized state is imp for passive diffusion through membrane so imp for absorption.

o Ionized state is imp for solubility.

7.      Drug pKa  & lipophilicity  & GI pH --- pH partition hypothesis:

o pH – partition theory states that for drug compounds of molecular weight more than 100, which are primarily transported across the biomembrane by passive diffusion, the process of absorption is governed by

§  pKa of drug

§  The lipid solubility of the unionized drug

§  pH at the absorption site.

o pKa of drug: Amount of drug that exist in unionized form and in ionized form is a function of pKa of drug & pH of the fluid at the absorption site and it can be determined by Henderson-hesselbach equation:

o Lipophilicity and drug absorption:

§  Ideally for optimum absorption, a drug should have sufficient aq solubility to dissolve in fluids at absorption site and lipid solubility (Ko/w) high enough to facilitate the partitioning of the rug in the lipoidal biomembrane i.e. drug should have perfect HLB for optimum Bioavailability.

§  And      Ko/w = Distribution of drug in organic phase (octanol) / Distribution of drug in aq phase

§  As Ko/w i.e. lipid solubility i.e. partition coefficient increases percentage drug absorbed increases.

C.    Formulation Factors:

1.      Disintegration time:

o Rapid disintegration is important to have a rapid absorption so lower D.T is required.

o Now D.T of tablet is directly proportional to

§  amount of binder

§  Compression force.

o And one thing should be remembered that in vitro disintegration test gives no means of a guarantee of drugs B.A. because if the disintegrated drug particles do not dissolve then absorption is not possible.

2.      Manufacturing variables:

o Method of granulation

§  Wet granulation yields a tablet that dissolves faster than those made by other granulating methods. But wet granulation has several limitations like formation of Crystal Bridge or chemical degradation.

§  Other superior recent method named APOC (agglomerative phase of communition) that involves grinding of drug till spontaneous agglomeration and granules are prepared with higher surface area. So tablet made up of this granules have higher dissolution rate.

o Compression force:

§  Higher compression force yields a tablet with greater hardness and reduced wettability & hence have a long D.T. but on other hand higher compression force cause crushing of drug particles into smaller ones with higher effective surface area which in decrease in D.T.

§  So effect of compression force should be thoroughly studied on each formulation.

3.      Nature and type of dosage form:

o Drug formulations are designed to provide an attractive, stable, and convenient method to use products. Conventional dosage forms may be broadly characterized in order of decreasing dissolution rate as solutions, solid solutions, suspensions, capsules and tablets, coated capsules and tablets, and controlled release formulations.

o Solutions

§  Aqueous solutions, syrups, elixirs, and emulsions do not present a dissolution problem and generally result in fast and often complete absorption as compared to solid dosage forms. Due to their generally good systemic availability, solutions are frequently used as bioavailability standards against which other dosage forms are compared.

o Solid solutions

§  The solid solution is a formulation in which drug is trapped as a solid solution or monomolecular dispersion in a water-soluble matrix. Although the solid solution is an attractive approach to increase drug absorption, only one drug, griseofulvin, is currently marketed in this form.

o Suspensions

§  A drug in a suspension is in solid form, but is finely divided and has a large surface area. Drug particles can diffuse readily between the stomach and small intestine so that absorption is relatively insensitive to stomach emptying rate.

§  Adjusting the dose to a patient‘s needs is easier with solutions and suspensions than with solid dosage forms. Liquid dosage forms, therefore, have several practical advantages besides simple dissolution rate.

§  However, they also have some disadvantages, including greater bulk, difficulty in handling, and perhaps reduced stability.

o Capsules and tablets

§  These formulations differ from each other in that material in capsules is less impacted than in compressed tablets. Once a capsule dissolves, the contents generally disperse quickly. The capsule material, although water soluble, can impede drug dissolution by interacting with the drug, but this is uncommon.

§  Tablets generally disintegrate in stages, first into granules and then into primary particles. As particle size decreases, dissolution rate increases due to of increased surface area.

§  Tablet disintegration was once considered a sufficient criterion to predict in vivo absorption. 

o As a general rule, the bio-availability of a drug from various dosage forms decrease in the following order: Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated Tablets> Enteric coateds Tablets > Sustained Release Products.

4.      Pharmaceutical ingredients/Excipients:

o More the no. of excepients in dosage form, more complex it is & greater the potential for absorption and Bioavailability problems.

o Changing an excipient from calcium sulfate to lactose and increasing the proportion of magnesium silicate, increases the activity of oral phenytoin. 

o Systemic availability of thiamine and riboflavin is reduced by the presence of Fuller‘s earth.

o Absorption of tetracycline from capsules is reduced by calcium phosphate due to complexation.

o Most of these types of interactions were reported some time ago and are unlikely to occur in the current environment of rigorous testing of new dosage forms and formulations.

o Vehicle

§  Rate of absorption – depends on its miscibility with biological fluid.

§  Miscible vehicles (aq or water miscible vehicle) –rapid absorption e.g. propylene glycol.

§  Immiscible vehicles - absorption –depends on its partitioning from oil phase to aq body fluid.

o Diluents

§  Hydrophilic diluents-form the hydrophilic coat around hydrophobic drug particles – thus promotes dissolution and absorption of poorly soluble hydrophobic drug.

o Binders & granulating agent

§  Hydrophilic binders

§  imparts hydrophilic properties to granule surface

§  better dissolution of poorly wettable drug. e.g. starch, gelatin, PVP.

§  More amount of binder – increases hardness of tablet – decrease dissolution & disintegration rate.

o Disintegrants

§  Mostly hydrophilic in nature.

§  Decrease in amount of disintegrants – significantly lowers B.A.

o Lubricants

§  Commonly hydrophobic in nature – therefore inhibits penetration of water into tablet and thus dissolution and disintegration.

o Suspending agents/viscosity agent

§  Stabilized the solid drug particles and thus affect drug absorption.

§  Macromolecular gum forms unabsorbable complex with drug e.g. Na CMC.

§  Viscosity imparters – act as a mechanical barrier to diffusion of drug from its dosage form and retard GI transit of drug.

o Surfactants

§  May enhance or retards drug absorption by interacting with drug or membrane or both.

§  Surfactants have been considered as absorption enhancers, again mostly in animals. Polyoxyethylene ethers have been shown to enhance gastric or rectal absorption of lincomycin,penicillin, cephalosporins, and fosfomycin in rats and rabbits.

§  However, in humans, oral polyoxyethylene-20-oleyl ether resulted in poor and variable insulin absorption.

§  In general, unionic surfactants have little effect on membrane structure but cationic surfactants have been associated with reversible cell loss and loss of goblet cells.

§  Physiologic surfactants – bile salts – promotes absorption – e.g. Griseofulvin, steroids.

§  It may decrease absorption when it forms the unabsorbable complex with drug above CMC.

o Bile salts

§  Bile contains conjugates of cholic acid and chenodeoxycholic acid, which emulsify dietary fat, facilitate lipolysis, and transport lipid molecules through the unstirred layer of the intestinal mucosa by micellar solubilization. The ability of bile salts to promote lipid absorption has prompted their investigation as absorption enhancers for drugs, with modest success.

§  Absorption of insulin can be increased by bile salts, both in experimental animals and in humans.

o Colourants

§  Even a low concentration of water soluble dye can have an inhibitory effect on dissolution rate of several crystalline drugs.

§  The dye molecules get absorbed onto the crystal faces and inhibit the drug dissolution. For example: Brilliant blue retards dissolution of sulfathiazole.

5.      Product age and storage conditions

o Product aging and improper storage conditions adversely affect B.A.

o E.g. –precipitation of drug in solution Change in particle size of suspension & Hardening of tablet which decrease rate of drug dissolution & absorption.