METHODS OF ENHANCEMENT OF BIOAVAILABILITY

Class Solubili Perme Absor Examples ty ability ption

High

High

Well

Diltiazem Propranolol Metaprolol

II

Low

High

Variab Nifedipine le Carbamazepine Naproxen Variab Insulin le Metformin Poor Taxol Chlorthiazide

III

High

Low

IV

Low

Low

CLASS V DRUGS:

1. 2. 3.

1.

2.
3. 4.

Includes drugs whose absorption is limited due to its poor stability due to: Gastric instability Complexation in GI lumen First Pass Metabolism. Approaches to overcome these problems are: Prodrug Approach Enteric Coating Enzyme Inhibition Lipid Technologies

CONCEPTUAL APPROACHES IN OVERCOMING BIOAVAILABILITY PROBLEMS:

1.

2. 3. 4.

Pharmaceutical Approach: Enhancement of drug solubility or dissolution rate. Enhancement of drug permeability. Enhancement of drug stability Enhancement of gastrointestinal retention. Pharmacokinetic Approach Biological Approach

METHODS OF ENHANCING DRUG SOLUBILITY TO ENHANCE BIOAVAILABILITY:

Micronization Nanonization Super Critical Fluid Recrystallization Spray freezing into liquid Evaporative precipitation into aqueous solution Use of Surfactants Use Of Salt Forms Use of precipitation inhibitors

Alteration of pH of the drug microenvironment. Use of amorphs, Anhydrates, Solvates, Metastable Polymorphs. Solvent Deposition Precipitation Selective adsorption on insoluble carriers. Solid Solutions Eutectic Mixture Solid Dispersions Molecular encapsulation with Cyclodextrins.

MICRONIZATION:

Reducing size of solid drug particle to 1 to 10 microns by spray drying or air attrition methods(jet or fluid energy mill). Eg: Griseofulvin Steroidal Drugs Sulpha Drugs

NANONIZATION:

Drug powder is converted to nanocrystals of sizes 200-600 nm in water(Nanosuspension). Basic technologies to prepare nanoparticles: a. Pearl Milling b. Homogenization in Water(colloid mill). c. Homogenization in nonaqueous media or in water with water miscible liquids. Eg: Amphotericin B.

SUPER CRITICAL FLUID RECRYSTALLISATION:

Fluids whose temperature and pressure are greater than its critical temperature and critical pressure allowing it to assume properties of liquid and gas. Drug particles are solubilized in SCF and recrystallised to at greatly reduced particle sizes to nano level.

SPRAY FREEZING INTO LIQUID:

Aqueous ,organic, aqueous organic cosolvent solution, organic aqueous suspension or emulsion containing drug and pharmaceutical excipients are

Directly atomized into a compressed gas or Cryogenic liquid.

Lyophillized to obtain dry free flowing powder

EVAPORATIVE PRECEPITATION INTO AQUEOUS SOLUTION:

Dissolve drug(Lipid soluble) in a low boiling point liquid. Solution is passed through a tube heated under pressure to a temperature above solvents boiling point. Sprayed through fine atomizing needle into a heated aqueous solution.

Surfactant added to organic solution and aqueous solution to optimize particle formation. Surfactant migrates to the interface covering the particle inhibiting crystallization

USE OF SURFACTANTS:

Promote wetting and penetration of dissolution fluid into the solid drug particles. Used below Critical Micellar Concentration. Nonionic Surfactants like polysorbates are widely used Eg: Spironolactone.

USE OF SALT FORMS:

1. 2. 3. 4. 5.

Alkali metal salts of acidic drugs (Pencillins) and acid salts of basic drugs (atropine) are prepared. Limitations: Not feasible to form salts of neutral compounds. Difficult to form salts of very weak bases or acids. Conversion of salt to free acid or base form of the drug. Precipitation of unionized drug Salt may be hygroscopic, or exhibit polymorphism.

USE OF PRECIPITATION INHIBITORS:

Achieved by use of PVP,PVA,HPMC, PEG. They reduce precipitation by one of the following mechanism

a.

Increase in viscosity and there by decrease in crystallization.

Specific intermolecular interactions acting as a barrier to growing crystal structures. Adsorb onto faces of host crystals.

b.

c.

ALTERATION OF pH OF DRUG MICRO ENVIRONMENT:

Achieved by in situ salt formation Addition of buffers Eg: Buffered aspirin tablets

USE OF AMORPHS, ANHYDRATES, POLYMORPHS:

Selection of the suitable form depends on internal structure of the solid.
Order of Solubility: Amorphs>Meta stable polymorphs Anhydrates> Hydrates Solvates> NonSolvates.

SOLVENT DEPOSITION:

Poorly water soluble drugs dissolved in suitable organic solvent This is deposited on inert hydrophillic matrix by solvent evaporation.

PRECIPITATION:

Poorly water soluble drug is dissolved in organic solvent. This is rapidly mixed with non solvent to effect precipitation of drug nano size particles. This product is known as hydrosol.

SELECTIVE ADSORPTION ON INSOLUBLE CARRIERS:

A highly active adsobent such as inorganic clays like Bentonite can enhance the dissolution rate of poorly water soluble drugs like griseofulvin by maintaining Conc gradient

The reason for rapid release is a. Weak chemical bonding between adsorbent and adsorbate b. Hydration and swelling of clay in aqueous medium.

SOLID SOLUTIONS:

It is a binary system comprising of solid solute dispersed in a solid solvent. Also known as molecular dispersions or mixed crystals. In this method physical mixture of solute and solvent are melted together followed by rapid solidification. Ex: Griseofulvin- Succinic acid. Glass Solution: The resultant solution is homogenous, transparent and brittle. Carriers used are Citric acid, Urea,PVP,Dextrose,Sucrose.

CLASSIFICATION OF SOLID SOLUTIONS:

Solid Solutions Miscibility between drug and carrier Continuous and discontinuous solid solutions Distribution of Drug in carrier System. Substitutional And Interstitial Crystalline Solid solutions.

MECHANISM:

Soluble carrier dissolves rapidly when exposed to water and leaves the insoluble drug in state of microcrystalline dispersion.

EUTECTIC MIXTURES:

Similar to solid solutions but the fused melt of solute solvent show complete miscibility but negligible solid-solid solubility. When the mixture is exposed to water, soluble carrier dissolves leaving the drug in a microcrystalline state Ex: Paracetamol-Urea Griseofulvin- Succinic Acid

The method cannot be applied to: Drugs which fail to crystallize from the mixed melt. Drugs which are thermo labile Carriers such as succinic acid that decompose at their melting point.

1.

2. 3.

SOLID DISPERSIONS:

Drug is precipitated in an amorphous form. The dispersions are called as coprecipitates.

 1. 1. 2. 3.

Advantages: Suitable for thermolabile substances Disadvantages: Higher cost of processing Use of large quantities of solvent Difficulty in complete removal of solvent.

LIMITATIONS:

Since carrier is hydrophilic and drug is hydrophobic, it is difficult to find common solvent to dissolve both components Product possess poor compressibility and flow ability. Physical instability of solid dispersion. Difficulty in preparation of reproducible product.

MOLECULAR ENCAPSULATION WITH CYCLODEXTRINS:

Beta and gamma cyclo dextrins and their derivatives have ability to form inclusion complexes with hydrophobic drugs. They are bucket shaped oligosaccharides produced from starch. They have hydrophobic cavity of size suitable to accommodate the guest molecule. The outside of the host molecule is relatively hydrophilic. Thus the molecularly encapsulated drug has greatly improved aqueous solubility and dissolution rate.

Ex: Thiazide diuretics, Barbiturates, Benzodiazepines.