Bioavailability Enhancement Through Enhancement of Drug Solubility or Dissolution Rate

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Chapter: Biopharmaceutics and Pharmacokinetics : Bioavailability and Bioequivalence

Bioavailability Enhancement Through Enhancement of Drug Solubility or Dissolution Rate


There are several ways by which drug solubility or the dissolution rate can be enhanced.

Some of the widely used methods are discussed briefly.

1. Micronization: The process involves reducing the size of the solid drug particles to 1 to 10 microns commonly by spray drying or by use of air attrition methods (fluid energy or jet mill). The process is also called as micro-milling. Examples of drugs whose bioavailability have been increased by micronization include griseofulvin and several steroidal and sulpha drugs.

2. Nanonisation: It‘s a process whereby the drug powder is converted to nanocrystals of sizes 200 - 600 nm, e.g. amphotericin B. The main production technologies currently in use to produce drug nanocrystals yield as a product a dispersion of drug nanocrystals in a liquid, typically water (called nanosuspension). There are three basic technologies currently in use to prepare nanoparticles:

i. Pearl milling

ii. Homogenisation in water (wet milling as in a colloid mill)

iii. Homogenisation in non-aqueous media or in water with water-miscible liquids.

3. Supercritical Fluid Recrystallization: Another novel nanosizing and solubilisation technology whose application has increased in recent years is particle size reduction via supercritical fluid (SCF) processes. Supercritical fluids (e.g. carbon dioxide) are fluids whose temperature and pressure are greater than its critical temperature (Tc) and critical pressure (Tp), allowing it to assume the properties of both a liquid and a gas. At near-critical temperatures, SCFs are high compressible, allowing moderate changes in pressure to greatly alter the density and mass transport characteristics of a fluid that largely determine its solvent power. Once the drug particles are solubilised within SCF, they may be recrystallised at greatly reduced particle sizes.

4. Use of Surfactants: Surfactants are very useful as absorption enhancers and enhance both dissolution rate as well as permeability of drug. They enhance dissolution rate primarily by promoting wetting and penetration of dissolution fluid into the solid drug particles. They are generally used in concentration below their critical micelle concentration (CMC) values since above CMC, the drug entrapped in the micelle structure fails to partition in the dissolution fluid. Nonionic surfactants like polysorbates are widely used. Examples of drugs whose bioavailability have been increased by use of surfactants in the formulation include steroids like spironolactone.

5. Use of Salt Forms: Salts have improved solubility and dissolution characteristics in comparison to the original drug. It is generally accepted that a minimum difference of 3 units between the pKa value of the group and that of its counterion is required to form stable salts. Alkali metal salts of acidic drugs like penicillins and strong acid salts of basic drugs like atropine are more water-soluble than the parent drug. Factors that influence salt selection are physical and chemical properties of the salt, safety of counterion, therapeutic indications and route of administration.

Salt formation does have its limitations

·           It is not feasible to form salts of neutral compounds.

·           It may be difficult to form salts of very weak bases or acids.

·           The salt may be hygroscopic, exhibit polymorphism or has poor processing characteristics.

·           Conversion of salt to free acid or base form of the drug on surface of solid dosage form that prevents or retards drug release.

·           Precipitation of unionised drug in the GI milieu that has poor solubility.

6. Use of Precipitation Inhibitors: A significant increase in free drug concentration above equilibrium solubility results in supersaturation, which can lead to drug precipitation or crystallization. This can be prevented by use of inert polymers such HPMC, PVP, PVA, PEG, etc. which act by one or more of the following mechanisms -

·            Increase the viscosity of crystallization medium thereby reducing the crystallization rate of drugs.

·            Provide a steric barrier to drug molecules and inhibit crystallization through specific intermolecular interactions on growing crystal surfaces.

·            Adsorb onto faces of host crystals, reduce the crystal growth rate of the host and produce smaller crystals.

7. Alteration of pH of the Drug Microenvironment: This can be achieved in two ways—in situ salt formation, and addition of buffers to the formulation e.g. buffered aspirin tablets.

8. Use of Amorphs, Anhydrates, Solvates and Metastable Polymorphs: Depending upon the internal structure of the solid drug, selection of proper form of drug with greater solubility is important. In general, amorphs are more soluble than metastable polymorphs, anhydrates are more soluble than hydrates and solvates are more soluble than non-solvates.

9. Solvent Deposition: In this method, the poorly aqueous soluble drug such as nifedipine is dissolved in an organic solvent like alcohol and deposited on an inert, hydrophilic, solid matrix such as starch or microcrystalline cellulose by evaporation of solvent.

10. Precipitation: In this method, the poorly aqueous soluble drug such as cyclosporine is dissolved in a suitable organic solvent followed by its rapid mixing with a non-solvent to effect precipitation of drug in nanosize particles. The product so prepared is also called as hydrosol.

11. Selective Adsorption on Insoluble Carriers: A highly active adsorbent such as the inorganic clays like bentonite can enhance the dissolution rate of poorly water-soluble drugs such as griseofulvin, indomethacin and prednisone by maintaining the concentration gradient at its maximum. The two reasons suggested for the rapid release of drugs from the surface of clays are—the weak physical bonding between the adsorbate and the adsorbent, and hydration and swelling of the clay in the aqueous media.

12. Solid Solutions: The three means by which the particle size of a drug can be reduced to submicron level are—

·            Use of solid solutions,

·            Use of eutectic mixtures, and

·            Use of solid dispersions.

In all these cases, the solute is frequently a poorly water-soluble drug acting as the guest and the solvent is a highly water-soluble compound or polymer acting as a host or carrier.

A solid solution is a binary system comprising of a solid solute molecularly dispersed in a solid solvent. Since the two components crystallize together in a homogeneous one phase system, solid solutions are also called as molecular dispersions or mixed crystals. Because of reduction in particle size to the molecular level, solid solutions show greater aqueous solubility and faster dissolution than eutectics and solid dispersions. They are generally prepared by fusion method whereby a physical mixture of solute and solvent are melted together followed by rapid solidification. Such systems, prepared by fusion, are often called as melts e.g. griseofulvin-succinic acid (Fig. 11.5). The griseofulvin from such solid solution dissolves 6 to 7 times faster than pure griseofulvin.

Fig. 11.5 Binary phase diagram for continuous solid solution of A and B. TA and TB are melting points of pure A and pure B respectively.

If the diameter of solute molecules is less than 60% of diameter of solvent molecules or its volume less than 20% of volume of solvent molecule, the solute molecule can be accommodated within the intermolecular spaces of solvent molecules e.g. digitoxin-PEG 6000 solid solution. Such systems show faster dissolution. When the resultant solid solution is a homogeneous transparent and brittle system, it is called as glass solution. Carriers that form glassy structure are citric acid, urea, PVP and PEG and sugars such as dextrose, sucrose and galactose.

Solid solutions can be classified on two basis –

A. Miscibility between the drug and the carrier on this basis the solid solutions are divided into two categories –

1. Continuous solid solution is the one in which both the drug and the carrier are miscible in all proportions. Such a solid solution is not reported in pharmaceutical literature.

2. Discontinuous solid solution is the one where solubility of each of the component in the other is limited (see fig. 11.5).

B. Distribution of drug in carrier structure on this basis the solid solutions are divided into two categories –

1. Substitutional crystalline solid solution is the one in which the drug molecules substitute for the carrier molecules in its crystal lattice. This happens when the drug and carrier molecules are almost of same size.

2. Interstitial crystalline solid solution is the one in which the drug molecules occupy the interstitial spaces in the crystal lattice of carrier molecules. This happens when the size of drug molecule is 40% or less than the size of carrier molecules (fig. 11.6).

The two mechanisms suggested for enhanced solubility and rapid dissolution of molecular dispersions are:

·           When the binary mixture is exposed to water, the soluble carrier dissolves rapidly leaving the insoluble drug in a state of microcrystalline dispersion of very fine particles, and

·           When the solid solution, which is said to be in a state of randomly arranged solute and solvent molecules in the crystal lattice, is exposed to the dissolution fluid, the soluble carrier dissolves rapidly leaving the insoluble drug stranded at almost molecular level.

Fig. 11.7 shows a comparison between the dissolution rates of different forms of griseofulvin.

Fig. 11.7 Dissolution rates of griseofulvin as coarse particles, as micronized particles and as eutectic and solid solution with succinic acid.

13. Eutectic Mixtures: These systems are also prepared by fusion method. Eutectic melts differ from solid solutions in that the fused melt of solute-solvent show complete miscibility but negligible solid-solid solubility i.e. such systems are basically intimately blended physical mixture of two crystalline components. A phase diagram of two-component system is shown in Fig. 11.8. When the eutectic mixture is exposed to water, the soluble carrier dissolves leaving the drug in a microcrystalline state which solubilises rapidly.

Fig. 11.8 Simple binary phase diagram showing eutectic point E. The eutectic composition at point E of substances A and B represents the one having lowest melting point.

Examples of eutectics include paracetamol-urea, griseofulvin-urea, griseofulvin-succinic acid, etc. Solid solutions and eutectics, which are basically melts, are easy to prepare and economical with no solvents involved. The method, however, cannot be applied to:

·            Drugs which fail to crystallize from the mixed melt.

·            Drugs which are thermolabile.

·            Carriers such as succinic acid that decompose at their melting point. The eutectic product is often tacky, intractable or irregular crystal.

14. Solid Dispersions: These are generally prepared by solvent or co-precipitation method whereby both the guest solute and the solid carrier solvent are dissolved in a common volatile liquid solvent such as alcohol. The liquid solvent is removed by evaporation under reduced pressure or by freeze-drying which results in amorphous precipitation of guest in a crystalline carrier. Thus, the basic difference between solid dispersions and solid solutions/eutectics is that the drug is precipitated out in an amorphous form in the former as opposed to crystalline form in the latter; e.g. amorphous sulphathiazole in crystalline urea. Such dispersions are often called as co-evaporates or co-precipitates. The method is suitable for thermolabile substances but has a number of disadvantages like higher cost of processing, use of large quantities of solvent, difficulty in complete removal of solvent, etc. The carriers used are same as for eutectics or solid solutions. With glassy materials, the dispersions formed are called as glass dispersions or glass suspensions. Fig. 11.9 shows comparative dissolution rates of griseofulvin from PVP dispersions. Other polymers such as PEG and HPMC are also employed to prepare solid dispersions of poorly water-soluble drugs such as nifedipine and itraconazole.

Fig. 11.9 Dissolution rate enhancement of griseofulvin by solid dispersion technique.

Preparation of solid dispersions also presents several limitations

·            Since the carrier is hydrophilic and the drug is hydrophobic, it is difficult to find a common solvent to dissolve both components.

·            The product is often soft, waxy and possesses poor compressibility and flowability.

·            Physical instability of the solid dispersion.

·            Difficulty in preparation of a reproducible product.

15. Molecular Encapsulation with Cyclodextrins: The beta- and gamma-cyclodextrins and several of their derivatives are unique in having the ability to form molecular inclusion complexes with hydrophobic drugs having poor aqueous solubility. These bucket-shaped oligosaccharides produced from starch are versatile in having a hydrophobic cavity of size suitable enough to accommodate the lipophilic drugs as guests; the outside of the host molecule is relatively hydrophilic (Fig. 11.10). Thus, the molecularly encapsulated drug has greatly improved aqueous solubility and dissolution rate. There are several examples of drugs with improved bioavailability due to such a phenomenon — thiazide diuretics, barbiturates, benzodiazepines and a number of NSAIDs.

Fig. 11.10 Functional and structural feature of a cyclodextrin molecule showing an encapsulated drug.

16. Spherical Crystallization: add some text

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