Poorly Water Soluble Drugs Biology Essay

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Use of surfactants: Surface active agents enhance dissolution rate by promoting wetting and penetration of dissolution fluid into solid drug particles.

Example: Steroids like spironolactone.

Use of salt forms: Salts have improved solubility and dissolution characteristics in comparision to the original drug.

Example: Salt of basic drug like atropine is soluble than parent drug.

Alteration of pH of the Drug Microenvironment: It is achieved in two ways insitu salt formation and addition of buffers to the formulation.

Example: Buffered Aspirin tablets.

Use of metastable polymorphs: Metastable polymorphs are more soluble than the stable polymorphs of drug that exhibits polymorphism.

Example: Chloramphenicol palmitate.

Solute-solvent complexation: Solvates of drugs with organic solvents generally have higher aqueous solubility than the original drug.

Example: 1:2 griseofulvin benzene solvate.

Selective adsorption on insoluble carriers: A highly active adsorbent can enhance the dissolution rate.

Example: Bentonite.

Solid solution

Use of solid solution: Solid solution is a binary system comprising of solid solute molecularly dispersed in a solid solvent.

Use of eutectic mixtures: These systems are also prepared by fusion method. It is slightly different from solid solution in that fused melt of solute-solvent show complete miscibility but negligible solid-solid solubility.

Use of solid dispersions: These are generally prepared by solvent or co-precipitation method where both guest solute and the solid carrier solvent are dissolved in common volatile liquid such as alcohol.

The liquid removed by evaporation under reduced pressure or by freezedrying which result in amorphous precipitation of guest in crystalline carrier.

Molecular encapsulation with cyclodextrins: The beta and gamma cyclodextrins and several of their derivatives are unique in having the ability to form molecular ivclusion with hydrophobic drugs having poor aqueous solubility. These cyclodextrin molecule are versatile in having hydrophobic activity of size suitable enough to accommodate hydrophilic drug as a guests; the outside of the host molecule is relatively hydrophilic. Thus, the molecularly encapsulated drug has greatly improved aqueous solubility and dissolution rate.

However, among them, the technique of "liquisolid compacts" is one of the most promising technique. Low cost, simple formulation technique and capability serve to be advantages of this technique.

Liquisolid Technique:

The poor dissolution rate of water insoluble drugs is still a substantial problem confronting the pharmaceutical industry. A great number of new and possibly, beneficial chemical entities do not reach the public merely because of inadequate dissolution release profile. Over the years, various solid dosage formulation techniques, to enhance the dissolution of poorly soluble substances, have been introduced with different degrees of success.

Classification of liquisolid systems:

Liquisolid systems which are prepared by liquisolid technique are classified as follows:

Classification based on the type of liquid medication contained. They are divided into three subgroups of liquisolid systems are:

Powdered drug solution.

Powdered drug suspensions.

Powdered liquid drugs.

The first two may be produced from the conversion of drug solutions or drug suspensions and the latter from the formulation of liquid drugs into liquisolid systems8.

Classification based on the formulation technique used liquisolid system is divided into two categories namely,

Liquisolid Microsystems.

Liquisolid compacts.

Liquisolid Microsystems:

They are based on a new concept which employs similar methodology combined with the inclusion of an additive, e.g., Poly vinyl pyrrolidone (PVP), in the liquid medication which is incorporated into the carrier and the coating materials to produce an acceptably flowing admixture for encapsulation. The advantage stemming for this new technique is that the resulting unit size of liquisolid Microsystems may be as five times less than that of liquisolid compacts.

Liquisolid compacts:

According to Spireas et al., the term "liquisolid compacts " refers to preparation of immediate (or) sustained release tablets (or) capsules using "liquisolid systems" combined with the inclusion of appropriate excipients required for tabletting (or) encapsulation, such as disintegrant for immediate release, binders for sustained release action.

Ideal characteristics of components used in liquisolid compact formulation:

Drug - Poorly soluble, insoluble, liquid or lipophilic.

Non-Volatile solvent- Water miscible.

Carrier- Coarser, granular, good compatibility.

Coating material- High surface area, good adsorptive properties.

Need of liquisolid compact technique is mainly for class of drugs which are:

Poorly water soluble, insoluble, liquid drugs (or) lipophilic drugs.

Poorly flowable powder admixtures.

To aid direct compression.

To improve efficiency of tablet manufacturing.

Principle involved in formulation of liquisolid compacts:

Inert, preferably water-miscible organic solvent systems with high boiling point such as propylene glycol, liquid polyethylene glycols, or glycerine are best suitable as liquid vehicles. Once the carrier is saturated with liquid, a liquid layer is formed on the particle surface which is instantly adsorbed by the fine coating particles. Thus, an apparently dry, free flowing, and compressible powder is obtained. Usually, microcrystalline cellulose is used as carrier material and amorphous silicon dioxide (colloidal silica) as coating material. Various excipients such as lubricants and disintegrants may be added to the liquisolid system to produce liquisolid compacts (Fig. 1).

Solid Drug

Carrier material

Drug - Non volatile solvent mixture

Non-volatile solvent system

Wet particles

By addition of adjuvants

Simple admixture

Final formulation


Coating material incorporation

Tabletting (or) Encapsulation

Fig. 1: Depiction of liquisolid compacts.

Liquisolid compacts of poorly soluble drugs containing a drug solution or drug suspension in a solubilizing vehicle show enhanced drug release due to an increased surface area of drug available for release, an increased aqueous solubility of the drug, and an improved wettability of the drug particles9-14 thereby enhancing the dissolution properties of poorly water soluble drugs.

Advantages of Liquisolid tablets15-19:

Liquisolid tablets have many advantages like;

Number of water-insoluble solid drugs can be formulated into liquisolid systems.

Can be applied to formulate liquid medications such as oily liquid drugs.

Better availability of an orally administered water insoluble drug.

Lower production cost than that of soft gelatin capsules.

Production of liquisolid systems is similar to that of conventional tablets.

Can be used for formulation of liquid oily drugs

Exhibits enhanced in-vitro and in-vivo drug release as compared to commercial counterparts, including soft gelatin capsule preparations.

Can be used in controlled drug delivery.

Drug release can be modified using suitable formulation ingredients.

Drug can be molecularly dispersed in the formulation.

Capability of industrial production is also possible.

Limitations of liquisolid tablets15-17:

Low drug loading capacities.

Requirement of high solubility of drug in non-volatile liquid vehicles.

Applications of liquisolid techniques15-19 :

Rapid release rates are obtained in liquisolid formulations.

These can be efficiently used for water insoluble solid drugs or liquid lipophilic drugs.

Sustained release of drugs which are water soluble drugs such as propranolol hydrochloride has been obtained by the using this technique.

Solubility and dissolution enhancement.

Designing of controlled release tablets.

Application in probiotics.

Anti-convulsant drug (Clonazepam):

Status epileptics is a neurological disorder, which requires quick management of seizures in order to avoid risk of permanent brain damage. Clonazepam, a benzodiazepine derivative is used widely in the treatment of status epileptics. Clonazepam is preferred over the other benzodiazepines due to its longer duration of action (24h)20.

Clonazepam, the drug of choice in suppression of myoclonic seizures, acts by increasing the effectiveness of the inhibitory neurotransmitter, gamma amino butyric acid (GABA), within the central nervous system.

Presently, Clonazepam is available in tablet and injectable dosage forms(Revotril,Hoffmann,LaRoche,NJ,USAhttp://www.fda.gov/cder/foi/nda/index.htm)21. These formulations release clonazepam into the peripheral circulation resulting in limited drug uptake across the blood-brain-barrier and in drug distribution to nontargeted sites22. Although intravenous administration provides rapid seizure suppression, the most convenient and commonly employed route of drug delivery has been by oral ingestion.

Clonazepam being poorly soluble in water its rate of oral absorption is often controlled by the dissolution rate in the gastrointestinal tract and by liquisolid technique the solubility and dissolution of clonazepam can be enhanced.

Table 1: List of drugs as liquisolid compacts


Drug Name

Polymers used