Solid Dispersion via Fusion Method for Improving Ivermectin Performance: A Critical Review

The most advantageous route of administration is undoubtedly the oral route. Oral drug delivery system is the simplest and easiest way of administering drugs, Because of the greater stability, smaller bulk, accurate dosage and easy production. Solid oral dosages forms have many advantages over other types of oral dosage forms. Therefore, most of the new chemical entities (NCE) under development inthese days are intended to be used as a solid dosage form that originate an effective and reproducible in-vivo plasma concentration after oral administration, but the fact is that some of that NCEs are poorly water soluble drugs, not well absorbed after oral administration and the oral delivery of drugs is frequently associated with low bioavailability, high intra and inter-subject variability, and a lack of dose proportionality Almost 60% of drug molecule available in market possesses either solubility or permeability related pharmacokinetic problems.

The most important and common problem associated with the oral dosage form is low aqueous solubility of drug not only in dissolution media but also in gastrointestinal fluid.  When a drug is administered orally in a solid dosage form such as tablet, it must be drug released from the dosage form and dissolved in the gastrointestinal fluids before it can be absorbed.

Drug absorption from the gastrointestinal (GI) tract can be limited by a variety  of factors with the most significant contributors being poor aqueous solubility or poor membrane permeability of the drug molecule. When delivering an active agent orally, it must first dissolve in gastric or intestinal fluids before it can then permeate the membranes of the GI tract to reach systemic circulation. Therefore, a drug with poor aqueous solubility will typically exhibit dissolution rate limited absorption, and a drug with poor membrane permeability will typically exhibit permeation rate limited absorption.

Poorly water soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration. Improvement in the extent and rate of dissolution is highly desirable for such compounds, as this can lead to an increased and more reproducible oral bioavailability and subsequently to clinically relevant dose reduction and more reliable therapy.

Biopharmaceutical Classification Systems (BCS):

Biopharmaceutical classification system was introduced in 1995; it is the scientific frame work for classifying drug substances based on their aqueous solubility and intestinal permeability as well as increasing impact on regulatory practices. These guidelines are provided by U.S. Food and Drug Administration (USFDA), World Health Organization (WHO) and European Medicines Agency (EMEA).The BCS was introduced as a method to identify situations that might allow in-vitro dissolution.

This lead to classification of drugs into four classes as follows,

Class 1: High solubility-High permeability.

Class 2: Low solubility-High permeability.

Class 3: High solubility-Low permeability.

Class 4: Low solubility-low permeability.

Solubility:

Solubility of a substance in a solvent at given temperature and pressure is the amount of substance that has passed into solution when equilibrium is attained between the solution and the undissolved substance and the solution is known as saturated solution. The substance that dissolved is known as solute and in which it dissolved or dispersed known as solvent. Solubility is generally expressed as the number of grams of solute in one liter of saturated solution.The process of solubility is depends on the bonding between the solute and solvent molecule. When an attraction of solute-solvent molecule is more than the solute-solute molecule, at that time solvent-solute bond formed and solubilization occur e.g., the sugar molecular solid, dissolves in water, the weak bonds between the individual sucrose molecules are broken, and molecules are release into solution and solubilize, it takes energy to break the molecules.

Mechanism of Solubility:

Solubility process is depends on the bonding between the solute and solvent Molecule. The bonds involves in solubilization is mainly dipole interaction, London Forces, hydrogen bonding, ionic bonding etc.

This happens when the positive end of a solvent molecule approaches the negative end of a solute molecule. The solute molecule is pulled into solution when the force overcomes the attractive force between the solute molecule and its neighbouring solute molecule. Ethyl alcohol and water are examples of polar substances that readily dissolve in each other.

Factors Affecting Solubility:

The solubility of one substance in another is determined by the balance of intermolecular forces between the solvent and solute and the entropy change that accompanies the solvation. Factor such as temperature and pressure will alter this balance.

• Temperature:

Generally, an increase in the temperature of the solution increases the solubility of a solid solute. Temperature significantly affect on the solubility of the drug molecule in solvent.

• Pressure:

In the solids and liquid solutes, there changes in pressure have practically no effect on solubility. For gaseous solutes, an increase in pressure increases solubility and a decrease in pressure decrease solubility. Henry’s law states that the solubility of a gas in a liquid is directly proportional to the partial pressure of that gas above the liquid, which may be written as,

p = kc (1)

Where, k is a temperature-dependent constant, p is the partial pressure (atm), and c is the concentration of the dissolved gas in the liquid (mol/L).21

• Molecular size:

Molecular size will affect the solubility. The larger the molecule or the higher its molecular weight the substance will be less soluble. Larger molecules are more difficult to surround with solvent molecules in order to solvate the substance. In case of organic compounds the amount of carbon "branching" will increase the solubility since more branching will reduce the size (or volume) of the molecule and make it easier to solvate the molecules with solvent. As the particle size reduces the surface area of the solute particle increases and the solute dissolves more rapidly.

• Particle Size:

The size of the solid particle influences the solubility because as a particle becomes smaller, the surface area to volume ratio increases. The larger surface area allows a greater interaction with the solvent. The effect of particle size on solubility can be described by,

Polarity:

Polarity of the solute and solvent molecules will affect the solubility. Generally non-polar solute molecules will dissolve in non-polar solvents and polar solute molecules will dissolve in polar solvents. The polar solute molecules have a positive and a negative end to the molecule. If the solvent molecule is also polar, then positive ends of solvent molecules will attract negative ends of solute molecules. This is a type of intermolecular force known as dipole-dipole interaction. All molecules also have a type of intermolecular force much weaker than the other forces called London Dispersion forces.

Polymorphism and related phenomenon:

Halebian and McCrone have defined polymorphism as a “solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of that compound in the solid state”.In general polymorphs of a given compound have different physicochemical properties, such as melting point, solubility and density. The polymorphism has importants in formulation, biopharmaceutical and chemical process implications. In addition to polymorphs, solvates (inclusion of the solvent of crystallization), hydrates (inclusion of water of crystallization) and amorphous form (where no long range order exists) may also exist. The energy required for a molecule of drug to escape from a crystal is much greater than required to escape from an amorphous powder. Therefore, the amorphous form of a compound is always more soluble than a corresponding crystal form.

Approaches to Enhancement the Solubility:

As solubility plays an important role in the oral bioavailability and therapeutic effectiveness of any drug substances there occurs a lots of work in the direction of oral bioavailability enhancement of poorly soluble drugs. Initially salt formation, particle size reduction and solubilization approaches are being widely used for solving bioavailability related problems. There are certain practical limitations of these techniques. Even when salts can be prepared, an increased dissolution rate in the gastrointestinal tract may not be achieved in many cases because of the reconversion of salts into aggregates of their respective acid or base forms. Also the solubilization of drugs in organic solvents or in aqueous media by the use of surface active agents & co-solvents leads to liquid formulation those are usually undesirable from the view point of patient’s acceptability & commercialization. The use of very fine powder in dosage form may also be problematic because of handling difficulties & poor wettability.

With the advancement of technology instead of using above mentioned conventional techniques, some novel techniques such as solid dispersion, micro and nanoemulsion are now a day’s being widely used. Detailed classification of various solubility enhancement techniques has been given below. Principally all the methods.

have been classified as following main headings.

1. Physical approach.

2. Chemical Approach.

3. Other method.

Further classification into each category depends on whether the techniques are conventional or of some novel origin. Detailed classification of various solubility enhancement techniques:

1. PHYSICAL MODIFICATIONS

Particle size reduction

• Micronization

• Nanosuspensions

• Sono-crystalisation

• Supercritical fluid process

Modification of the crystal habit

• Polymorphs

• Pseudopolymorphs

Drug dispersion in carriers

• Eutectic mixtures

• Solid dispersions

• Solid solutions

Complexation

• Use of complexing agents

Solubilization by surfactants:

• Microemulsions

• Self-microemulsifying drug delivery systems

2. CHEMICAL MODIFICATION:

• Soluble Prodrugs

• Salt Formation

3. OTHER METHODS

• Co-crystallisation

• Co-solvency

• Hydrotrophy

• Solvent deposition

• Selective adsorption on insoluble carrier

• Use of soluble prodrug

• Functional polymer technology

• Porous microparticle technology

• Nanotechnology approaches

Many approaches, such as salt formation, solubilization and particle size reduction have commonly been used to increase dissolution rate and thereby oral absorption and bioavailability of such drugs. However all the above mentioned methods are having some limitations like all poorly soluble drugs are not suitable for improving their solubility by salt formation. Use of co-solvents or surfactants to improve dissolution rate pose problems, such as patient compliance and commercialization. Also there are some novel techniques such as Conversion to nanoparticles, Spray drying technique, Microwave induced method, Self Emulsifying

Drug delivery systems (SEDDS), Nanosuspensions. But they have the limitations of laboratory level scaling and cost because the materials used in the formulations are of synthetic origin and are very costly.

Solid Dispersion:

Historical Background Solid Dispersion:

The effect of particle size of drugs on their dissolution rates and biological availability was reviewed comprehensively by Fincher30. For drugs whose GI absorption is rate limited by dissolution, reduction of the particle size generally increases the rate of absorption or total bioavailability. This commonly occurs for drugs with poor water solubility. For example, the therapeutic dose of Griseofulvin was reduced to 50% by micronization, and it also produced a more constant and reliable blood level.

Particle size reduction is usually achieved by (a) conventional trituration and grinding (b) ball milling; (c) fluid energy micronization; (d) controlled precipitation by change of solvents or temperature, application of ultrasonic waves, and spray drying; (e) administration of liquid solutions from which, upon dilution with gastric fluids, the dissolved drug may precipitate in very fine particles; and (f) administration of water soluble salts of poorly soluble compounds from which the parent, neutral forms may precipitate in ultrafine form in GI fluids.

Solid Dispersion Definition:

Chiou and Riegelman defined the term solid dispersion as “a dispersion involving the formation of eutectic mixtures of drugs with water soluble carriers by melting of their physical mixtures” The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly in amorphous particles (clusters) or in crystalline particles.The enhancements of oral bioavailability of such poorly water soluble drugs often show poor bioavailability because of low absorption. Drugs that undergo dissolution rate limited gastrointestinal absorption generally show improved dissolution and bio availability as a result of reduction in particle size. However, micronizing of drugs often leads to aggregation and agglomeration of particles, which results in poor wettability. Solid dispersions of poorly water soluble drugs with water soluble carriers have been reduced the incidence of these problems and enhanced solubility as well as dissolution rate of poorly water soluble drug.

In this technique a poorly soluble drug are dispersed in a highly soluble hydrophilic carrier (matrix), which enhances the solubility and dissolution of that poorly soluble drug candidate. Solid dispersion technique can yield eutectic (non molecular level mixing) or solid solution (molecular level mixing) product. Eutectic solid dispersion is homogeneous dispersion of crystalline or amorphous drug in crystalline or amorphous carrier and the solid solution form. The drug could be partially or completely soluble in the dispersing matrix. Presence of drug in microcrystalline state, improved the wettability and formation of high free energy amorphous of the drug during solid dispersion formation contributes towards enhanced drug solubility.

Classification of Solid Dispersion:

Following classification of solid dispersion on the basis of carrier used in solid dispersion,

• First generation solid dispersion.

• Second generation solid dispersion.

• Third generation of solid dispersion.

• First generation solid dispersions

The first description of solid dispersions was from Sekiguchi and Obi in 1996.Formulation of eutectic mixtures improves the rate of drug release and as well as, the bioavailability of poorly water soluble drugs.In the same decade, several solid dispersions were described using poorly water soluble drugs, such as Sulfathiazole and Chloramphenicol using Urea as high-water soluble carrier. These solid dispersions produced faster release and higher bioavailability than conventional formulations of the same drugs. The small particle size and the better wettability of the drug were the main reasons for the observed improvements in bioavailability.

Second generation solid dispersions

In the late sixties it was observed that solid dispersions, where the drug was maintained in the crystalline state, might not be as effective as the amorphous, because the former were more thermodynamically stable. Therefore, a second generation of solid dispersions appeared, containing amorphous carriers instead of crystalline. Indeed, the most common solid dispersions do not use crystalline carriers but amorphous. In the latter, the drugs are molecularly dispersed in an irregular form within an amorphous carrier, which are usually polymers. Polymeric carriers have been the most successful for solid dispersions, because they are able to originate amorphous solid dispersions. They are divided into fully synthetic polymers and natural product-based polymers. Fully synthetic polymers include povidone (PVP), polyethyleneglycols (PEG) and polymethacrylates. Natural product based polymers are mainly composed by cellulose derivatives, such as hydroxypropyl methylcellulose  (HPMC), ethyl cellulose or hydroxypropylcellulose or starch derivates, like cyclodextrins.

Amorphous solid dispersions can be classified according to the molecular interaction of drug and carriers in solid solutions, solid suspensions or a mixture of both. In amorphous solid solutions, drug and carrier are totally miscible and soluble, originating a homogeneous molecular interaction between them, in these systems, the drug and carrier interaction energy is extremely high, resulting in a really true solution. The use of polymers in the preparation of a true solid solution creates an amorphous product in which the crystalline drug is dissolved. This type of amorphous solid dispersion is homogeneous on a molecular level. Therefore, only one phase is present. Amorphous solid suspensions occur when the drug has limited carrier solubility or an extremely high melting point. Molecularly, the obtained dispersion does not have a homogeneous structure, but is composed of two phases. Small drug particles, when dispersed in polymeric carriers, are able to provide an amorphous final product.

When a drug is both dissolved and suspended in the carrier, a heterogeneous structure is obtained with mixed properties of amorphous solid solutions and amorphous solid suspensions. In second generation solid dispersions, the drug is in its supersaturated state because of forced solubilization in the carrier. These systems are able to reduce the drug particle size to nearly a molecular level, to solubilize or co-dissolve the drug by the water soluble carrier, to provide better wettability and dispersibility of the drug by the carrier material, and to produce amorphous forms of the drug and carriers. In these solid dispersions, the carrier dissolution (or mixtures of carriers) dictates the drug release profile.

Third generation solid dispersions

Recently it has been shown that the dissolution profile can be improved if the carrier has surface activity or self-emulsifying properties, hence third generation solid dispersion appeared. This third-generation solid dispersion contains a surfactant carrier, or a mixture of amorphous polymer. These third-generation solid dispersion are intended to achieve the highest degree of bioavailability for poorly soluble drug and to stabilize the solid dispersion, avoiding drug recrystallization. The use of surfactant such as Inulin, Inutec, Compritol-888 ATO, Gelucire 44/14 and Poloxamer-407 as carriers was shown to be effective in originating high polymorphic purity and enhanced in vivo bioavailability. The association of amorphous polymer and surfactant has also been reported. For instance, the dissolution rate and bioavailability of poor water soluble drug were improved after being dispersed in a mixture of PEG and polysorbate 80. The bioavailability of this solid dispersion was 10 fold higher compared to the dry blend of micronized drug. HPMC was also associated with poloxamer and polyoxyethylene hydrogenated castor oil to prepare an amorphous Felodipine solid dispersion. The inclusion of surfactants in the formulation containing a polymeric carrier may help to prevent precipitation and protect a fine crystalline precipitate from agglomeration into much larger hydrophobic particles.

Advantages of Solid Dispersion:

• Particles with reduced particle size:

Solid dispersions represent the last state on particle size reduction, and after carrier dissolution the drug is molecularly dispersed in the dissolution medium. Solid dispersions apply this principle to drug release by creating a mixture of a poorly water soluble drug and highly soluble carriers. Due to this a high surface area is formed resulting in an increased dissolution rate and improved bioavailability.

• Particles with improved wettability:

A strong contribution to the enhancement of drug solubility is related to the drug wettability improvement verified in solid dispersions. It was observed that even carriers without any surface activity, such as urea improved drug wettability. Carrierwith surface activity such as cholic acid and bile salts. When used can significantly increase the wettability property of drug. Moreover, carriers can influence the drug dissolution profile by direct dissolution or co-solvent effects.

• Particles with higher porosity:

Particles in solid dispersions have been found to have a higher degree of porosity. The increase in porosity also depends on the carrier properties for instance, solid dispersions containing linear polymers produce larger and more porous particles than those containing reticular polymers and, therefore, result in a higher dissolution rate. The increased porosity of solid dispersion particles also hastens the drug release profile.

• Drugs in amorphous state:

Poorly water soluble crystalline drugs, when in the amorphous state tend to have higher solubility. The enhancement of drug release can usually be achieved using the drug in its amorphous state, because no energy is required to break up the crystal lattice during the dissolution process. In solid dispersions, drugs are presented as supersaturated solutions after system dissolution, and it is speculated that, if drugs precipitate, it is as a metastable polymorphic form with higher solubility than the most stable crystal form. For drugs with low crystal energy (low melting temperature or heat of fusion), the amorphous composition is primarily dictated by the difference in melting temperature between drug and carrier. For drugs with high crystal energy, higher amorphous compositions can be obtained by choosing carriers, which exhibit specific interactions with them.

Disadvantages of Solid Dispersion:

• Poor stability is a major disadvantage of solid dispersion. The amorphous state of drug may undergo crystallization.

• Ageing may decrease the dissolution rate and there may be change in crystallinity.

• Due to thickness in some solid dispersion, it sometimes leads to handling problem.

Solid dispersion may be deteriorated in presence of moister and excessive temperature. The presence of moisture influences the crystallinity of drug.

• Some polymers used in solid dispersion are hygroscopic in nature and may absorb moisture, that can result in crystal growth or the amorphous form may get converted to crystalline state.

• Sometimes the metastable form of drug may change to stable form. So there may be decreased solubility and dissolution.

Pharmaceutical Application of Solid Dispersion:

The pharmaceutical applications of solid dispersions technique are numerous.

They may be employed,

• To enhance the absorption of drug.

• To obtain a homogeneous distribution of a small amount of drug in solid state.

• To stabilize unstable drugs and protect against decomposition by processes such as hydrolysis, oxidation, racemization, photo oxidation etc.

• To dispense liquid or gaseous compounds.

• To formulate a fast release priming dose in a sustained release dosage form.

• To formulate sustained release preparation of soluble drugs by dispersing the drug in poorly soluble or insoluble carrier.

• To reduce side effects:

(a) The binding ability of drugs to the erythrocyte membrane is decreased by making its inclusion complex,

(b) The damage to the stomach mucous membranes by certain non-steroidal anti-inflammatory drugs can be reduced by administration as an inclusion compound.

• To mask unpleasant taste and smell. The very unpleasant taste of anti-depressant famoxetine hindered the development of oral liquid formulations. The bitter taste was greatly suppressed when the solid complex of famoxetine was formulated as aqueous suspension.To convert liquid compounds into formulations. Liquid drugs can be manufactured as solid drug formulations such as powders, capsules or tablets e.g.,unsaturated Essential oils, Nitroglycerin, Benzaldehyde, Prostaglandin, Clofibrate etc.

 Mechanism of Bioavailability Enhancement:

The enhancement in dissolution rate because of solid dispersion formation, relative to pure drug varies from as high as 400 fold to less than two fold. The increase in dissolution rate can be attributed to myriad factors and it is very difficult to show experimentally that any one particular factor is more important than the other. Solid dispersions increase the dissolution rate of poorly water soluble drugs by one of the following mechanisms.

1. Reduction in particle size.

2. Improvement in wettability and dispersibility.

3. Changing crystalline form of drug to amorphous form.

4. Reduction in aggregation and agglomeration of drug particles.

Methodologies:

There are different methods used to formulation of the solid dispersion but, the core steps involved in the formation of solid dispersion between a drug and polymer are as follow.

1. Transforming drug and polymer from their solid state to fluid or fluid like state

through processes such as melting, dissolving in solvent, co-solvent or subliming.

2. Mixing the components in their fluid state.

3. Transforming the fluid mixture into solid phase through processes such as congealing, solvent removal, and condensation of sublimed mixture.

Basically, there are two methods of preparing solid dispersions, fusion and solvent processes. In case of thermolabile drugs or those with high melting points, a modified method is employed known as melting solvent method. The latter method is limited to drugs with low therapeutic doses, i.e. below 50 mg. However, for the preparation of solid dispersions, several methods have been reported in literature, which are described as below.

Methods of Preparation of Solid Dispersion:

Various methods used for preparation of solid dispersion system. These methods are given bellow.

1. Melting method.

2. Solvent evaporation method.

3. Melting solvent method (melt evaporation).

4. Melt extrusion methods.

5. Lyophillization techniques.

6. Melt agglomerations process.

7. Electrospinning.

8. Super critical fluid (SCF) technology.

1. Melting method:

The fusion method is sometimes referred to as the melt method, which is correct only when the starting materials are crystalline. Therefore, the more general term fusion method is preferred. The melting or fusion method was first proposed by Sekiguchi and obi5 to prepare fast release solid dispersion dosage form. The first solid dispersions created for pharmaceutical applications were prepared by the fusion method. The dispersion consisted of Sulfathiazole and Urea as a matrix, which was melted using a physical mixture at the eutectic composition, followed by a cooling step.

The melting or fusion method is the preparation of physical mixture of drug and water soluble carrier was heated directly until it melted. The melted mixture was then cooled and solidifies rapidly in an ice bath under vigorous stirring. Then the final solid mass was crushed, pulverized using a porcelain morter and pestal. The pulverized powders were classified by using sieve.

2. Solvent method: Until the advent of the solvent method, solid solutions were prepared exclusively by the melting method. Tachibani and Nakumara38 were the first to dissolve both the drug and the carrier in a common solvent and then evaporate the solvent under vacuum to produce a solid solution. This enabled them to produce a solid solution of the highly lipophilic B-carotene in the highly water soluble carrier polyvinylpyrrolidone (PVP). The evaporation method was then taken up by Mayersohn and Gibaldi38. By dissolving both Griseofulvin and PVP in chloroform, and then evaporating the solvent, they were able to achieve a solid dispersion. The release rate of Griseofulvin from the solid dispersion was having11 times higher than that of micronized drug, depending on the drug/carrier ratio.The drug and the excipients were dissolved in sufficient volume of methanol with continuous stirring. Melting solvent method (melt evaporation): It involves preparation of solid dispersions by dissolving the drug in a suitable liquid solvent and then incorporating the solution directly into the melt of polyethylene glycol, which is then evaporated until a clear, solvent free film is left. The film is further dried to constant weight. The 5-10% (w/w) of liquid compounds can be incorporated into polyethylene glycol6000 without significant loss of its solid property. It is possible that the selected solvent or dissolved drug may not be miscible with the melt of the polyethylene glycol. Also the liquid solvent used may affect the polymorphic form of the drug, which precipitates as the solid dispersion. This technique possesses unique advantages of both the fusion and solvent evaporation methods. From a practical standpoint, it is only limited to drugs with a low therapeutic dose e.g., below 50 mg.

4. Melt extrusion method: Melt extrusion is essentially the same as the fusion method except that intense mixing of the components is induced by the extruder. The drug carrier mixture is typically processed with a twin screw extruder. The drug carrier mix is simultaneously melted, homogenized and then extruded and shaped as tablets, granules, pellets, sheets, sticks or powder. The intermediates can then be further processed into conventional tablets. An important advantage of the hot melt extrusion method is that the drug carrier mix is only subjected to an elevated temperature for about 1 min, which enables drugs that are somewhat thermo labile to be processed. Solid dispersion by this method is composed of active ingredient and carrier, and prepare by hot-stage extrusion using a co-rotating twin-screw extruder. The concentration of drug in the dispersions is always 40% (w/w). The screw configuration consist of two mixing zones and three transport zones distribute over the entire barrel length, the feeding rate is fix at 1 kg/h and the screw rate is set at 300 rpm. The five temperature zones are set at 100, 130, 170, 180, and 1850C from feeder to die.

Lyophilization Techniques: Lyophillization has been thought of a molecular mixing technique where the drug and carrier are co dissolved in a common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion. This technique was proposed as an alternative technique to solvent evaporation. An important advantage of freeze drying is that the drug is subjected to minimal thermal stress during the formation of the solid dispersion.

However, the most important advantage of freeze drying is that the risk of phase separation is minimized as soon as the solution is vitrified. Betageri et al.,have successfully investigated the potential applications of lyophilization technique using Glyburide, Ketoprofen, Meloxicam, Amylobarbitone in solid dispersion manufacturing. Moreover, spray freeze drying offers the potential to customize the size of the particle to make them suitable for further processing or applications like pulmonary or nasal administration.

6. Melt agglomeration Process: This technique has been used to prepare solid dispersion wherein these binder acts as a carrier. In addition, solid dispersions are prepared either by heating binder, drug and excipient to a temperature above the melting point of the binder (melt-in procedure) or by spraying a dispersion of drug in molten binder on the heated excipient (spray-on procedure) by using a high shear mixer. The rotary processor might be preferable to the high melt agglomeration because it is easier to control the temperature and because a higher binder content can be incorporated in the agglomerates.

7. Electrospinning: Electrospinning is a process in which solid fibres are produced from a polymeric fluid stream solution or melt delivered through a millimetre scale nozzle. This process involves the application of a strong electrostatic field over a conductive capillary attaching to a reservoir containing a polymer solution or melt and a conductive collection screen.

8.Super Critical Fluid (SCF) Technology: The supercritical fluid antisolvent techniques, carbon dioxide are used as and antisolvent for the solute but as a solvent with respect to the organic solvent. Different acronyms were used by various authors

to denote micronization processes aerosol solvent extraction system, precipitation with a compressed fluid antisolvent, gas anti-solvent, solution enhanced dispersion by supercritical fluids, and supercritical antisolvent. The SAS process involves the spraying of the solution composed of the solute and of the organic solvent into a continuous supercritical phase flowing concurrently Use of supercritical carbon dioxide is advantageous as it is much easier to remove from the polymeric materials when the process is complete, even though a small amount of carbon dioxide remains trapped inside the polymer.

5.Drug Profile.

Ivermectin (5-O-demethyl-22, 23- dihydroavermectin) is poorly soluble drug which is a broad-spectrum antiparasitic action, having pKa 13.17. Aqueous in-vitro solubility of Ivermectin is low 4μg/mL at pH 7 and 37°C. Ivermectins are  closely related 16-membered macrocyclic lactones derived from the fermentation products of the actinomycete Streptomyces avermitilis. Although they share structural features with the macrolide antibiotics and antifungal macrocyclic polyenes, they are virtually devoid of any antibacterial or antifungal activity.

Brand names:

• Stromactol in the United States

• Ivomec in Europe by Mariel Animal Health.

• Mectizan in Canada by Merck.

• Ivexterm in Mexico by Valeant Pharmaceuticals International.

Chemical Structure: