INTRODUCTION:

Microwave irradiation is an electromagnetic irradiation in frequency range of 0.3 to 300 GHz. All microwave ovens eighter domestic type or scientific microwave reactors operate at a particular frequency of 2.45 GHz, which is equivalent to a wavelength of 12.24 cm. It avoids interference with cellular phone frequencies and telecommunication. The energy of a microwave photon in frequency region of 0.0016 eV is lower as compared to the energy of Brownian motion and is also lacking physical strength to break chemical bonds. It is clear that microwaves cannot induce chemical reactions. Microwave irradiation is actually an electromagnetic irradiation in the frequency range of 0.3 to 300 GHz.

Microwave irradiation chemistry is based on heating of materials by microwave dielectric heating effects. This phenomenon is material specific. The solvent or reactant absorbs microwave energy and converts into heat. The electric component of an electromagnetic field causes heating by Dipolar polarization and ionic conduction mechanisms.

The microwave irradiation of the solvent or reactant at microwave frequencies results in dipoles aligning in the applied electric field. The dipole aligning results in field oscillation, under such situation the dipole or ion field tries to realign itself with the alternating electric field. During this process, heat energy is lost through molecular friction and dielectric loss. The quantity of heat generated by this process is directly correlated with the ability of the matrix to align itself with the frequency of the applied field.

If dipole does not have enough time to realign with the oscillating applied electromagnetic field or if dipole reorients itself too rapidly with the applied field, no heating will occurs.

The allocated frequency of 2.45 GHz used in all commercial microwaves lies in between the Dipolar polarization and ionic conduction. The frequency gives the molecular dipole time to align in the field, but it will not follow the alternating field with its frequency.

The heating properties of a particular material are dependent on its dielectric properties. The ability of a specific substance to convert electromagnetic energy into heat with respect to given frequency and temperature is determined by loss factor or loss angle or loss tangent, tanδ.

tanδ = e′′ e′ --------(I)

Where, e′′ is the dielectric loss, which is indicative for conversion of electromagnetic radiation into heat and e′ is the dielectric constant.

A reaction medium/ solvent system with a high tanδ value is more effective for absorption and rapid heating. Generally more the value of loss factor or loss angle (tanδ), the dielectric heating of a material will be more under microwave irradiation (Table I).

Table I: Correlation of tan δ value with absorbing power

Sr. No.	Solvents tan δ value	Absorbing Power
1	tanδ > 0.5	High
2	tanδ 0.1 - 0.5	Medium
3	tanδ < 0.1	Low

Microwave Oven:

The Apparatus: Two types of microwaves are available as Monomode and multimode.

Monomode (single-mode microwave oven):

Single mode Microwave Oven is able to create a standing wave model. The interference of fields produced by wave has the same amplitude but have different oscillating directions. This amplitude and oscillation direction generates an arrangement of nodes where microwave energy intensity is minimum i.e. zero and a collection of antinodes. At antinodes the magnitude of microwave energy is maximum. The main wave mechanical factor for the structural design of single mode apparatus is the distance between the sample and magnetron. The sample vessel generally is placed at the antinodal position of the standing electromagnetic wave pattern. An advantage of single mode microwave oven is their high rate of heating. Major disadvantage of single mode microwave oven is one vessel can be irradiated at a time¹.

Multi-Mode Microwave Oven:

Currently household microwave ovens are of multi mode microwave ovens. It avoids generation of a standing wave pattern inside the oven. This is done so as to generate as much chaos as possible inside the oven. The greater the chaos/disarray higher the dispersion of radiation, which leads to increases in effective heating. Thus, a multi mode microwave oven apparatus can be used for a number of samples simultaneously. Based on this properties, a multi mode oven is used for bulk heating and to carry out chemical analysis like ash value, extraction etc. Control on heating of samples is a disadvantage of multi mode ovens. Improper heating is because of the chaos that makes it practically impossible to generate equal heating. Actually chaos creates hot spots and cold spots in the material when sample is kept inside the oven.

Main Features of Microwave Heating:

1. By electromagnetic waves, heating takes place

2. Heating of reaction mixture proceeds directly inside the material avoiding the vessel.

3. No need of physical contact of reaction vessel with the higher temperature source.

4. Heating mechanism involve dielectric polarization and ionic conduction

5. In microwave, the temperature of a substrate can be raised higher than its boiling point, i.e., superheating may take place.

6. In microwave heating, specifically a particular component can be heated more depending on its dielectric characteristics. Heating rate is several (from 10 to 1000 in best cases) fold high¹.

Principle of Microwave Heating:

The heating in microwave oven is because of the interaction of charged particle of the reaction material with electromagnetic wavelength of specific frequency. The phenomena of producing heat by electromagnetic irradiation are ether by collision or by conduction or it may be summation of collision and conduction mechanism. The wave energy changes the polarity from positive to negative with each cycle of the wave. It causes rapid orientation and reorientation of molecule, which cause heating by collision. If the charge particles are free to travel through the material (e.g. Electron in a sample of carbon), charge particle induces a current which will travel in phase with the electromagnetic field. If charge particle are bound within the material, the electric field component will cause them to orient and reorient until opposing force balancing the electric force².

Heating Mechanism:

In microwave oven, material may be heated by the use of high frequency electromagnetic waves. The interaction of electric field component of the wave with charge on material leads to heating.

Two basic principal mechanisms involved in the heating of material

Dipolar Polarization:

The heat is generated in polar molecules by dipolar polarization process, When the polar molecules are exposed to an oscillating electromagnetic field of appropriate frequency, they tries to follow the field and align themselves with the electromagnetic field. However, because of the inter molecular forces polar molecules experience inertness and are not able to follow the field. It results in the random motion of particles and random interaction generates heat.

Dipolar polarization can generate heat by the following mechanisms

1. Reaction between polar solvent molecules such as water, methanol and ethanol.

2. Reaction between polar solute molecules such as ammonia and formic acid.

Interfacial Polarization:

Interfacial polarization is an effect observed as combination of conduction and dipolar polarization effects. This mechanism is important where a dielectric material is not homogenous but conducting inclusion of one dielectric material to other.

Conduction Mechanism:

The conduction mechanism generates heat via resistance to an electric current. The oscillating electromagnetic field generates an oscillation of electrons in a conductor and it results in an electric current. The electric current generated faces internal resistance, which heats the conductor³.

Application of Microwave in Pharmaceutical Science:

1. Conventional techniques i.e. Soxhlet extraction, is used for the extraction of active constituents.⁴

2. Microwave drying technology shortens/reduce drying times and minimizes drying defects and it increases the potential for product improvement. Therefore in recent years microwave drying has gained much popular.

3. Microwave irradiation techniques are popularly used to prepare pharmaceutical formulations such as agglomerates, gel beads, microspheres, nanomatrix, solid dispersion, controlled release tablets formulation etc⁵.

Cyclodextrin Based Formulation Development:

Cyclodextrins are a family of cyclic oligomers containing α-(1-4) linked D-glucopyranose units in the chair conformation. The cyclodextrin features a cavity which is hydrophobic. The most common cyclodextrins have six, seven, and eight glucopyranose units known as α, β and γ- cyclodextrins respectively. The cavity is limited by hydroxyl groups of different chemical character. The hydroxyl groups positioned at the narrow side of the glucopyranose ring are primary hydroxyl, while those located at the wide entrance are secondary due to this they are less prone to chemical transformation (secondary side). The reactivity of cyclodextrins is due to hydroxyl groups and reactivity depends on reaction conditions. The non reducing trait of cyclodextrins allows them to as polyols. The inner diameter of the cavity in cyclodextrins varies from 5 to 10 Å and depth is about 8 Å. These dimensions allow the inclusion of several types of guest molecules/ drugs to form inclusion complexes. Because of host guest interaction, there is change in some properties of guest molecule. That is the main basis of cyclodextrin complexation. The lipophilic cavity of cyclodextrin molecules provides an environment into which appropriately sized non polar moieties can interact to form inclusion complexes. Generally bonds are formed between guest and cyclodextrin molecules. Generally no covalent bonds are formed or broken during complexation process. Driving force of complexation is the release of water molecules from the cavity. An apolar–apolar association is achieved as water molecules are replaced by lipophilic guest molecules. Binding strength of the inclusion complex depends on host guest interaction. Orientation of guest molecule inside the cavity is a result of interactions between atoms. Complexes can be formed either in solution or in the crystalline state. Water is preferred choice of solvent. Co-solvents (organic solvents) as well as hydroalcoholic solvents are also choice of solvent for the preparation of inclusion complexes⁶.

Applications of Cyclodextrins:

Cyclodextrin complexation leads to changes in the physicochemical properties of the guest molecules/API^7.

1. Increase in oral bioavailability attributed to increased solubility and stability. e.g. thalidomide⁸, nimesulide⁹ etc

2. Increase in solid state stability drug. e.g. quinapril¹⁰

3. Increased absorption through development of nasal drug delivery system. e.g. morphine¹¹ and insulin¹²

4. Increased absorption through ocular drug delivery system. e.g. Dexamethasone¹³

Inclusion Complex Formation:

The most salient feature of cyclodextrins is their ability to form solid inclusion complexes via host guest interaction with a variety of solid APIs through a molecular complexation.

Technique to prepare inclusion complexes:

Physical mixture:

A solid physical mixture of drug with cyclodextrins will be prepared by mechanical trituration. In laboratory cyclodextrins and drug are mixed together by trituration in a mortar¹⁴.

Kneading Method:

This method is based on preparation of cyclodextrin paste with little amount of water or hydro alcoholic solutions. The drug is then added to the paste and kneaded/triturated for a specified time. The kneaded mixture is then dried and passed through a sieve^15,16.

Solution/Solvent Evaporation Method:

This method involves dissolving of the drug and cyclodextrins separately into miscible solvents. The both solutions are mixed to get molecular dispersion of drug with complexing agents and finally evaporation of the solvent under vacuum to obtain solid powdered inclusion compound¹⁷.

Milling/Co-Grinding Technique:

Drug and cyclodextrins are mixed with the help of mechanical devices like ball mill. The physical mixture of Drug with cyclodextrin is introduced in a mill and grinded for suitable time.¹⁸.

Atomization/Spray Drying Method:

Spray drying is a common technique used in pharmaceutical industry to produce a dry powder from a solution. Spray dried complex has greater storage stability due to the water elimination. This method is one of the most widely used techniques to produce the inclusion complex from a solution phase¹⁹.

Lyophilization/ Freeze Drying Technique:

Freeze-drying process is a removal of water by sublimation. Freeze drying is a process in which water is frozen, frozen water is removed from the sample by sublimation (initial primary drying) followed by desorption (secondary drying)²⁰.

Microwave Irradiation Method:

Technique involves the microwave irradiation reaction between drug/API and cyclodextrin using a microwave oven.

RESULTS:

The drug/API and cyclodextrin in definite molar ratio are dissolved in a mixture of water and organic solvent in a specified proportion into a round bottom flask or drug/API and cyclodextrin paste is prepared using water/ hydroalcoholic mixture. The mixture is reacted for short time of about one to two minutes at elevated temperature in microwave oven. After the reaction completes, the precipitate so obtained is separated using whatman filter paper, and dried in vacuum oven²¹.

The table II gives the account about the use of microwave irradiation technique for the preparation of inclusion complexes with enhancement of solubility for poorly soluble drugs.

Table II: Use of Microwave Irradiation Technique for the Preparation of Inclusion Complex using cyclodextrin and its derivatives

Drug	CD	MWI Parameter		Result
Drug	CD	Watt	Time Min	Result
Gemfibrozil²²	β- CD	900	2	Study shows that the microwave drying is the most suitable drying techniques. MWI powder showed the highest solubility, dissolution rate over plain drug.
Cefdinir²³	β- CD	245	1.5	Two different advantages, shorter drying time and it excludes excess amount of potentially hazardous organic solvents. MWI method can be used to prepare CEF-β-CD complex with better yield at large scale.
Ibuprofen²⁴	HP-β-CD	600	6-15	Microwaves method was applied to the preparation of solvent-free solid dispersions. HP-β-CD as carriers, were able to increase the dissolution of Ibuprofen. It is attributed to amorphous state of the ibuprofen by MWI.
loratadine²⁵	2,6-di-O-methyl- β- CD	150	1.5	Hydrogen bonds developed between loratadine and 2,6-di-O-methyl-β-CD. The solubility and dissolution of loratadine were increased. MWI is found to be best with good solubility and bioavailability.
Carvedilol²⁶	β- CD	60	1.5	Carvedilol interacts with β-CD and results in increased solubility because of inclusion complex formation through MWI.
Lornoxicam²⁷	β- CD	60	1-2	Lornoxicam forms inclusion complex with β-CD in aqueous phase through MWI and showed better solubility.
Gossypol²⁸	β- CD	60	1.5	The inclusion complex of Gossypol-β-CD was prepared using MWI. Solubility of Gossypol is increased due to formation of the inclusion complex.
Diclofenac²⁹	β- CD	75	40	Diclofenac-β-CD conjugate is formed with the use of MWI. Conjugate acts as a prodrug and is capable of enhancing release of the diclofenac to the colon.
Cefixime³⁰	Soluplus	510	7-8	Significant improvement in solubility and dissolution of Cefixime through MWI
Repaglinide³¹	PEG	600	5	MWI technique showed better solubility for repaglinide with PEG 6000.
Aceclofenac³²	β- CD HP-β-CD	120	0.2-2	In microwave irradiation method, as the irradiation time is increased, the dissolution rate decreases because of strong bonding between the aceclofenac and cyclodextrin when irradiated for a longer period.
Irbesartan³³	β- CD, β- CD with PEG 400	420	15 to 120	Improvement in solubility over plain irbesartan. PEG 400 ternary system showed reduced solubility of irbesartan as that of binary system irbesartan-β-cyclodextrin irradiated.
Efavirenz³⁴	β- CD	60ᵒC	1.30	Microwave irradiated system leads to significant enhancement of dissolution for Efavirenz as compared to co-grinded technique.
Aripiprazole³⁵	β- CD HP-β-CD	60ᵒC	1.30	The inclusion complex prepared as Aripiprazole: HP-β-CD microwave irradiation technique and freeze drying technique results in improvement in solubility for MWI and freeze dried complex. The more time MWI leads to reduced solubility because of bond interaction between drug and HP-β-CD.
Nebivolol HCl³⁶	β- CD		60	The inclusion complex prepared as Nebivolol HCl:β-CD microwave irradiation technique and freeze drying technique. The dissolution study showed improvement in solubility for microwave irradiated and freeze dried complex.
Itraconazole³⁷	β- CD, plasdone s-630	60ᵒC	2	Binary and ternary solid inclusion complexes made by freeze drying and microwave irradiation techniques showed greater dissolution rate, an increase of 1.23 fold (freeze drying) and 1.17 fold (microwave irradiation) in dissolution efficiency was observed.
Ziprasidone³⁸	HP-β- CD, Kollidon, Soluplus, Pluronic	510	7-8	MWI technique showed least improvement in solubility of drug as that of kneaded, spray drying, freeze drying.

DISCUSSION:

The poor water solubility of the drug is major obstacle for the development of dosage form. For the drug Glimepiride, inclusion complexes with β- CD and HP-β- CD prepared by microwave irradiation and spray drying technique showed similar dissolution behavior. In case of microwave irradiation shorter duration of exposure may be responsible for improvement in solubility. It may be attributed to weak vanderwals force of attraction, weak hydrogen bonding; no strong bonds were formed between drug and cyclodextrin. For Cefdinir-β-CD inclusion complex prepared by MWI technique has advantage of shorter drying time and avoids excess amount of potentially hazardous organic solvents with excellent yield. MWI irradiated inclusion complex showed highest solubility. For the drugs ibuprofen, loratidine, carvediol, lornoxicam, diclofenac, cefixim inclusion complexes prepared by MWI showed highest solubility and dissolution rate as that of physical mixture and plain drug, this could be attributed to possible hydrogen bonding between drug and cyclodextrin under MWI.

For the drugs Aceclofenac, MWI leads to reduced solubility as that of plain drug, physical mixture and spray dried inclusion complex. The characterization of MWI inclusion complex of Aceclofenac: β-CD by fourier transfer infra red spectroscopy and differential scanning calorimetery confirms the formation of strong bond between aceclofenac and β-CD which may be probable reason confirmed by characterization. Excess exposure of aceclofenac with β-CD as paste under MWI leads to formation of strong bond. Similar reduction in solubility has been observed for irbesartan.

An extensive literature survey revealed that Microwave irradiation technique has the capacity to improve the solubility of poorly water soluble drugs. The technique has the advantage of cost effective, less time consuming for the preparation of complexes in comparison to spray drying/ freeze drying techniques. The selection of irradiation time and solvent is critical factor for the preparation of inclusion complex by microwave irradiation. The microwave irradiations have capacity to induce drying, polymeric crosslinkages/drug-polymer interaction and modify the crystal habit via heating under microwave.

CONCLUSION:

The microwave irradiation technique is found to be novel technique for the preparation of inclusion complex with cyclodextrins. An extensive literature survey revealed that Microwave irradiation technique has the capacity to improve the solubility of poorly water soluble drugs. The technique has the advantage of cost effective, less time consuming for the preparation of complexes in comparison to spray drying/ freeze drying techniques. The application of microwave is a newer approach to modify the physicochemical properties and development of drug delivery without the need for excessive heat, lengthy process and toxic reactants.

ACKNOWLEDGMENT:

The authors are thankful to Chairman, P.E. Society, Pune, Maharashtra for providing necessary facilities.

CONFLICT OF INTEREST:

None.

ABBREVIATIONS:

CD- cyclodextrin, HP-β-CD- Hydroxy propyl β-cyclodextrin, PEG- Poly ethylene glycol, MWI- microwave irradiation technique.

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Received on 15.01.2020 Modified on 08.03.2020

Research J. Pharm. and Tech. 2021; 14(2):1131-1136.

DOI: 10.5958/0974-360X.2021.00203.1