Microwave - A Potential Tool In Pharmacy

Dr. S. S. Poddar

Microwave is apparently heading for exhibiting good potential in the field of Pharmaceutical industry. The write up attempts to throw light on what is microwave, how is it generated and what importance may it have.

It is an electromagnetic wave lying in the range of 3 X 10⁸    -   3 X 10¹¹ Hz, produced through devices mainly exemplified by magnetron, klystron & traveling wave tube. The main application of microwave energy is through its heating effect. The heating produced, have been found to be superior to the conventional in numerous situations. The application of microwave extends to thawing, drying, sterilization, production of ointments & sustained release dosage forms. The superiority of microwave lies in the uniform and efficient heating, and at times in localized and focused heating. Through the exhaustive search of literature it could be concluded that microwave, when used with certain precaution, is a promising energy in pharmacy. 

INTRODUCTION

Microwave, which has gained recent popularity in the kitchen, has a great potential in pharmaceutical industry. In this article we will explore its involvement in the pharmaceutical scenario. Waves are generally of two types 1) Electromagnetic waves. 2) Mechanical waves. The main point of differentiation is electromagnetic waves do not require a medium for transportation, as required by mechanical waves. Both these types of waves transport energy from source to receiver [1]. Microwave is a type of electromagnetic wave whose wavelength range falls in between Radio waves & Infrared waves as shown in Table I [2]. 

Table 1: -Range of frequencies of Electromagnetic waves

TYPE	APPROXIMATE WAVELENGTH RANGE (METERS)	APPROXIMATE FREQUENCY RANGE (HERTZ)
RADIO WAVES	10  -  1000	3 X 105    -    3 X 107
TELEVISION WAVES	1 -  10	3 X 107   -    3 X 108
MICRO WAVES	1 X 10-3  -   1	3 X 108    -   3 X 1011
INFRARED	8 X 10-7    -   1 X 10‑ 3	8 X 10-7   -   4 X 1014
VISIBLE LIGHT	4 X 10-7    -   7 X 10‑ 7	4 X 1014   -  7 X 1014
ULTRA VIOLET	1 X 10-8    -  4 X 10‑ 7	7 X 1014   -  3 X 1016
X-RAYS	5 X 10-12    -    1 X 10‑ 8	3 X 1016   -  6 X 1019
GAMMA RAYS	1 X 10-13    -   5 X 10‑ 12	6 X 1019   -  3 X 1021
COSMIC RAYS	Less than   1 X 10-13	Greater than   3 X 1021

Microwave is generally used for drying & thawing, but now its use has been extended to sterilization, control release formulation etc as well. This write up attempts to describe what exactly is microwave, how is it produced in the industry, and its applications, advantages & disadvantages. The frequencies applicable to industrial, scientific, medical & domestic uses for heating purpose lie between 9.15 MHzto 2.45 GHz_. However lots of obstacles coming in the way of microwave usage had to be overcome as shown in Table II [3]. 

Table 2: - The obstacles to microwave technology.

OBSTACLES TO MICROWAVE TECHNOLOGY

1) Microwave safety misunderstood. 2) Confirmation of regulatory authorities. 3) Mixed message from equipment vendors. 4) Lack of published papers. 5) Availability of laboratory scale processors.

GENERATION OF MICROWAVES  

Microwave is generated in special type of electron tubes. These contain cathode, anode and grid inside an evacuated envelope. For generation of microwaves these should operate at very high frequency range (300 – 3000 MHz). Ordinary electron tubes can operate at frequencies up to about 30 MHz [4]. So the tubes must be designed in a different manner, because the frequency is comparable to the electron transit time (it is the time needed for electrons to travel between electrodes).

PRINCIPLE OF MICROWAVE HEATING

Microwave processings involve dielectric materials. A dielectric is an electrical insulator that gets polarized by the action of an applied electrical field. In the influence of electric fields, electrons move freely through a conductor but in case of a dielectric these electric fields displace electrons only slightly from their normal positions. The electric field causes a separation of negative charges (electrons) from positive charges (proton in the atomic nuclei). Thus an electric dipole is created in the molecule and the material is said to be polarized [5]. The dielectric materials can be divided into 2 groups, polar & nonpolar. A polar dielectric is one in which the molecules have an intrinsic dipole moment, where as in a nonpolar it is not so. In polar substance, where each molecule posses a dipole, the material becomes polarized due to the potential rotation of each molecule so that it is aligned in the direction of the applied electric field. Because this involves rotation of the complete molecule there is strong coupling to the lattice. In general, this coupling causes the material to exhibit a high dielectric constant Î' and a high loss factor Î'', and makes its dielectric properties depend upon frequency and temperature. The variations of dielectric constant Î with frequency can often be expressed in the terms of a single relaxation time according to formula.

Î = Î' - jÎ'' = Îp + (Î_s-Îp)/(1+jwt)

where,

Îp = Î for w = ∞ ,

Î_s = Î for w = 0,

w is frequency in radians per seconds, t is the relaxation time in seconds,and j is the square root of minus one.

The advantage of microwave heating is derived mainly from this direct interaction of a varying electric field with the material being heated. There is no heat per se in the microwave radiation. The radiation is converted in to the heat within the material itself and throughout its whole bulk. When microwave energy is used for the evaporation of polar solvents the conversion into heat takes place in the direct proportion to the amount of solvent present.

The rate of conversion of microwave energy to heat is given by the formula.

P = 2.78 X 10^-11 f E² V_s Î''

where,

P is in watts, f is frequency in Hz, E is the electric field in volts/meter (V/m), V_s is the volume in m³ & Î'' is the dielectric loss factor. [6]    

The vacuum tube for the microwave generation is Magnetron, while other tubes amplify the microwave signal. Examples of the later are Klystron and Traveling wave tube.

MAGNETRON

The important features of the magnetron are shown in Figure 1. Magnetron, a thermionic diode, consists of an anode and a directly heated cathode. As cathode gets up heated it releases electrons, which are then attracted towards the anode. The anode is made up of even number of small cavities, each of which acts as a tuned circuit, and the gap across each end cavity behaves to provide a desired capacitance. Anode, which is a series of such circuits, is tuned to oscillate at a specific frequency. Path of electrons bends when they travel from cathode to anode, due to axially induced magnetic field at the anode assembly. The deflected electrons then pass through the cavity gaps where they induce a small charge into the tuned circuit resulting in the oscillations getting generated in the cavity. This continues until sufficiently high amplitude is generated. The waves with this high amplitude are taken out of the anode via an antenna [7].

Figure 1: Schematic illustration of a magnetron

KLYSTRON.

Klystron a cylindrical tube that is specialized vacuum tube (electron tube) capable of amplifying microwave signals. Electron gun at one end of the tube serves as the cathode, which generates an intense electron beam that is directed towards the collector. The beam traveling through the axis of the tube is focused by an electromagnet that surrounds the tube. One of the beams passing through open chamber is called the input buncher cavity. The input signal (microwave signal that has to amplify) is coupled to this cavity in such a way that it modulates the velocity of individual electrons in the beam, converting the initially steady current of the beam into a fluctuating current. One or more intermediate cascade cavities along the beam’s path encourage the formation of bunches of electrons by allowing faster electrons to catch up with slower ones. The fully modulated beam, which’s current of which is an amplified version of the incoming microwave signal, then enters an output wave-guide. This is the desired amplified output signal. The electron beam continues out of the end of the tube into a collector chamber. This chamber may require water cooling, because the dissipating beam produces considerable heat. Klystrons can also be used as microwave oscillators if a portion of the output signal is fed back into the input cavity [8].

TRAVELING WAVE TUBE

A Traveling wave tube is a specialized electron tube capable of amplifying a microwave signal. An electron gun at on end of the cylindrical tube generates electrons that are conveyed into a narrow beam by electromagnetic coil wound around the circumference of the tube. Microwave energy entering the tube near the electron gun travels by means of a wave-guide along the path of the electron beam, where it modulates the beam by forcing the electrons in the beam to group into bunches. This amplified microwave energy then passes out of the far end of the tube. The electron beam leaves the tube through a collector. Traveling wave tube is quite efficient in amplifying microwave signals over a wide range of frequencies [9].

ADVANTAGES.

Microwave include following advantages, over the conventional heating.

1)Uniform heating occurs throughout the material as opposed to surface and conventional heating process.

2)Process speed is increased.

3) Desirable chemical and physical effects are produced.

4) The energy source is not hot.

5) Floor space requirements are decreased.

6) Better and more rapid process control is achieved

7) In certain cases selective heating occurs which may significantly increase efficiency and decrease operating cost. [6].

{mospagebreak title=Applications:Drying}

APLLICATIONS

These waves have wide application in pharmaceutical industry.

1. DRYING

Microwave was conventionally and even today is mainly used in industry for drying purpose because of the advantages shown by the microwave dryer over the other types of dryer, Figure 1 [10 & 11]. This is due to the ability of water and most of the industrial solvents, which absorb microwave energy more rapidly than solids causing their preferential & efficient heating leading to evaporation. It is mainly used to remove water and/or polar organic solvents from brittle and heat sensitive powders, granules, bulk drugs, pastes and slurries etc [12]. Microwave vacuum dryers are more efficient as compared to sole microwave dryers, Figure 2.

Figure 2: Comparison of drying curves for different modes of drying : ■ ,microwave ▲ , vacuum only  ● , vacuum with air.

This is because when a product to be dried is kept under vacuum the liquid evaporates at low temperature and thus drying is completed at low heat exposure saving time, money and heat labile substance [13]. Microwave is typically applied in vacuum range of 40 -100 mBar. If it is below 40 mBar, risk of ignition of surrounding air is high. Such a condition is called “arching” [11]. Studies show that drying of pharmaceutical excipients depends on their dielectric values. Some materials require agitation during drying, eg starch (high loss factor). However to avoid overheating, it will be necessary to check for every material whether agitation is required or not [14]. A laboratory sized microwave fluid-bed dryer was constructed & evaluated for drying performance. For the evaluation, four typical granulations were dried in it. Results indicated that drying rates improved as much as 6 fold depending upon the granulation type & drying conditions. Drying was efficient and the rate higher when done employing microwave energy of 1000 watts in association with 60C inlet temperature. It can be seen in Figure 3, 4, 5 and 6 [15 & 16]. L. Leloup developed mixer-Granulator & microwave dryer.

Figure 3: Drying curves for aqueous dicalcium phosphate granulation at various microwave power inputs. [30 inlet temperature]

Figure 4: Drying curves for aqueous starch granulation at various microwave power inputs. [30 inlet temperature]

Figure 5: Drying curves for aqueous starch granulation at various microwave power inputs. [60 inlet temperature]

Figure 6: Drying curves for aqueous dicalcium phosphate granulation at various microwave power inputs. [60 inlet temperature]

The machine granulates rather gently without the use of shredders or similar mechanisms and does drying in a vacuum with a mixed heating system of heat evacuation fluid and microwave [17]. Drying rates during film coating were 2 to 22 times higher using microwave energy, as compared to conventional drying. It can be seen in the Figure 7. [18].

Figure 7: Drying rates in percent of water mass loss per min of various formulation using different procedures. Bars represent S. D. (n=4)

      The amount of microwave energy absorbed by a material is given by

P = 2 p f V² E₀ E_r tan d

where P is power density of material [Watts/meter³ (W/m³)], f is frequency (Hz),

V is voltage gradient, E₀ is the dielectric permissivity of free space [8.85 X 10¹² farads/meter (F/m)], and E_r is the dielectric constant of the material and tan d is the loss tangent.

The dielectric constant can be related to the polarisability of the material and the loss tangent can be compared to the viscosity of the material to the movement of the molecules. The product E_r tan δ is known as loss factor and is a relative measure of how easily a material will be heated by microwave energy. The loss factor of some solvents is given in Table II. The loss factors of some common pharmaceutical excipients are given in Table IIIA & IIIB [19].

Table: 3A Loss factors of some materials.

Material	Loss factor
Lactose	0.02
Starch	0.41

Table: 3B Loss factors of some solvents.

Solvent	Loss factor
Methanol Ethanol Iso-propranol Acetone Pure water	13.6 8.6 2.9 1.25 6.1

 

Figure 8 demonstrates the values of the absorbed dose of radiation D_abs and the loss of water [20]. During drying process, not all of the transmitted microwave energy is absorbed by materials.

Figure 8: Effect of microwave radiation on loss of water of ○ , of lactose trials and ● , calcium citrate trials.

Some remain unabsorbed and is denoted as ‘free energy’. As drying continues the moisture in the material goes on decreasing and thus the amount of free energy goes on increasing. Therefore in a dryer an E-field monitor is provided which detects the electric (E) component of the electromagnetic wave and thereby able to measure this free energy. The power provided by the magnetrons is suitably reduced in case of excessive free energy. This can be seen in the Figure 9 [19].

Figure 9: Typical drying curve for microwave vacuum drying.

Microwave equipment is also used nowadays to measure the moisture content in the pharmaceuticals [21]. Online moisture can be detected for microwave vacuum dryer using Near Infrared Spectroscopy (NIS), though only if the moisture content of product is 6% or less. Thus, drying can be made continuous process with precise control of moisture [22]. The effect of drying on granular products, treated in microwave and conventional tray dryer was evaluated. It showed that loose and tapped bulk densities, percentage compressibility, hardness and dissolution time of granules prepared through microwave & conventional tray dryer were not significantly different (p> 0.05). Reduction in drying time was the only difference. This lack of shift of granule characteristics was noted as an added advantage [23]. Introduction of application of microwave for drying of pharmaceuticals led to its utility in single pot processes i.e. incorporating mixer granulator & dryer. In this method the process is continuous and faster, thus, reducing loss of product during change of processes. Therefore it helps in cost reduction & increase in annual yield, which was demonstrated by Glaxo (Evreux, France) [24 & 25]. Solute migration is a usual problem faced when granulations are dried but certain data also suggests that microwave drying minimizes such migration [26]. When migrations were compared between fluidized, vacuum, infrared & microwave dryer, maximum migration was seen in infrared dryer, where as microwave and vacuum dryer showed good uniformity in comparison throughout the bed of material [27].     

MECHANICAL DESIGN OF MICROWAVE DRYER

Figure 10: Production scale microwave dryer.

Production scale microwave processor is illustrated in the Figure 10. The dryer cavity is cylindrical with a dished top on which magnetrons are mounted. The product is made available on a polypropylene bowl, which in turn is mounted on dryer platten. The bowl is also dished to withstand vacuum. Its material of construction is suitable for passage of microwave energy to the product. The platten lifts the bowl into the dryer and also forms the base cavity. The dryer shell and platten, which are mirror polished for ease of cleaning & are fully jacketed to prevent condensation on inner walls. Each magnetron is mounted on its own waveguide, which in turn is fixed directly to dryer shell. A polypropylene window on each waveguide allows microwaves to enter dryer cavity but prevents the magnetrons being exposed to vacuum or to the product being dried. The magnetrons require a high tension DC supply, as well as low voltage heaters. They are water and air cooled to remove the heat generated within them. A 3-phase high voltage transformer followed by full wave rectifier supplies high voltage for the magnetrons. This insures a controlled 7.2 KV direct current supply to the anode. The water vapor generated from the material being dried is removed via the vacuum lines, condensed and then discharged through the liquid ring pump. As inside of the dryer should reflect microwave to improve its utilization, it is made of metal, and material of choice is mirror polished Stainless Steel. Teflon is inert to microwaves, thus a common material of construction for components in the processing bowl.

      Temperature of the operator’s body parts rises if exposed to microwave, due to absorption of the energy. At high energy levels excessive heating results. Thus, there should be steps taken to minimize microwave leakage. Following could be considered for this. 1) Instillation of hard wired interlocks. 2) Programming of sequence controller so that magnetrons do not operate unless the base cavity is at correct vacuum. 3) Installation of a microwave seal separate to vacuum seal. 4) Use of E-field control system. 5) Placement of microwave detectors to monitor the platten seal area and the magnetron area. Controlling vacuum at 35 torr can ensure that fire & explosion hazard won’t occur and for the same magnetrons are never operated at maximum power. Under microwave condition breakdown of air may take place resulting into “arching”. This could be eliminated by 1) Earthing 2) Elimination of sharp protrusions 3) Avoidance of gaps between the dryer shell and platten.

Advantages of a microwave dryer.

1)        Uniform drying.

2)        Efficient drying.

3)        Easily controllable.

4)        Detection of end point of drying possible.

5)        Dust free.

6)        Easily cleanable.

Disadvantages

1)        Not suitable for materials with high loss factor & high solubility

2)        Vacuum is required for reasonable drying.

The stability of pharmaceutical granulations dried by microwave is comparable with that provided by alternative methods. The interesting part about microwave energy is that they are non-ionizing and do not contain sufficient energy that is required for the formation of Free Radicals or even liberation of bound water. There are lots of new and supplemental drug applications that include the use of microwave-vacuum drying for wet granulations. Mandal, Moss and others [28-30] have published data showing the comparability of physiochemical characteristics of granulation dried in microwave processors versus tray dryers as well as fluid bed dryers.

{mospagebreak title=Applications:Sterilization}

2. STERILIZATION

The need for new drugs has gone up; similarly to develop suitable methods for their sterilization. This is critical aspect for industry as well as regulatory authority. Every method will have its advantages and disadvantages. Advent of a new method i.e., microwave sterilization carries significance [31 & 32]. The sterilization is brought about by microwave dielectric heating effect. The efficiency of microwave sterilizer was put to test via sterilization of two heat labile drugs, ascorbic acid & pyridoamine phosphate, both in solution form. The result showed that though reduction of bio-burden was equal to that of autoclaving, autoclaved drugs showed certain deteriorations in quality, which was not observed in microwave sterilized drugs. Therefore microwave was reported to be holding an upper hand over autoclave [33]. The validation requirement of microbicidal suitability of microwave created a need to find out biological indicator for microwave sterilization. Sasaki and the co-workersshowed that sterilization effect of microwave is due to production of heat and there is no other non-thermal mechanism. Thus, they used spores of heat resistant species i.e. Bacillus stearothermophilus for validation of microwave in sterilization. When compared with other thermal methods of sterilization it showed satisfactory results. This suggested that spores of Bacillus stearothermophilus are an appropriate biological indicator in validation of microwave sterilization [34]. Sterilization of vials was not affected regardless of its position in the sterilizer thus indicating uniform heating ability of the microwave [35]. A continuous microwave sterilizer (CMWS) has been developed [36]. The high temperature and short time sterilization by microwave heating in a CMWS were evaluated. Bacillus stearothermophilus spores were used as biological indicator. The lethal effect of microwave sterilizer was equal to that of autoclave. The reliability of microwave sterilization in CMWS was confirmed using more than 25000 test ampoules containing biological indicators. All ampoules were sterile indicating its reliability. It can be observed in Figure 11 [37].

Figure 11: Temperature curves of sterilization process in CMWS and Autoclave F₁, F₁₂₁- value in heating up phase, F2, F₁₂₁- value in peak dwell phase, F₃, F₁₂₁- value in cool down phase, F_t, F₁₂₁- value in all phases.

There was reduction in bioburden when microwave was used for drying of granulation with temperature kept at 40-60C and input power between 250-1000 Watts. Optimum microbial reduction occurred at 1000 Watts. At low moisture levels and low relative humidity, greater inactivation of test organism was observed [38]. Microwave caused reductions of both bacteria and molds at 300 – 1200 watts in herbal crude drugs [39]. Microwave sterilization is now utilized for sterilization of heat labile drugs where a high temperature is generated for sterilization in a shorter period of time and thus creating a possibility of making the process continuous. Such a process can benefit the industry due to its economy & lesser production time. Microbiological properties of liquid preparations were improved by treating the finished products in the containers with microwaves for short time. The finished products had been challenged with Bacillus subtilis, Pseudomonas aeruginosa or Eschericha coli. Treatment in a simple microwave oven for 20 to 60 seconds showed reduction in germ count. 60% preparations were sterile and remaining 40% preparations showed 60-90% reduction in germ count [40]. Many researchers have studied the destruction of microorganisms by microwave [41-50]. The intracellular fluid of the microorganisms has tightly bound water & ions, which has low dielectric “loss factor” as compared to water. The colloidal solids and tightly bound water & ions, in biological materials are less active at microwave frequencies and transit energy with less power absorption because of low loss levels as compared with those of other aqueous fluid. Microwave energy was found to be more effective against microorganisms at low moisture levels [51]. A sterilization method for empty glass containers, using a laser and a microwave oven, was developed and evaluated.  Sterilization procedures were evaluated at power levels up to 2000 watts.  Spore destruction was logarithmically related to exposure time. B. subtilis spores were used to check the efficiency; all the spores got destroyed with no particulate contamination being introduced into the glass containers [52].

3.CONTROLLED RELEASE FORMULATIONS

Research scholars have being using various approaches for controlled release formulations. In one of the cases Magentoliposomes (liposomes with enwrapped magnetite particles in their bilayers) were used which contained the drug 6-carboxy Fluorescein. Release of the drug was dependent on the specific absorbed power by the Magnetoliposomes. When a power of 200 mW/g was applied almost complete release of the drug occurred within 20 minutes. The release of entrapped liposome content was 2-3 orders of magnitude higher at relatively low specific absorbed power compared with conventional liposomes [53]. In other case, Magnetoliposomes, which are strong microwave absorbers got heated to higher temperatures, which subsequently lead to leakage of, encapsulated drug. Being magneto-sensitive they can be maneuvered to the given site in the body and so its programmable release could be carried out. Thus targeting of drug was also possible [54]. In another approach release characteristics of the polymer was modified. Three different systems of beads were prepared for the drug Sulphathiazole, viz. Alginate-drug, chitosan-drug and alginate-chitosan-drug. These three systems were exposed to microwave radiations of different intensity and for various durations. They were studied for drug content, drug dissolution, drug stability, drug polymorphism, drug-polymer interactions, polymer cross linking & complexations. The chemical stability of drug was unaffected by microwave irradiations. But drug in chitosan beads underwent polymorphic changes. However, these polymorphic changes had no effect on the drug release. These changes were not seen in alginate & alginate-chitosan beads. The drug release showed varying effect. The drug release in alginate at 80 Watts for 10 minutes & alginate-chitosan beads at 80 Watts for 21 minutes showed retardation. The reason for retarded release of drug from these beads was due to formations of additional nonionic bonds, involving alginate cross-linking & alginate-chitosan complexation. But it required careful selection of the input power & duration of irradiation to bring about desired release retardation [55].

Eroding matrices were prepared from albuminoidal proteins extracted from Soybean and compacted under the influence of moisture & pressure by exposing to various levels of water vapor and progressively heated by microwave irradiations, this produced non-eroding matrices that released water soluble drugs (Quinacrine dihydrochloride) by various diffusion-controlled mechanisms The transition from one mechanism to other is the function of length of time of microwave irradiations (at a fixed energy level) and equilibrium moisture content [56]. Tablet formulations of Diltiazem hydrochloride were prepared using plantago (ispaghula) seed husk as a hydrophilic matrixing agent that was physically modified. This physical modification was carried out in a microwave oven. Microwave oven treated samples showed rigid gel formation and were studied using exposure time and amount of water as independent variables. Duration of microwave exposure was found to have a predominant effect in sustaining the drug release. The tablets exhibited more axial swelling than radial swelling. The results revealed that the drug release pattern fitted well in the Higuchi model [57]. Surface solid dispersions of Felodipine were prepared by various solvent free methods using silicon dioxide and sodium chloride as carriers. The solid dispersions were characterized using Differential Scanning Calorimetry (DSC), X-ray powder diffractometry, and Dissolution studies. The use of vacuum or microwave energy led to a significant improvement in Felodipine dissolution [58].

4.THAWING

Freeze stored drugs are brought to normal physiological temperature before administration especially if an injection. Such a process is called as thawing. One of the methods for thawing is the use of microwave. Stability of majority of drug preparation was unaffected except for some preparations, thus providing criticism for microwave thawing [59]. The stability of many drugs both physical and chemical was not affected after microwave thawing [60-88]. Microwave thawing reduced process cost as well as preparation time [73-82]. G. J. Sewell, A. J. Palmer & P. J. Tidy showed the effect of infusion volume, infusion load size and microwave power on rate of thawing. Frozen infusions of 100-500 ml volume were thawed evenly and reproducibly without overheating. Linear relationships were demonstrated for microwave power output and thawing rate and for infusion load size and thawing time. It was noted that these relationships enable predetermination of microwave thawing times. On the basis of the results guidelines for this system were developed [89]. Microwave thawing also caused about 10% reduction in microbial count [64]. Cloxacillin sodium, Flucloxacillin sodium and Ticarcillin disodium were reconstituted in 0.9% sodium chloride and in 5% dextrose solutions, stored frozen for up to 9 months, and stability of the antibiotics were assayed following microwave thawing.  All of them retained at least 90% of their original potency throughout the study period. However, Cloxacillin and Flucloxacillin in 5% dextrose showed a yellow discoloration after 6 months' storage. It was suggested that these 2 formulations not be stored for more than 3 months before use [90]. The stability of intravenous Augmentin (Amoxycillin sodium and Clavulanate potassium) in a range of vehicles was investigated. Aqueous solutions frozen at –20 C and thawed by microwave radiation lost more activity than those stored at 25 C [91]. Intravenous Adriamycin (Doxorubicin hydrochloride) could not be thawed with microwave as it got overheated leading to decomposition of the drug [92]. Thawing frozen solutions in a microwave oven adversely affected the stability of Cefuroxime sodium (Zinacef) in aqueous solutions, with or without phosphate buffer, and in 5% dextrose and 0.9% sodium chloride injections. Local sequestration of the antibiotic during freezing and that of heating rapidly to boiling may be the possible reason for degradation during microwave radiation [93 & 94]. It was observed that oligo-elements are unstable when stored at -20 C for 60 days and then thawing in a microwave oven.  They must be added after defrosting the solution [84]. The stability of 6 antibiotics in IV fluids in polyvinyl chloride (PVC) containers after freezing and microwave thawing were established.  Tobramycin sulfate 160 mg, Amikacin sulfate 1 g, Ticarcillin disodium 3 g, Clindamycin phosphate 300 mg, Nafcillin sodium 1 g, and Ampicillin sodium 1 g were diluted in plastic bags of 5% dextrose injection 50 ml. Ampicillin sodium was also diluted in plastic bags of 0.9% sodium chloride injection 50 ml. All antibiotics except Ampicillin retained 90% or more potency when microwave thawed after storage at –20 C for 30 days, and after subsequent storage at room temperature for 24 hr [95]. 

5.  PREPARATION OF TISSUES FOR STUDIES

The separation of dermis & epidermis is very important in the evaluation of topical/transdermal dosage forms and pro-drugs. The different methods for this are 1) Chemical 2) Hot water immersion 3) Enzyme digestion 4) Adhesive tape stripping 5) Mechanical. They are tedious, having their own disadvantages.

Using a simple microwave oven it was possible to separate epidermis & dermis from the intact skin. This required exposure only to the microwave for a specified time and then the two layers could be peeled off. However, it needed prior calibrations of the equipment for specific skin area & point of placement in the oven. This would help in various invivo and invitro modalities.

In invivo studies, the skin area from the animal was removed and then exposed to microwave energy. In invitro studies the vertical diffusion cells, at the conclusion of the experiment is exposed to microwave energy for time & position, the layers are separated & then used for further studies. Nevertheless, it still has one more advantage, its utility in preparation of membranes for permeability studies.

Words of precautions: - Possibility of shrinkage and alteration in the permeability characteristics of the dermal layers [96].

6.OINTMENT PRODUCTION

   Various ointments were prepared according to official monograph of German Pharmacopoeia 9 (DAB 9). During this, heating ability of microwave was evaluated. The products were prepared at various uncontrolled temperatures including the one adjusted to official preparation method. Ointments prepared by this method (both controlled & uncontrolled) were evaluated for organoleptic, microbiological & rheological qualities of ointments. The ointments prepared with microwave & traditional methods did not show any significant difference [97].   

7.REDISSOLUTION OF PRECIPITATED MATTER

The study was carried out for the use of microwave to redissolve the precipitated matter from the injections. Simple microwave oven was used to redissolve these materials. It was found that the time required to redissolve them using microwave was less than through other means, such as autoclave & hot water bath. There was no change in the potency of the injections studied [98-99].

CONCLUSION

Though few references hint towards lack of support for microwave, there are many reports favoring its use. Having several advantages microwave is emerging as need of the day. It has shown definite benefits over conventional ways of heating in thawing, drying, sterilization, and production of sustained release dosage units etc. Knowledge available for safe & efficacious use of this energy is growing day by day. It can be concluded that microwave energy will have an enhanced and prominent role to play in pharmacy.  

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56) C. D. Teng and M. J. Groves, “Microwave thermal denaturation of protein matrices as control release devices”, J. Controlled Release, 13 (1) 43 –49 (1990).

57) M. C. Gohel and K. V. Patel, “Formulation optimization of Diltiazem hydrochloride matrix tablets containing modified ispaghula husk using factorial design" , Drug Dev. Ind. Pharm. 23 (11) 1055 –1061 (1997).

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64) P. J. Tidy, G. J. Sewell and T. M. Jefferies, “Microwave freeze-thaw studies on Azlocillin infusion”, Pharm. J. 241(Nov 12 Suppl) R22-R23 (1988).

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66) F. Kedzierewicz, C. Finance, A. Nicolas and M. Hoffman, “Comparative study of the stability of Carbenicillin solutions in relation to temperature: effect of cyclic freezing-thawing in microwave oven”, Pharm. Acta. Helv. 62 (4) 109 –115 (1987).

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69) L. M. Stolk, A. Fruijtier and R. Umans, “Stability after freezing and thawing of solutions of Mitomycin C in plastic minibags for Intravesical use”, Pharm Weekbl Sci. 8 (Dec 12) 286 –288 (1986).

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71) L. Keusters, L. M. L. Stolk, R. Umans and P. Van Asten, “Stability of solutions of doxorubicin and epirubicin in plastic minibags for Intravesical use after storage at -20DGC and thawing by microwave radiation”, Pharm Weekbl Sci, 8 (Jun 20) 194 –197 (1986).

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73) P. H. Thomas, R. L. Tredree and M. I. Barnett, “Evaluation of two microwave ovens for thawing intravenous solutions stored at -25 C”, Br. J. Parenter. Ther. 5 (Jul) 144 -146, 148, 149, 152 and 153 (1984).

74) B. Kirk, C. D. Melia, J. V. Wilson, J. M. Sprake and S. P. Denyer, “Chemical stability of Cyclophosphamide injection: effect of low temperature storage and microwave thawing”, Br. J. Parenter. Ther. 5 (May) 90, 92, 94, 96 and 97 (1984).

75) D. E. Hilleman, G. K. McEvoy, R. T. Bailey and J. Reich, “Stability of Cephapirin sodium admixtures after freezing and conventional or microwave thaw techniques”, Hosp. Pharm. 19 (Mar) 202, 207, 211 –213 (1984).

76) V. Karlsen, H. H. Tonnessen and I. R. Olsen, “Stability of Cytotoxic intravenous solutions subjected to freeze-thaw treatment”, Nor. Pharm. Acta. 45 (2) 61—67 (1983).

77) G. T. Elliott, M. W. McKenzie, S. H. Curry, J. A. Pieper and S. L. Quinn, “Stability in Cimetidine hydrochloride in admixtures after microwave thawing”, Am. J. Hosp. Pharm. 40 (Jun) 1002 –1006 (1983).

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91) J. Ashwin, B. Lynn and C. B. Taskis, “Stability and administration of intravenous Augmentin”, Pharm. J. 238(Jan 24), 116 —118 (1987).

92) M. Williamson and J. K. Luce, “Microwave thawing of doxorubicin hydrochloride admixtures not recommended”, Am. J. Hosp. Pharm., 44 (Mar), 505 -- 510 (1987). 

93) V. D. Gupta and K. R. Stewart, “Stability of Cefuroxime sodium in some aqueous buffered solutions and intravenous admixtures”, J. Clin. Hosp. Pharm. 11 (Feb), 47—54 (1986).

94) E. Tabor and R. Norton, “Freezing and rapid thawing of antibiotic admixtures”, Am. J. Hosp. Pharm. 42 (Jul) 1507—1508 (1985).

95) C. J. Holmes, R. K. Ausman, R. B. Kundsin and C. W. Walter, “Effect of freezing and microwave thawing on the stability of six antibiotic admixtures in plastic bags”, Am. J. Hosp. Pharm. 39 (Jan) 104—108 (1982).

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99) M. L. Kleinberg, G. L. Stauffer and C. J. Latiolais, “Effect of microwave radiation on redissolving precipitated matter in fluorouracil injection”, Am. J. Hosp. Pharm., 37(May), 678—679 (1980).  

Chivate Amit Ashok, Poddar Sushilkumar Sharatchandra^*

Correspondence Address: Dr. S. S. PoddarDepartment of Pharmaceutics, Prin. K. M. Kundnani College of Pharmacy, Dr. R. G. Thadani Marg,      Worli Sea Face, Mumbai – 400 018 (India)

Email:amitchivate@rediffmail.com, ssp306@rediffmail.com

Telephone No: - +91-22-25688845, +91-251-2609571.

Affiliation: - Principal K.M.Kundnani College of Pharmacy, Plot 47, R.G.Thadani Marg, Worli Sea face, Mumbai 400018.

Dr. S. S. Poddar^*

Dr. S. S. Poddar done Masters and Doctorate in Pharmacy with specialization in Pharmaceutics. He has more than 25 years of rich experience in teaching and guiding U.G. & P.G. students. His specialization is in the field of development of Novel Drug Delivery Systems. There are about 15 National/International publications and 130 National/International presentations. Many of them have been awarded as best papers. He has industrial links ups for formulation development and scale up activities and also with other institutes as advisor for P.G. & Industrial collaboration activities. He is also member of government quality evaluation body for teaching institutes

Mr. Amit A. Chivate
Mr. Amit Chivate is pursuing his Masters in Pharmaceutics under the able guidance of Dr. S. S. Poddar. He has one International presentation at 32nd Exposition of Controlled Release Society, Hawaii, USA and 6 National presentations. He has published one International and 2 National publications. His area of specialization is in drug delivery of enzymes & peptides through oral route by preparing pellets using extrusion – spheronization technology.