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European Journal of Scientific ResearchISSN 1450-216X Vol.46 No.2 (2010), pp.194-203 EuroJournals Publishing, Inc. 2010http://www.eurojournals.com/ejsr.htm

Evaluation and Standardization of Essential Oils for

Development of Alternative Dosage Forms

Anupam K SachanDayanand Dinanath College, Institute of Pharmacy, Kanpur, India

Nikhil K SachanUniversity Institute of Pharmacy, Chhatrapati Shahu Ji Maharaj University, Kanpur, India

E-mail: [email protected]: +91-9307755497; Fax: +91-512-2573231

Shailesh Kumar

Dayanand Dinanath College, Institute of Pharmacy, Kanpur, India

Ayushy Sachan

Dayanand Dinanath College, Institute of Pharmacy, Kanpur, India

Sudhir S. Gangwar

Department of Pharmacy, G.S.V.M. Govt. Medical College, Kanpur, India

Abstract

Conventional means for delivery of essential oils are elixirs or the soft gels. In

present study, the chewable tablets are proposed as means for their utility in delivery ofvolatile therapeutic ingredients like essential oils as a better alternative of conventionaloptions. This study envisage the pharmaceutical characterization and evaluation of carawayoil and peppermint oil through marker compounds using TLC, HPLC, HPTLC and gaschromatography. The two oils are used internally for symptomatic treatment of irritablebowel syndrome, and digestive disorders such as flatulence, gastritis antispasmodic,carminative, analgesic and for cure of dyspepsia. The oils were loaded to granulespreviously standardized through GC and HPTLC for their identity and quantification ofmarker compound, and their compatibility testing with excipients was performed usingTLC and HPLC. Accelerated stability testing, for availability of marker compound informulated tablets, conducted by storing the tablets under different stress conditions.

Keywords: Volatile oils, drug delivery, chewable tablets, chromatographicstandardization

1. IntroductionEssential oils have been used by human being since long back for various therapeutic purposes(Thompson, Coon, and Erenst, 2002) externally and internally, described in the pharmacopoeia,traditional systems of medicine and reported in folk medicine. The selected oils atheroleum menthaepiperitae (WHO) i.e. thepeppermint oil and caraway oil are having proven therapeutic potential andused internally for the treatment of non-ulcer dyspepsia, flatulence, gastritis also have antispasmodic,

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Evaluation and Standardization of Essential Oils for Development of Alternative Dosage Forms 195

carminative, analgesic, flavouring properties (British Herbal Pharmacopoeia, 1979; Wren, 1985;Wichtl, 1994; May, 1996). In India the two oils are used widely in different forms by common peoplefor the relief of dyspepsia, gastric spasm and carminative purpose in the form of aromatic waters, softgelatin capsules or as elixirs, moreover the people are taking several products as breath freshener. Thepresent concept to formulate these essential oils in the form of chewable dosage forms so that these canbe administered for such therapeutic uses and can provide simultaneously breath freshness to consumerin view of the urban lifestyle. Chewable dosage forms, such as soft pill, tablets, gums, and, most

recently, chewy squares,have long been part of the pharmacists armamentarium (Liberman,Lachman and Schwartz, 2005). Delivery of essential oils through chewable tablets offers betterpalatability, by-passing first pass metabolism, better bioavailability through enhancing dissolutionsteps, patience convenience for the no need of water for swallowing, rapid onset of action, improvedpatient acceptance (especially in pediatrics) through pleasant, and product distinctiveness from amarketing perspective, improved entrapment stability and comparative low production cost (Sachan,2005). The people usually suffering with the gastric problems and used to take these oils veryfrequently and the fresh feel that can be rendered by such chewable dosage forms will be an addedadvantage. The present study proposed and examined a commercially feasible approach forstandardization and quantification of the peppermint oil and caraway oils for their further formulationto chewable tablets as a better alternative of conventional options.

Aetheroleum Menthae Piperitae (peppermint oil) is the essential oil obtained by steamdistillation of the fresh overground parts ofMenthapiperita L. (Labiatae), commercially cultivated inIndia, eastern and northern Europe and the United States of America, and is found in Africa (FCC,2001). The plant is vernacularly known as Amentha, american mint, balm mint, brandy mint, cabra-caa, curled mint, dounmenta piperita, hierbabuena, hortela pimenta, Katzenkraut, lamb mint, lamenta,lamint, mentapiemonte, mentea peperina, mentha pepe, menthe, menthe anglaise, menthepoivre, motoyuyo, nna, ni naa, nina el fulfully, pepermin, pepper mint, peppermint, Pfefferminze,Pfefferminzbltter, piperita, pudeena, pum hub, yerba mota. It is a perennial herb, with 3090cm hight,stems square erect or ascending, branched, the upper portion always quadrangular and leaves opposite,petiolate, ovate-oblong to oblong-lanceolate, serrate, pointed; dark green on the upper surface (Foster,1996). The peppermint oil is a colourless or pale yellow or a pale greenish yellow liquid with its

characteristic penetrating odour and characteristic pungent taste followed by cooling sensation (Peirce,1999). The major constituents are menthol (3055%) and menthone (1432%). Menthol occurs mostlyin the free alcohol form, with small quantities as the acetate (35%) and valerate esters. Othermonoterpenes present include isomenthone (210%), 1, 8-cineole (614%), a-pinene (1.01.5%), b-pinene (12%), limonene (15%), neomenthol (2.53.5%) and menthofuran (19%). It is taken 0.2 to0.4 ml three times a day for therapeutic use or may be taken in such doses when felt required by aperson for removal of mouth odour or as breath freshener (Adams, 1995; Scavroni et al., 2005).

Caraway oil is the essential oil obtained by steam distillation of the dried, ripe fruit of Carumcarvi, Linne (Family: Umbelliferae), found in Europe, Siberia, Caucasus, India, Mongolia andMorocco etc. Caraway is normally a biennial much-branched herb, 30 - 80cm in height, with narrowfinely grooved leafy stems. It produces a deep taproot and a rosette of dark green, finely cut, feathery

leaves in the establishment year. It has a high vernalisation requirement to initiate the production offlowering stems in the second year, which grow to a height of up to 75cm. The flowers are producedon umbels, are white and 2-3 mm across, the outer ones larger than the inner ones. They open from lateApril onwards and are succeeded by fruits which are 3-6 mm long, and light brown, ripening fromearly July. Oil is a clear, colourless or pale yellow liquid, visibly free from water with characteristicaromatic odour and a caraway taste. Caraway oil contains 50 to 60% of the ketone carvone and from 40to 50% of the terpene d-limonene with small amounts of other constituents, including carveol anddihydrocarvone (B.P. 1988). The average single dose of oil is 2 to 3 drops on sugar. The average dailydose of oil is 3 to 6 drops essential oil for internal use (Schulz, Hnsel, Tyler, 1998; Grieve, 1982;Castleman 1991).

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196 Anupam K Sachan, Nikhil K Sachan, Shailesh Kumar,Ayushy Sachan and Sudhir S. Gangwar

The oils were subjected to identification as per compendia method by TLC and quantificationby gas chromatography and by HPTLC identifying a marker compound and subjected to acceleratedstability testing one by one and in combination to demonstrate the physical and chemical stability of adrug product at a variety of environment conditions including temperature, humidity & light (USP24/NF18, 2000). Requirements for stability studies are defined in several international conferences onharmonization guidelines and include storage conditions of 250C/60%RH, 300C/60%RH and 400C/75

% relatively. A drug-excipient compatibility analysis was performed by storing the pre-compressedgranules formulated for tablet preparation in glass vials at different storage conditions.

2. Materials and Methods2.1. General

Materials: Peppermint oil (Arora Pharmaceuticals), Caraway oil (Siva Aromatics), Mannitol (GetecLtd), Dicalcium phosphate (Enar Chemie Ltd), Hydroxy propyl cellulose (Dow Chemicals), Syloid(W.R. Grace), Cabosil (Cabot Sanmar Ltd), Stearic acid(Mallinckdrot), Magnesium stearate (S. KantHealthcare), Fl Novamint Peppermint 5060 40T (Firmenich), Fl Taste Mask Powder 501482 T P0424(Firmenich), ProSolv SMCC50 (Penwest), NutraSweet Powder (NutraSweet), Carbopol 974 P NF(Noveon). Instruments: Planetary mixer (M/s Dito Sama, France), Tablet friability test apparatus(Arkey Labtromix, India), Monsanto tester (Aarkey Labtromix, India), Fluidized bed dryer (RetschGmbh & Co, Germany), USP Tapped density apparatus (Electrolab, India), Rotatory tabletcompression-machine (Rimek, India), Mechanical stirrer (Remi, India), Digimatic caliper (Mitutoyo,Japan), Humidity chamber (Thermolab, India), 784KFP Titrino (Metrohm), HPTL Chromatography(Camag, Switzerland), I.R. moisture balance (Guru Nanak Instrument, India), Clarus500 GasChromatograph (Perkin Elmer).

2.2. Methods

Identification of the Marker Compound: Identification of the marker compoundwas carried out by

thin layer chromatography; the samples were applied in the form of bands on a precoated silica gelGF254 aluminium plate (Camag, Switzerland). The solvent system of toluene and ethyl acetate (95:5)was used for the development; compounds were detected by spraying anisaldehyde sulfuric acidreagent after drying at 1050C for 5 minutes. The plate was visualized after spraying anisaldehydesulfuric acid reagent and Rf values for standard and samples were recorded and colour of band wasmatched (Mukharjee, 2002; Harbone, 1998; Abourashed et al., 2004; Jones, 1998; krinjar, 2009).

Quantitative Estimation of the Marker Compound: High Performance Thin Layer

Chromatography: Quantitative estimation of the marker compound was carried out by HPTLC; thesamples were applied in the form of bands on a precoated silica gel GF254 aluminium plate (Camag,LinomatIV, Switzerland). The solvent system of toluene and ethyl acetate (95:5) was used for thedevelopment, compound were detected by spraying anisaldehyde solution after drying at 1050C for 5minutes. The plate was visualized after spraying anisaldehyde sulfuric acid reagent. The scanning wasdone at max-515 nm for carvone and max-610 nm for menthol, using Camag TLC scanner 3.Regression analysis and statistical data were generated. Draw calibration curve of menthol and carvoneand then calculated the marker compound in the sample with reference to area by using wimCATSPlanar Chromatography Manager(Jones, 1998; krinjar, 2009; Mukharjee, 2002).

AREA (sample) X DILUTION (standard) POTENCYFORMULA = ---------------------------------------------- X ------------------X100

AREA (standard) X DILUTION (sample) 100

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Gas Chromatography: A very dilute concentration of peppermint oil and caraway oil was runin the column DB-1 (30mx250m) with reference to standard menthol and carvone. The flow rate was0.8ml/min; tenperature maintained 900C for 5 minute1500C for 5 minute and 2300C for 10 minute.Injector and detector were used 2400 and 2800C respectively. The quantitative amount of markercompound was calculated in the sample with reference to the area by using CLARUS-500GasChromatograph (Mukharjee, 2002; Adams, 1995).

AREA (sample) X DILUTION (standard) POTENCYFORMULA = ------------------------------------------- X ----------------X100

AREA (standard) X DILUTION (sample) 100

Drug Stability Studies: The drug (peppermint oil & caraway oil) was packed in sealed glass vialsindividually and the admixture of both the drug at the ratio 1:1 were kept at different storageconditions, 50C, 250C & 60%RH and 400C&75% relative humidity for one month and evaluated afterinterval of one week (ICH Guidelines, 2003).

Drug- Excipients Compatibility Studies: Admixtures of the drug and excipients was mixed properlyin proportions of 1:5 respectively and packed in glass vials, then compatibility studies3 was done by

storing at different storage conditions50C, 250C & 60%RH and 400C&75% relative humidity for onemonth and evaluated after interval of one week (Bhattacharya et al., 2006; IPEC, 2008; Liberman,Lachman and Schwartz, 2005).

3. Results and Discussion3.1. Identification of the Marker Compound

The menthol and carvone were taken as suitable markers for the estimation of peppermint and carawayoils respectively, and were identified for their presence in the essential oils samples by highperformance thin layer chromatography by taking the standard marker compound loaded side by side

in the TLC and comparing colour and retention factor after development of plate (Jones, 1998;krinjar, 2009; Mukharjee, 2002). Results of HPTLC chromatograms (Fig. 1) of samples depicted thesame Rf value and colour of the peak for essential oil samples by high performance thin layerchromatography as of the, selected marker compounds for quantification of the essential oils (Table 1).

Figure 1: HPTLC plate chromatogram of oils and standard marker compounds

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Table 1: Identification of the marker compound

Description Standard

(Menthol)Peppermint

oil

Standard

(Carvone)Caraway oil

Rf values 0.22 0.23 0.52 0.52Colour Blue Blue Raspberry Red Raspberry Red

3.2. Physical Standards

Essential oils were subjected to tests for physical parameters for compliance or otherwise not with thepharmacopoeial standards. The results tabulated below (Table 2) for two oils showed them to becompliant with the standard limits, which supports the identity of sample and give an indication abouttheir quality (Singhal, Kulkarni, Rege, 2001; B.P. 1988, Jones, 1998).

Table 2: Physical standards of the peppermint oil and caraway oil

Sample. Colour Odour Acid

Value

Relative

Density

Refractive

Index

Optical

Rotation

Miscibility

Peppermint

oil

Greenishyellow

Characteristic 0.83 0.912 1.451 -213 Miscible with ethanol (96%),ether & methylene chloride

Caraway oil Paleyellow

Characteristic 0.41 0.904 1.484 +782 Miscible in 2-10 volume of80% ethanol, withopalescence; clearly solublein equal volume of 90%alcohol.

3.3. Quantitative Estimation of Marker Compound

Quantitative estimationof the marker compound, carried out by HPTLC (Fig. 2) and GC (Fig. 3), theGC seems to be a better accurate method than HPTLC for the estimation of essential oil (Adams,1995). The percentage of marker compound estimated by both HPTLC and GC is shown in table 3.The methods are sufficiently reproducible and validated to be used for estimation of these oils. The GCand HPLC both are widely accepted techniques in the pharmaceutical industry thus it presents a scopefor these oils in herbal and polyherbal formulations (Mukharjee, 2002; Harbone, 1998; Abourashed etal., 2004; Jones, 1998; krinjar, 2009).

Figure 2.1: HPTLC chromatograms all tracks of standards (menthol) and sample at 610 nm

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Figure 2.2: HPTLC chromatograms all tracks of standards (carvone) and sample at 515 nm

Figure 3.1: Gas Chromatogram of CARVONE (Standard)

Table 3: Quantitative estimation of marker compound

S.N. Techniques Menthol (%w/w) Carvone (%w/w)

1. HPTLChromatography 58.64 58.532. Gas Chromatography 57.80 62.66

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Figure 3.2: Gas Chromatogram of menthol (Standard)

Figure 3.3: Gas Chromatogram of caraway oil (Sample)

Figure 3.4: Gas Chromatogram of peppermint oil (Sample)

3.3. Drug Stability Studies

A thorough knowledge of the chemical and physical stability of drugs and dosage forms is critical inthe development and evaluation of pharmaceuticals (Yoshioka and Stella, 2002). Chemical degradationand physical degradation of drug substances may change their pharmacological effects, resulting inaltered efficacy therapeutic as well as toxicological consequences. Because pharmaceuticals are used

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therapeutically based on their efficacy and safety, they should be stable and maintain their quality untilthe time of usage or until their expiration date (Yoshioka and Stella, 2002). The quality should bemaintained under the various conditions that pharmaceuticals encounter, during production, storage inwarehouses, transportation, and storage in hospital and community pharmacies, as well as in the home.Therefore, understanding the factors that alter the stability of these essential oils and identifying waysto guarantee their stability are critical before formulating any dosage form (USP, 2006). The DrugStability studies conducted for the peppermint and caraway oils showed that there was no physical

change observed in any sample of peppermint oil or caraway oil or their mixture in 1:1 ratio storedunder 50C, 250C with 60%RH, and 400C with 75%RH stored in glass vial packaging moreover therewas no any new peak or alteration of retention time observed for these samples when compared withzero time observations under similar conditions. Thus the two oils are sufficiently stable suitable forthe formulation of chewable tablets and there is no any degradation observed on accelerated stabilitytest condition for a month time period.

3.4. Drug- excipients Compatibility Studies

Almost all pharmaceutical dosage forms include excipients (Sharma and Joshi, 2007). Indeed, in mostdosage forms the amounts of one or more excipients are greater than the amounts of the activepharmaceutical ingredients (APIs) present in them (Sachan and Singh, 2006). Excipients interact withthe API in the final formulated dosage form and/or provide a matrix that affects the critical qualityattributes of the active pharmaceutical ingredients, including stability and bioavailability (Crowley andMartini 2001). Excipients also influence the safety and effectiveness of drugs depending on the routeof administration, so qualitative and quantitative understanding of the excipients composition iscritically important to the understanding of a dosage forms bioavailability and bio-equivalence (USP2006; Sonal, S.Et al., 2008)

Table 4: Drug-excipient Compatibility Studies

Storage time: Four weeks Packing: Glass vials

StressConditions 5

0

C 25

0

C with60%RH

40

0

C with75%RH

Composition

of granules

Lactose, Sucrose, Mannitol, CMC Sodium, Mg stearate,Light Mg carbonate, Di calcium Phosphate, Talc,Aerosil, Syloid, Starch, Microcrystalline Cellulose, EthylCellulose, Hydroxypropyl- methyl cellulose, Stearic acid,Aspartame, ProSolv SMCC, Carbopol974P NF

No physical changesin samples and nonew peak observedin GC.



The quality of medicines depends not only on the active principles and manufacturing processbut this also depend upon performance of excipients (Sachan and Bhattacharya, 2006). The magnitudeof this effect will depend on the characteristics of the drug and on the quantity and properties of the

excipients. Chemical and physical stability of active ingredients in fixed dosage forms may becomevery complicated due to the presence of two or more active ingredients, or because potentially more orunique excipients are required to achieve the desired release rate for both actives (Roger, et al., 2009).Not only active ingredients may react each other to form degradants which may not seen in singledosage form, but also active ingredients may react with excipients which are otherwise compatiblewith one of single active ingredients (Jin, Madieh, Augsburger, 2007). These attributes create manynew challenges for formulation development and pharmaceutical analysis of fixed combinationproducts. Strategic design in drug-drug and drug-excipient compatibility studies and development ofappropriate analytical method which is able to detect all potential impurities, and degradants, are veryimportant in successfully developing a stable fixed combination dosage form (Klick, S. Et al., 2005).

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The Drug- Excipient compatibility studies showed that there is no change at accelerated storagecondition for a month time period.

4. Summary and Concluding RemarksIn conclusion, the peppermint oil and caraway oil were confirmed for their identity and could be

standardized for various parameters including the quantification by both HPTLC and gaschromatography. The method so developed is useful for routine analysis of these oils and can befurther adopted fot the assay of proposed chewable tablet dosage forms which seems to be promisingalternative of conventional means of therapeutic delivery of essential oils with added advantages ofmouth and breathe falouring, convenience of administration and low cost production. Drug excipientscompatibility study has shown no chemical interaction with volatile oil and excipients used. Thefurther research is ongoing towards the formulation, optimization, scale up, packaging and real timestability testing for the chewable tablet formulations with these essential oils.

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