FORMULATION AND IN-VITRO EVALUATION OF ANTIEMETIC ORODISPERSIBLE COMBINATION TABLETS OF DOMPERIDONE AND CINNERIZINE BY USING VARIOUS SUPERDISINTEGRANTS

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ABOUT AUTHORS:
Rajmahamad H. Shaikh¹*, Mohsin J. Jamadar¹, Amol D. Patil¹, Audumbar D. Mali², Sanauaha M.Tamboli^1
1Department of Pharmaceutics, Appasaheb Birnale college of Pharmacy, Sangali, Maharashtra, India.
²Department of Pharmaceutics, Sahyadri College of Pharmacy, Methwade, Sangola-413307, Solapur, Maharashtra, India
rajshaikh71@gmail.com

ABSTRACT:
The purpose of this investigation was to enhancement of solubility of cinnarizine by using solid dispersion technique solvent evaporation method using polymer PEG 6000 & develop combination ODT of cinnarizine with domperidone by using direct compression technique using crospovidone, croscarmellose sodium and sodium starch glycolateas a superdisintegrants. The preformulation study includes the compatability of drugs with the polymers by using FTIR,UV,TLC. The batches were evaluated for weight variation, hardness, friability, drug content, wetting time, IN In-vitro dispersion, in-vitro dissolution. The formulation F2 which contain 8% crospovidone and 10 % sodium starch glycolate showed best results and rapid in-vitro dissolution. The results revealed that the tablets containing superdisintegrants combination had a good dissolution profile. The drug content of all the batches was within the acceptable limits of the United States Pharmacopoeia with maximum drug being released at all timeintervals. The present study demonstrated potentials for rapidabsorption, improved bioavailability, effective therapy and patientcompliance. The results conclusively demonstrate successful enhancement of solubility, disintegration and dissolution of the formulated tablets.

REFERENCE ID: PHARMATUTOR-ART-2335

INTRODUCTION:
Many orodispersible tablets available in pharma market are single drug tablets & no combination form of orodispersible tablets is available in the market. Hence it is new drug delivery system that is alternative to conventional tablets. Domperidone and cinnarizine combination is rational combination and this combination is available in the market in conventional dosage form. but this combination not available in orodispersible tablet form which has fast dissolution, disintegration & better result than conventional tablets. Oro-dispersible tablet (ODT) is "A solid dosage form containing medicinal substance or active ingredient which disintegrates rapidly usually within a matter of seconds when placed upon the tongue”.The aim of this study is to formulate directly compressible rapidly disintegrating tablets of Domperidone and Cinnerizine and investigates different factors affecting the formula like the effect of diluents, the type and concentration of superdisintegrant (SD) on the characteristics of the resulted ODTs, and perform physical and chemical evaluation of the prepared formulas. Also to prepare ODTs that contains combination of Domperidone and Cinnerizine for the use in diseases that need antiemetic effect^[1].

MATERIAL AND METHODS:
Domperidone (Gift sample from Vasudha PharmaChem LTD. Andhra Pradesh.), cinnarizine (ZCL Chemicals LTD. Mumbai), crospovidone, croscarmellose sodium, sodium starch glycolate  (Maple Biotech PVT LTD, Pune), microcrystalline cellulose, magnesium stearate (Loba chemicals. Mumbai), sodium saccharine, colour and flavour (Symbiosis Pharmaceuticals, Sangli).

METHODS:
Formulation and optimization of solid dispersion:
Solvent evaporation systems were prepared by dissolving the quantities of cinnarizine as indicated in table no. 6, 7(equivalent to 20 tablets) in dichloro-methane to produce a clear solution, and then the solution was added in the various quantities of Polyethylene glycol 4000 and polyethylene glycol 6000 as per Table No.1,2. This was evaporated to form solid mass at 40⁰C with constant stirring with the help of magnetic stirrer. Then dry mass was collected, triturated. Dried power was passed through sieve no.60 and stored in desiccators until further evaluation. The binary system was optimized after studying its solubility study and entrapment^[2].

Table No 1:- Formulation of binary system with PEG 4000

Table No 2:- Formulation of binary system with PEG 6000

PHYSICOCHEMICAL EVALUATION OF THE COMPRESSED TABLETS:-^[2].

PREFORMULATION STUDY:-

FTIR spectroscopy:- IR spectrum showed dominant characteristic peaks of cinnarizine

Fig. No 1: IR spectrum of cinnarizine

IR spectrum of domperidone: IR spectrum showed dominant characteristic peaks of domperidone.

Fig. No 2: IR Spectrum of domperidone.

UV Spectrum:-Maximum absorption of cinnarizine was found to be 253 nm. This is characteristic property of cinnarizine in its pure form. Hence, it can be conformed that received sample is authentic^[3].

Fig. No 3: UV spectrum of cinnarizine

Maximum absorption of domperidone was found to be 284 nm. This is characteristic property of domperidone in its pure form. Hence, it can be conformed that received sample is authentic.

Fig. No 4: UV spectrum of domperidone.

Compatibility study:
The proper design and formulation of a dosage form requires consideration of physical, chemical and biological characteristics of all the drug substance and excipients that used in fabricating the product. The drug and the excipients must be compatible with one another to produce a products that is stable, effective, attractive, easy to administer and safe.

IR compatibility study:
Drug and all the polymers showed characteristic spectrum of their functional groups. All the physical mixture showed characteristics peaks of drug corresponding to N-H functional group. It indicated that the drug and polymer does not have any major interaction. Therefore it is enough to consider that the drug is compatible with given excipients ^[4].

Fig. No 5: IR Spectra study of pure drug (Dom+Cinn+ PEG 6000)

Fig. No 6: Initial IR Spectra study of physical mixture. (Dom+Cinn+ PEG 6000)

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CALIBRATION CURVE:
Calibration curve of cinnarizine (In pH 6.8):- observed values are listed below: The scanning of drug solution was done in the UV region 200-400nm to find out the wavelength of maximum absorption (λ_max) in the pH 6.8. The λ_max was found to be 284nm and 253 nm for domperidone and cinnarizine respectively. The calibration curve was linear between 3 to 15 µg/ml concentration ranges, the standard calibration curve was obtained by plotting absorbance vs concentration, and it follows Beer’s law ^{[5, 6]}.

Fig.No 7: Calibration curve of cinnarizine

Fig. No 8: Calibration curve of domperidone

Phase solubility study:
Solubility of cinnarizine in SSF was found to be 0.039 mg/ml this indicated that cinnarizine is practically insoluble in SSF.Graph and various parameters computed from the phase solubility studies (Table No. 3) showed a non linear increase in drug solubility with increased in carrier levels. Hydrophilic carriers are known to interact with drug molecule mainly by electrostatic forces and occasionally by other type of forces, like hydrogen bonding ^[7].

Table No.3:- Phase solubility study with PEG 6000

All value are mean ±S.D (n=3)

EVALUATION AND CHARACTERIZATION OF SOLID DISPERSIONS:

Drug entrapment:
The percentage of drug entrapment of various binary solid dispersions of cinnarizine prepared by solvent evaporation method is given in Table No.4 & 5 respectively. Polyethylene glycol 6000 showed higher percentage of drug entrapment. The values are ranging between 88.67±0.256 % to 96.22±0.354% and for PEG 4000 the drug entrapment was found to be in the ranging of 82.45±0.236 % to 91.97±0.342 %. Batch F4 showed higher percentage of drug entrapment with PEG 6000, while batch T7 showed higher drug entrapment with PEG 4000 ^[8].

Table No. 4: Drug entrapment of binary solid dispersion by using PEG 6000

All value are mean ±SD. (n=3)

Table No. 5: Drug entrapment of binary solid dispersion by using PEG 4000

All value are mean ±SD. (n=3)

Solubility studies:
Improved dissolution behavior of solid dispersion of drug can be attributed to increase the solubility of drug as per Noyes Whitney equation. Solid dispersion system leads to reduction in particle size; increase in hydrophilicity or due to micellar solubalization of drug because of which there is an enhancement of solubility. This effect was confirmed by conducting similar saturation solubility studies on untreated drug as control.There are various reports that withstand the increased solubility of cinnarizine with polyethylene glycol especially PEG 6000 that facilitates solubalization of poorly water soluble drugs ^{[9, 10]}.

Table No. 6: Solubility study of binary solid dispersion

All value are mean ±SD. (n=3)

The binary solid dispersion values were found to be 332.4±0.05 to 1198.1±0.17 µg/ml for PEG 6000.

IR Spectroscopy:
Drug and excipients interaction play a crucial role with respect to the stability and potency of the drug. FTIR techniques a have been used here to study the physical and chemical interaction between drug and excipients used. Compatibility studies were performed using FTIR spectrophotometer, the IR spectrum of pure drug cinnarizine and physical mixture of drug and polymer were studied. The FTIR scan shows characteristic absorption peak of cinnarizine 2808 & 3067 cm^-1 respectively.The peak obtained spectra of drug have correlation with the peak obtained when the drug and excipients were scanned together, thus indicating that drug was compatible with formulation, excipients. Based on this study it was concluded that there is no chemical interaction between drug and excipients used and thus it can be safely used in formulation ^[11].

Fig. No 9: IR spectra of drug and binary solid dispersion with PEG 6000

Drug release study:
Dissolution profile of pure cinnarizine& solid dispersion were indicated differences between dissolution rates. Solid dispersion showed enhancement in dissolution as compared to pure cinnarizine, which indicated the effect of PEG 6000 on cinnarizine. The system prepared with PEG 6000 resulted in dissolution enhancement. Extremely high concentration of cinnarizine in the state was maintained for the entire dissolution span in the case of PEG 6000 system. Solid dispersion of PEG 6000 showed more than 50 % drug released within 20 min ^{[12, 13]}.

Table No 7:- Drug release study for formulation S1,S2,S3

All value are mean ±SD. (n=3)

Table No. 8:- Drug release study for formulation S4, S5,S6