Design and Development of Fast Dissolving Cinnarizine Tablets by Sublimation Technique

 

N.G. Raghavendra Rao¹*, Upendra Kulkarni² and Basawaraj S. Patil²

¹PG. Department of Pharmaceutics, Luqman College of Pharmacy, Gulbarga- 585 103, Karnataka, India.             ²Department of Pharmaceutics. RME’s College of Pharmacy, Gulbarga-585102, Karnataka, India.

*Corresponding Author E-mail: ngraghu@rediffmail.com

ABSTRACT:

Cinnarizine is a piperazine derivative with antihistamine, sedative and calcium channel blocking activity. It is used for the systematic treatment of nausea and vertigo for the prevention and treatment of motion sickness. In the present invention Fast dissolving tablets of Cinnarizine were prepared by sublimation method. The prepared formulations were evaluated for pre-compressional and post-compressional parameters. The compatibility of drug with other ingredients was checked by FTIR and DSC studies, these results revealed that there was no interaction between dug and other excipients. The values of pre-compressional parameters were within prescribed limits and indicated good free flowing properties. In all the formulations the hardness test indicates good mechanical strength. Friability of all formulations was less than 1. Drug content was found to be high (≥ 101.50%) and uniform in all the formulations. The tablet thickness was found to be 3.59 – 3.62. The weight variation results revealed that average percentage deviation was less then ± 7.5 %, which provides good uniformity in all formulations. The disintegration time of the tablets decreased significantly with increase in the concentration of subliming agent. The formulations C4 50 % of drug released in 6.25 min, and 90 %  of drug released in 19.74 min. Stability study carried out as per ICH guidelines for three months and results revealed that upon storage disintegration time of tablets decreased significantly (p<0.05). The results concluded that fast dissolving tablets of Cinnarizine with sublimation technique, an optimum point can be reached in the shortest time with minimum efforts and this technique would be an effective alternative approach compared with the use of more expensive adjuvants in the formulations.

 

 

 

INTRODUCTION:

Now a day fast dissolving tablets are gaining more importance in the market. Currently these tablets are available in the market for treating many disease conditions. More is concerned on hypertension, migraine, dysphasia, nausea and vomiting, Parkinson’s disease, schizophrenia, pediatric emergency^1-7. These conditions are those, which require the drug to be formulated as fast dissolving tablets. Some patient prefers fast dissolving tablets to conventional tablets best of ease of administration, swallowing, pleasant taste and availability in several flavors⁸.

 

The pediatric and geriatric patients are of particular concern. To overcome this, dispersible tablets⁹ and fast-disintegrating tablets¹⁰ have been developed. Most commonly used methods to prepare these tablets are; freeze-drying/lyophilization¹¹ tablet molding¹² and direct-compression methods¹³.

 

Lyophilized tablets show a very porous structure, which causes quick penetration of saliva in to the pores when placed in oral cavity¹⁴. The main disadvantages of tablets produced are, in addition to the cost intensive production process, a lack of physical resistance in standard blister packs and their limited ability to incorporate higher concentrations of active drug. Molded tablets dissolve completely and rapidly. However, lack of strength and taste masking are of great concern¹⁵. Main advantages of direct compression are low manufacturing cost and high mechanical integrity of the tablets.¹⁶

 

Cinnarizine is a piperazine derivative with antihistamine, sedative and calcium channel blocking activity. It is used for the systematic treatment of nausea and vertigo caused by Meniere’s disease and other vestibular disorders and for the prevention and treatment of motion sickness. It is also used in the management of various peripheral and cerebral vascular disorders^17-20. In the present invention Fast dissolving tablets of Cinnarizine were prepared for the immediate and effective treatment of motion sickness by adopting sublimation method.

 

MATERIAL AND METHODS:

Cinnarzine gift sample was obtained from Hikal Ltd Bangalore, crospovidone gift sample from Maple Biotech Pvt. Ltd Pune. Camphor, directly compressible MCC, mannitol, talc and magnesium stearate was purchases from S.D Fine Chemicals Mumbai. All other ingredients used were of pharmaceutical grade.

 

Preparation of Tablets:

Cinnarizine 25mg was taken and mixed with mannitol, directly compressible microcrystalline cellulose, superdisintegrant and different concentrations of camphor (1%, 2%, 3%, 5% and 10%) in a plastic container. Magnesium stearate, aspartame and talc were passed through sieve no. 60 and blended with initial mixture in the plastic container followed by direct compression of the blend (table-1). After compression the tablets were collected and vacuum dried at 60⁰C (Lab care Bangalore) until a constant weight was obtained to ensure the complete removal of sublimable component to make the tablet porous.

 

Table 1: Formula used in the preparation of Cinnarzine Tablets

 

Evaluation of Tablets:

Tablet was evaluated for hardness, friability, weight variation, thickness, disintegration time, wetting time, and stability study. The Pfizer hardness tester and Roche friabilator were used to test hardness and friability loss respectively. In weight variation test, 20 tablets were selected at random and average weight was determined using a electronic balance (Shimadzu, AX 200, Japan). Tablets were weighed individually and compared with average weight. Disintegration time was determined using USP Tablet disintegration test apparatus (ED 21, Electrolab, Mumbai) using 900 ml distilled water at room temperature. Thickness of the tablets was determined by using dial caliper (Mitutoya, model CD-6 CS Japan), wetting time study, a piece of tissue paper folded twice was kept in a culture dish containing 6 ml of distilled water.  A tablet having a small amount of amaranth power on the upper surface was placed on the tissue paper. The time required to develop a red colour on the upper surface of the tablet was recorded as the wetting time. For drug content analysis, a total 10 tablets were weighed and powered. The powder equivalent to 25 mg of Cinnarizine was taken and dissolved Hydrochloric acid buffer pH 2.0. After that an aliquot of the filtrate was diluted and analyzed spectrophotometrically (UV 1700 Shimadzu Corpn Japan) at 253 nm. Using 900 ml of Hydrochloric acid buffer pH 2.0 monitored in-vitro dissolution of Cinnarizine from tablets at 37 ± 0.5°C at 50 rpm using programmable dissolution tester (Paddle type, model TDT- 08 L, Electrolab (USP), India). Aliquots were withdrawn at 5 min time intervals and were replaced immediately with same volume of fresh buffer medium. Aliquots, following suitable dilutions were assayed spectrophotometrically at 253 nm. The stability study of the tablets was carried out according to ICH guidelines by storing the tablets in stability chamber (Lab-Care, Mumbai) at 40 ± 2°C / 75 ± 5 % RH for 3 months.

 

RESULTS AND DISCUSSIUON:

Since, the flow properties of the powder mixture are important for the uniformity of mass of the tablets, the flow of the powder mixture was analyzed before compression into tablets. The values of pre-compressional parameters were within prescribed limits as per USP XXVII and indicated good free flowing properties. The results are shown in Table 2. The post- compressional parameters results are shown in Table 3. In all the formulations the hardness test indicates good mechanical strength. Hardness of the tablets decreased with increase in the amount of sublimable component. Friability of all formulations was less then 1%, which indicates that the tablets had a good mechanical resistance. Drug content was found to be high (≥ 101.50%) and uniform in all the formulations. The tablet thickness was found to be 3.59 – 3.62. The weight variation results reveled that average percentage deviation of 20 tablets of each formula was less then ± 7.5 %, which provides good uniformity in all formulations.  The disintegration time of the tablets decreased significantly with increase in the concentration of subliming agent. The tablets prepared by sublimation technique rapidly exhibit high pores and disintegrates the tablets rapidly. It may be due to their lowest hardness and maximum porous structure was responsible for faster water uptake, hence it facilitates wicking action of crospovidone in bringing about faster disintegration¹. Wetting time of tablets was decreased with the increase in the concentration of the subliming agent.

 

Table 2: Pre-compress ional parameters of powder blend.

Formu lation	Parameters.
	Angle of repose (θ) (± SD), n=3	Compressibility (%) (± SD), n=3	Hausner’s ratio (%) (± SD), n=3
C	22.72 (0.37)	12.56 (O.67)	1.24 (0.08)
C1	21.49(0.29)	10.22 (0.58)	1.21 (0.09)
C2	23.55 (0.58)	11.44 (0.39)	1.18 (0.05)
C3	22.32 (0.95)	12.45 (0.68)	1.22(0.07)
C4	23.12 (0.38)	11.33 (0.89)	1.19 (0.04)

 

 

The dissolution of Cinnarizine from the tablets is shown in Fig 1. In-vitro dissolution studies on the promising formulation C3 and C4 and C control formulations without camphor were carried out in hydrochloric acid buffer pH 2.0, and the various dissolution parameter values viz., percent drug dissolved in 5 min, 10 min, 20 min and 30 min (D₅, D₁₀ D_20, and D₃₀ ), t _50%, and t _{90 %} are shown in Table 4. This data reveals that among all the formulation C4 shows nearly faster drug release.

Table 3: Post-compressional parameter of Cinnarzine tablets.

Parameters	Formulations
	C	C1	C2	C3	C4
Thickness (mm) (± SD), n=6	3.55 (0.27)	3.59 (0.33)	3.61 (0.42)	3.58 (0.52)	3.62 (0.22)
Weight variation  (±SD), n=20	0.6 (1.22)	0.9 (1.00)	0.7 (1.50)	0.3 (0.95)	0.8 (1.30)
Hardness test (Kg/cm2) (± SD), n=6	4.20 (0.10)	4.10 (0.34)	4.00 (0.45)	3.89 (0.76)	3.68 (0.45)
Friability (%) (± SD), n=10	0.52 (0.09)	0.41 (0.08)	0.56 (0.08)	0.49 (0.06)	0.39 (0.07)
Disintegration Time (Sec) (± SD), n=6	102 (5.00)	59 (3.00)	49 (4.00)	41 (2.00)	32 (3.00)
Wetting time (Sec) (± SD), n=6	202 (13.00)	100 (7.00)	89 (5.00)	76 (3.00)	64 (6.00)
Drug Content (%) (± SD), n=3	100.00 (0.92)	101.20 (1.20)	101.50 (1.00)	99.58 (0.90)	100.30 (1.38)

 

Table 4: In- vitro Dissolution parameters of different Cinnarizine fast dissolving tablet formulations.

Formulation Code	Parameters
	D 5	D 10	D 20	D 30	T 50%	T 90%
C0	20.14	27.96	41.74	54.69	> 20 min	> 60 min
C3	34.65	46.61	67.85	90.95	10.72 min	30 min
C4	40.00	58.57	91.15	99.81	6.25 min	19.74 min

C is control formulation without camphor, C3 and C4 is promising fast dissolving tablet formulation, D₅ is percent drug released in 5 min, D₁₀ is percent drug release in 10 min, D₂₀ is percent drug release in 20 min, D₃₀ is percent drug release in 30 min, t _50% is time for 50 % drug dissolution, t _90% is time for 90% drug dissolution.

 

 

Fig 1: Dissolution Profile of Cinnarizine tablets

 

The formulations C4 50 % of drug released in 6.25 min, and 90 %  of drug released in 19.74 min, C control formulations 50 % and 90 %  of drug released were more than 60 min. Dissolution of drug from tablet containing subliming agent (C1 - C4) were quicker than other formulation (C). It may be due to the highest porosity, lowest hardness and disintegrating property of MCC, which leads to faster water uptake hence it facilitates wicking action of crospovidone in bringing about the faster disintegration and dissolution.

 

The stability studies results revealed that decrease in the disintegration and wetting time was observed in all the formulations (Table 5). Since during sublimation method tablets were exposed to six hours at 60⁰ C only, where as 90 days and 45⁰ C were used during stability studies. The long storage of 90 days at 45⁰ C might have removed the trace amount of subliming agent.

 

IR spectrum of cinnarizine shows prominent peaks of C-H stretching of methylene groups 2767 cm^-1, 2809 cm^-1 and 2934 cm^-1, C=C aromatic ring stretching 1596 cm^-1, 1492 cm^-1 and 1449 cm^-1, C-N stretching 1357 cm^-1 and monosubstituted benzene ring stretch 706 cm^-1.  IR spectrum of formulation C4 shows, all the peaks corresponding to C-H stretching of methylene groups 2767 cm^-1, 2809 cm^-1 and 2934 cm^-1, C=C aromatic ring stretching 1596 cm^-1, 1492 cm^-1 and 1449 cm^-1, C-N stretching 1357 cm^-1 and monosubstituted benzene ring stretch 706 cm^-1of cinnarizine indicating that there was no interaction between cinnarizine and other excipients (Fig.2.)

 

Fig 2: FTIR spectrum of pure cinnarizine and formulation C4.

 

Table 5: Results of Stability Study

Formulation	Disintegration time (sec)  (±SD), n=6	Wetting time (sec) (±SD), n=6	Drug content (%) (±SD), n=6
C	101 (4.00)	201 (12.00)	99.98 (0.64))
C1	57 (2.00)	101 (6.00)	100.78 (1.00)
C2	48 (3.00)	90 (7.00)	101.20 (1.00)
C3	40 (2.00)	77 (4.00)	99.12 (0.60)
C4	31 (5.00)	63 (3.00)	99.89 (1.10)

 

DSC thermograms of cinnarizine (A) shows a sharp endothermic peak at 124.02⁰C, which slightly decreased to 122.65°C in formulation C4 (B) (Fig. 3). A slight decrease in the melting point may be due to the presence of subliming agent (camphor). Results indicated that the drug was compatible with the excipients used.

 

Fig 3: DSC thermogram of drug cinnarizine [A] and formulation C4 [B]

 

CONCLUSION:

The results of disintegration time, wetting time and dissolution rate revealed that the amount of subliming agent significantly affect the dependent variables like disintegration time, wetting time and dissolution rate. With the adopted sublimation technique, an optimum point can be reached in the shortest time with minimum efforts and this technique would be an effective alternative approach compared with the use of more expensive adjuvants in the formulation of fast dissolving tablets.

 

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Received on 23.11.2010          Modified on 08.12.2010

Accepted on 20.12.2010         © RJPT All right reserved