Development of Novel Co-Processed Excipients for the Design and Evaluation of Directly Compressible Tablets of Rizatriptan Benzoate

R.K.V. Naga Sudha*, G. Padmini, T.E.G.K. Murthy

Bapatla College of Pharmacy, Bapatla-522101, Guntur (District), Andhra Pradesh, India.

*Corresponding Author E-mail: nagasudharkv@gmail.com

ABSTRACT:

A novel co-processed excipient containing different ratios of lactose: maize starch were prepared and tested their suitability for development of direct compressible tablets of Rizatriptan benzoate. Rizatriptan is a 5-HT1 agonist, used in the treatment of migraine headaches, The Rizatriptan dose is 10mg, so it is suitable for direct compression but it has poor flow, poor disintegration, and poor compressibility. To overcome these problems, the tablets were formulated by using co-processing excipients (lactose and maize starch). Co-processed excipients with α-lactose monohydrate and Maize starch in different ratios (100:0, 0:100, 50:50, 60:40, 70:30, 80:20, and 90:10) were fabricated by wet granulation technique and its influence on blend fluidity, friability of the tablet and dissolution characteristics of Rizatriptan benzoate from direct compressible tablets were studied. The flow properties of the blends were determined by Carr’s index and Hausner’s ratio. Higher proportion of lactose and maize starch individually imparted low flowability, low disintegration properties, and failed to meet the friability. Optimized co-processed formulation containing lactose and maize starch in the ratio of 90:10 was found to be more acceptable to formulate Rizatriptan benzoate tablets.

KEYWORDS: Rizatriptan benzoate, 5-HT1 agonist, Co-processed excipients, Wet granulation technique, Direct compressible tablets.

INTRODUCTION:

Rizatriptan is a 5-HT1 agonist triptan drug developed by Merck and Co. for the treatment of migraine headaches. It is a white crystalline solid and freely soluble in water. Commercially it is available in a form of tablets with 5 and 10 mg strengths. It is also available as orally disintegrating tablets. Direct compression technique is easy way to formulate tablets as it includes limited number of processing steps and this technique is less expensive. The direct compression process is highly influenced by the physical characteristics of the blend containing drug and other adjuvents¹. Most formulations (70-80%) contain excipients at a higher concentration than the active drug. Ideal directly compressible adjuvant must exhibit good flowability and compatibility. No single adjuvant is likely to possess all the ideal characteristics.

For this reason, the current trend in industry is to use multifunctional co-processed excipients. Excipients with improved functionality can be obtained by developing new chemical excipients, new grades of existing materials and new combination of existing materials. New combination of existing excipients is an interesting option for improving excipients functionality because all formulations contain multiple excipients. Many possible combinations of existing excipients can be used to achieve the desired set of performance characteristics². A much broader platform for the manipulation of excipients functionality is provided by co-processing or particle engineering of two or more excipients. Co-processing excipients impart better preformulation characteristics compared to individual excipients or the physical mixture containing the combination of selected diluents. Major limitation of co-processed excipients mixture is that the ratio of the excipients in a mixture is fixed and in the developing a new formulation, a fixed ratio of the excipients may not be an optimum choice for the Active Pharmaceutical Ingredient (API) and the dose per tablet under development⁶. Usually a combination of plastic and brittle materials is used for co-processing.

Table 1. Composition of Rizatriptan benzoate tablets.

Ingredients	Formulation code (mg)
	F1	F2	F3	F4	F5	F6	F7
Rizatriptan benzoate	10	10	10	10	10	10	10
Lactose granules	85	-	-	-	-	-	-
Maize starch granules	-	85	-	-	-	-	-
Physical mixture of lactose and maize starch(50:50)	-	-	85	-	-	-	-
Co-processed excipients lactose and maize starch (60:40)	-	-	-	85	-	-	-
Co-processed excipients lactose and maize starch (70:30)	-	-	-	-	85	-	-
Co-processed excipients lactose and maize starch (80:20)	-	-	-	-	-	85	-
Co-processed excipients lactose and maize starch (90:10)	-	-	-	-	-	-	85
Magnesiumstearate	4	4	4	4	4	4	4
Sodium starch glycolate	1	1	1	1	1	1	1
Total weight of tablet	100	100	100	100	100	100	100

This combination prevents storage of too much elastic energy during the compression, which results in a small amount of stress relaxation and a reduced tendency of capping and lamination thereby optimum tableting performance. Hence, co-processing these two kinds of materials produces a synergistic effect in terms of compressibility by selectively overcoming the disadvantages and can help improve functionalities such as compaction performance, flow properties, strain rate sensitivities, lubricant sensitivity or sensitivity to moisture³. Among the selected two diluents, lactose is having brittleness and hydrophilic property and starch is having good compatibility and better disintegration property. So this work is aimed to formulate a co processing excipient with different ratios of lactose and maize starch and to optimize the proportion of diluents based on the pre compression and post compression parameters.

EXPERIMENTAL MATERIALS:

Rizatriptan benzoate was obtained as a gift sample from Natco pharma Ltd, Hyderabad. Maize starch was procured from S.D. Fine chemicals, Mumbai. α- Lactose monohydrate was obtained from Qualigens, Mumbai. Sodium starch glycolate and Magnesium stearate was purchased from Healthy life Pharma Pvt Ltd, Mumbai. All materials used in the study complied with pharmaceutical and analytical standards. A Rotary tablet compression machine (CDM-3-16, Cad mach machinery Co. Pvt. Ltd., Ahmadabad); disintegration test apparatus (ED, 2L, Electrolab, Mumbai); dissolution test apparatus (Electrolab, TDT-08L, Dissolution tester, U.S.P), UV visible spectrophotometer(Shimadzu, pharmaspect, UV1700, Japan) were used in research work.

Methods:

Construction of standard calibration curve of Rizatriptan benzoate in water:

100mg of Rizatriptan benzoate was accurately weighed and dissolved in 100ml of distilled water in to a volumetric flask to obtain 1000 mcg/ml. From this stock solution, 1ml sample was pipette out and made up to 100ml with distilled water to obtain concentration of 10mcg/ml. From this secondary stock solution 2, 4, 6, 8 and 10ml of samples was pipette out and made up to 10ml with distilled water to obtain concentrations of 2, 4, 6, 8 and 10mcg/ml respectively. Absorbance of the diluted solutions was measured at λ _max of 282 nm and the calibration curve was plotted between concentration and absorbance.

Development of co-processed excipients by granulation method:

By using the granulation method, co-processed Excipients containing α-lactose monohydrate and Maize starch in different ratios like 60:40, 70:30, 80:20 and 90:10 (shown in table no.1) were prepared. Α-lactose monohydrate and Maize starch were weighed in definite proportions and then the blend was transferred into a mortor, triturated with a pestle to get a fine particle size of homogenous mixture. The powder blend was transformed into a wet coherent mass by adding drop by drop and sufficient quantity of water as a granulating fluid. The wet coherent mass was granulated through # 16 mesh, the resulting wet granules were dried in a hot air oven maintained at 60⁰c for 30 min. The dried granules were stored in a well closed, air tight container.

Preparation of α-lactose monohydrate granules and Maize starch granules:

Α-lactose monohydrate granules and Maize starch granules were also prepared separately by following the same procedure using water as a granulating fluid.

Evaluation of pre- compression parameters⁴:

The following micromeritic properties were evaluated, and the results were shown in table no. 2.

a) Bulk density (g/cc):25 g of blend containing the drug and the co- processing excipients (1:8.5) was weighed and transferred to a measuring cylinder. The bulk volume was noted. The bulk density was calculated by the formula.

Bulk density = mass/ bulk volume

b) Tapped density (g/cc): 25g of blend containing the drug along with the co-processed excipients was weighed and transferred to a measuring cylinder and then it was subjected to 100 tapings. The tapped volume was noted. The tapped density was calculated by the formula.

Tapped density= mass/ tapped volume

c) Carr’s index (%) :The Carr’s index was calculated by the formula

Carr’s index=tapped density-bulk density /tapped density*100

d) Hausner’s ratio (%): The Hausner’s ratio was calculated by the formula

Hausner’s ratio=tapped density/ bulk density.

Table 2. Micromeritic properties of co processing excipients formulated with different ratios of Lactose: Maize starch

Parameters	Formulation code
	F1	F2	F3	F4	F5	F6	F7
Bulk density(gm/cc)	0.316	0.339	0.339	0.358	0.365	0.395	0.365
Tapped density (gm/cc)	0.431	0.475	0.395	0.478	0.475	0.475	0.395
Carr’s index (%)	26.68	28.63	14.17	25	23.15	16.84	7.59
Hausner’s ratio	1.3639	1.4011	1.1651	1.333	1.301	1.202	1.082

Preparation of Rizatriptan benzoate tablets:

The Rotary tablet compression machine was used for the preparation of the tablets from the granules which were passed from sieve#16. Rizatriptan benzoate tablets were prepared by direct compression. All ingredients were weighed and mixed in geometric order to get uniform mixture and filled in to die. The tablets were compressed using rotary tablet press to obtain tablets of diameter 7 mm.

Evaluation of post compression parameters⁵:

The following post compression parameters were evaluated.

% weight variation:

The weight of the tablets was determined individually and collectively.The %weight variation of the tablets was determined by using the formula

% Weight Variation = Average weight-Individual weight × 100

Average weight

Determination of Drug content:

10 tablets were powdered and the quantity of powder equivalent to 10mg of Rizatriptan benzoate was utilized for assay. The powder was transferred to a volumetric flask and dissolved in required amount of water, filtered and suitably diluted with water and drug content was analyzed against blank by UV spectrophotometer at 282nm.

Hardness testing:

Hardness of the tablets was determined by using Monsanto hardness tester.

Tablet Friability:

This determination was carried out using the friabilator. Ten randomly selected tablets were weighed and placed in the friabilator. The friabilator was operated for 4min at 25rpm.The tablets were dusted to remove adherent particles and then re weighed. The percentage friability was calculated with the following formulae.

% Friability = Initial weight- Final weight× 100

Initial weight

In vitro disintegration time⁶:

The disintegration for all formulations was carried out using tablet disintegration test apparatus. Six tablets were placed separately in each tube of disintegration test apparatus and discs were placed. The water was maintained at a temperature of 37^o±2^oc and time taken for the entire tablet to disintegrate completely was noted.

In vitro dissolution characterization⁷:

In vitro dissolution studies were performed for all batches of tablet formulations by using USP dissolution apparatus type-ІІ.

Dissolution test was carried out for a period of 60min at 50 rpm using 900ml of distilled water as dissolution media. At appropriate time intervals, 5ml samples were withdrawn and replaced with the same volume of dissolution medium. The withdrawn samples were suitably diluted and analyzed spectrophotometrically at λ_max of 282 nm against blank using UV double beam spectrophotometer to determine the amount of drug released from the tablets.

Fig: 1 Comparative In-vitro dissolution profiles of Rizatriptan benzoate tablets formulated with different excipients.

Fig: 2 Comparative In-vitro dissolution profile of Rizatriptan benzoate tablets containing different ratios of co-processed diluents.

Table 3. Post- Compression properties of formulated Rizatriptan benzoate tablets

Parameters	Formulation code
	F1	F2	F3	F4	F5	F6	F7
Disintegration time(sec)	30 ±2	40 ±3	65± 1	42 ±2	45± 2	30 ±1	45 ±3
Hardness (kg/cm2)	3-4	3-4	3-4	3-4	3-4	3-4	3-4
% Friability index	2.3886 ±0.03	2.633 ±0.02	2.25 ±0.02	0.754 ±0.01	0.867 ±0.02	1.44 ±0.03	0.04 ±0.03
Average weight(mg)	96.40 ±1	87.43± 2	90.60 ±1	91.7 ±1	93.85 ±2	95.1±2	96.2±2

Table 4. In-vitro dissolution kinetics observed from Rizatriptan tablets.

S.NO	Formulation Code	Correlation coefficient		Dissolution efficiency (DE %)	K (min^--1)	T50% (min)	T90% (min)
		Zero order	First order
1	F1	0.926	0.97	72.57	0.345	2.005	6.66
2	F2	0.923	0.950	68.33	0.069	10.01	33.28
3	F3	0.900	0.943	68.82	0.106	6.500	21.60
4	F4	0.963	0.97	55.03	0.091	7.5	25.1
5	F5	0.886	0.994	74.50	0.095	7.271	24.16
6	F6	0.893	0.972	71.96	0.124	5.57	18.5
7	F7	0.883	0.914	66.66	0.110	6.902	22.93

RESULTS AND DISCUSSION:

This work is aimed to develop novel co-processed excipients to design and evaluate directly compressible tablets of Rizatriptan benzoate and the composition was presented in table.1. The Rizatriptan dose is 10mg, so it is suitable for direct compression but it has poor flow, poor disintegration, and poor compressibility. To overcome these problems, the tablets were formulated by using co-processing excipients (lactose and maize starch).The blend containing drug and co-processed excipients were subjected to micromeritic properties and the flow was found to be excellent and the results were represented in Table 2. So the co-processed excipients were prepared by granulation technique with different ratios of lactose and maize starch (100:0, 0:100, 50:50, 60:40, 70:30, 80:20, and 90:10). The flow properties are dependent on the composition of co processed excipients. The flow pattern was found to be poor flow with lactose: maize starch 100:0, 0:100; good with 50:50ratio; passable in case of 60:40, 70:30; fair in presence of 80:20 and found to be excellent with 90:10 ratio. The blends were compressed to form tablets and then subjected to various quality control tests. All the tablets were satisfied % weight variation, drug content (assay), and disintegration requirements and the results are represented in table 3.

The in-vitro dissolution profiles generated from these tablets was depicted in fig 1.The dissolution ate followed 1^storder kinetics and the corresponding rate constant (K), the time required for 50% drug dissolution (T50), 90% dissolution (T90) and extent of drug dissolution for a period of 30 minutes (%DE30) were calculated and given in table.4. Based on the dissolution rates of the formulated tablets, the composition of the co processing excipients (lactose: maize starch) can be ranked as 90:10>80:20>physical mixture>lactose>70:30>60:40>starch. Tablets prepared with the co processed excipient containing high proportion of lactose (90%) offered rapid dissolution rate compared to all other formulations. Hence this formulation was selected as best formulation. The experimental data indicated that the drug dissolution is dependent on the ratio of lactose and maize starch. This investigation is able to develop a direct compressable Rizatriptan benzoate with a direct compressible diluent having an optimized ratio of lactose : maize starch (90:10).

CONCLUSION:

The flow properties of the blend, the strength of the tablet and the dissolution properties were dependent on the composition of co-processed excipients. The co-processed excipients are relatively better than directly compressible diluents for ease of processing and performance. The co-processed excipients (lactose: maize starch 90:10) prepared by granulation technique was found to be more suitable for preparing Rizatriptan benzoate tablets. This study strongly recommends the use of an optimized co processed excipient to impart the desired properties to the tablet.

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Received on 13.09.2014 Modified on 28.09.2014

Accepted on 27.10.2014 ©A&V Publications All right reserved

Res. J. Pharm. Dosage Form. and Tech. 7(1): Jan.-Mar. 2015; Page 07-10

DOI: 10.5958/0975-4377.2015.00002.6