A Study on the Effect of disintegrants and Processing Methods on the Physicochemical and In Vitro Release Characteristics of Immediate Release Tablets of Bosentan Monohydrate

 

D. Akiladevi¹*, Dr. M. Nappinnai², Dr. T. Sudha³

¹Asst Professor, Department of Pharmaceutics, Adhiparasakthi College of Pharmacy, Melmaruvathur-603319.Tamilnadu, India.

²Department of Pharmaceutics, School of Pharmacy, Surya Group of Institutions, Vikravandi, Villupuram Dist.605 652. Tamilnadu, India

³Department of Pharmaceutical Analysis, Adhiparasakthi College of Pharmacy, Melmaruvathur-603319.Tamilnadu, India.

 

ABSTRACT:

The present investigation attempted to study the effect of disintegrants and processing methods on the physicochemical and in vitro release characteristics of immediate release tablets of Bosentan Monohydrate. To achieve this goal various formulations of Bosentan Monohydrate were prepared by direct compression, wet granulation and fluidized bed granulation methods to achieve maximum drug content with reference to innovator. Varying proportion of disintegrants such as sodium starch glycolate, pregelatinised starch used to compare drug release profile with innovator. Different formulations were prepared and evaluated with respect to various precompression and post compression parameters. The results indicated that the superdisintegrants used have influenced on the disintegration time. The final selection of the formulation F8 (f2 = 71) containing sodium starch glycolate was based on highest f2 value among all formulations with reference to marketed product.

 

 

 

INTRODUCTION:

Immediate release oral dosage forms such as tablets and capsules are most widely used conventional drug delivery systems available¹in the market^. . The tablets are the most widely used because of its convenience in term of self-administration, compactness, and ease in manufacturing².

 

The various formulation techniques can be used for manufacturing immediate release tablets like direct compression, wet granulation and dry granulation. Direct compression does not require the use of water or heat during the formulation procedure and the compression forces, when used to achieve tablets of suitable hardness without compromising the rapid disintegration characteristics³.

 

However the most common is wet granulation technique. The wet granulation process offers several advantages. For example, high dose drugs that experience poor flow and/or poor compatibility can be granulated to obtain suitable flow and cohesion for compaction. There is another approach of granulation of fine powders that can be performed in a fluid bed processor by spraying solvent or a solvent/binder solution onto a fluidized powder bed⁴. The mixing, spraying and drying phases are the consequent process stages needed to convert powders to free-flowing granules⁵.

 

Inspite of increasing interest in controlled-release drug delivery systems, the most common tablets that are intended to be swallowed whole and to disintegrate and release their medicaments rapidly in the gastro-intestinal tract still remains the dosage form of choice. An important variable in any tablet system is the rate at which the drug substance dissolves and for many solid dosage forms, disintegration precedes drug dissolution. Hence, the proper choice of disintegrants and its consistency of performance are of critical importance to the formulation development of such tablets. The disintegrants such as sodium starch glycolate and pregelatinised are now frequently used in tablet formulations to improve the rate and extent of tablet disintegration thereby increasing the rate of drug dissolution.

 

The formulation of potent drug molecules as dosage form still draws continuous interest and challenges against optimization towards pharmacokinetic parameters like absorption, onset of action, bioavailability and also economic factors. Pulmonary arterial hypertension (PAH) in which class IV which will make inability to carry out physical activities without any symptoms requires an antihypertensive agent which is having optimum therapeutic window concentration for a prolonged duration. Endothelin is a potent endogenous vasoconstrictor that is increased in individuals with PAH. The development of bosentan (Tracleer^®, Actelion), a novel, well-tolerated orally active endothelin antagonist, has significantly changed the therapeutic approach to PAH⁶. Bosentan monohydrate is used to treat pulmonary arterial hypertension. Bosentan prevents thickening of blood vessels especially those in lungs and heart. Bosentan lowers blood pressure in lungs helping heart pump blood more efficiently⁷.

 

Bosentan monohydrate was selected active therapeutic agent which is having 50% absolute bioavailability and 5 hours of terminal elimination half-life. The innovator Trachleer is successful brand tablet formulation of Bosentan monohydrate US manufactured by PatheonInc and marketed by Acteleon pharmaceuticals US was found to be expensive and exhibits high cost benefit ratio. Since the innovator product Trachleer formula is being protected by IPR patent in connection with the working formula. The efforts were made to develop with different process and different formula. As discussed earlier, the methods of granulation have influence on the outcome of the tablets with the desired quality. Taking this into account, the present study was aimed to develop Bosentan monohydrate immediate release tablets by different granulation techniques like direct compression, wet granulation and fluidized bed granulation and to evaluate physicochemical and release characteristics and compare with the commercial tablets. This study will help with advantage of the right processes for manufacturing of tablets that meet with the desired standards.

 

MATERIALS AND METHODS:

Bosentan monohydrate was obtained as gift sample from MSN laboratories Ltd. Hyderabad, India. Sodium starch glycolate, pregelatinised starch, maize starch, Povidone K30, and Magnesium stearate were obtained as gift sample from Signet Chemicals Mumbai, India. Other ingredients used were of analytical grade. Glyceryl di behenate was obtained from Gattefosse Private Ltd. Opadry white OY 58900 was obtained from colorcon. All other reagents purchased are of analytical grade.

 

Experimental work:

Immediate release tablets were prepared by direct compression, wet granulation, and fluidized bed granulation methods. The formulations were developed by using different techniques in various ratios of excipients. The formula of tablets prepared using three different methods is given in Table 1.

 

Formulations F1 and F2 were prepared by direct compression. Formulations F1 and F2 were prepared by direct compression. Bosentan monohydrate and excipients sifted through sieve no 40 # and thoroughly mixed in a octagonal blender approximately for 10 min. This mixer was lubricated for 2 min with glyceryl di behenate and Magnesium Stearate. The lubricated granules were then compressed in to tablets on a 16 station rotary machine punch size 8.0mm.Opadry white was sprayed on core tablet to get desired film formation. Formulations F3 to F6 were prepared by wet granulation method. Bosentan monohydrate and excipients sifted through sieve # 40 and thoroughly mixed in a Rapid Mixer Granulator (RMG) approximately for 10 min. The binder Povidone-K90 was dissolved in sufficient quantity of water, and used as a binder solution for F3 formulationPovidone-K90 (previously dissolved in water) were mixed with excipients for formulations F4-F6.Formulation F7 to F8 were prepared by fluidized bed granulation method. The Bosentan monohydrate was mixed with the excipients and binder solution and loaded into fluid bed process equipment by using top spray gun process with fluid bed process parameters of inlet temperature of 44˚C and exhaust temperature 36˚C with atomization of 20psig and spray rate 1gm/min at fluidization of 2hr. The obtained granules are sifted through sieve no 40 #. The dried granules were loaded with octagonal blender and blended with glycerylbehenate and magnesium stearate for 5 minutes. The lubricated granules were then compressed in to tablets on a 16 station rotary machine punch size 8.0mm.Opadry white coating suspension was sprayed on core tablet to get desired film formation.

 

Table 1: Formulation of Bosentan Monohydrate immediate release tablets

S. N0	Ingredients	F1 (mg)	F2 (mg)	F3 (mg)	F4 (mg)	F5 (mg)	F6 (mg)	F7 (mg)	F8 (mg)
1.	Bosentan	129.082	129.082	129.082	129.082	129.082	129.082	129.082	129.082
2.	Maize starch	22.918	22.918	46.918	44.918	46.918	46.918	46.918	46.918
3.	Pregelanitised starch	32	30	10	10	5	5	5	5
4.	Sodium starch glycolate	6	8	6	8	10	10	10	10
5.	Povidone K30	-	-	-	4	4	4	4	4
6.	Povidone K90	4	4	4	-	-	-	-	-
7.	Glyceryl Di behenate	3	3	2	2	3	3	3	3
8.	Magnesium stearate	3	3	2	2	2	2	2	2
9.	Water	-	-	105	100	100	140	140	140
10.	Core tablet weight	200	200	200	200	200	200	200	200
11.	Opadry white	5	5	5	5	5	5	5	5
12.	Coated tablet weight	204.5	204.5	204.5	204.5	204.5	204.5	204.5	204.5

F1-F2- Direct compression F3-F6- Wet granulation F7-F8 Fluid Bed process

 

 

 

Evaluation:

All formulations F1 – F8 were analyzed for precompression (angle of repose, Carr’s index, hausner’s index) and post compression (hardness, thickness, weight variation, disintegration time, content uniformity, in vitro dissolution studies) parameters.

 

In vitro dissolution study:⁸

The dissolution studies of the prepared tablets were carried out using USP XXIII apparatus II. Dissolution was performed in 900 ml of pH 6.8 phosphate buffer medium at 37±0.5°C and at 50 rpm. Aliquots samples were withdrawn at 5, 10, 15, 30, 45 and 60 minutes and analyzed by UV spectrophotometer at 220nm. Sink condition was maintained throughout experiment by replacing with pH 6.8 phosphate buffers medium.

 

RESULTS:

All formulations F1 – F8 showed Precompression parameters and post compression parameters like hardness, thickness, friability and weight variation were within acceptable limits in reference to innovator (Table 2 and Table 3). However variation in drug content was observed in formulations. Formulations F1 to F5 showed less than 95% drug content and formulations F6 to F10 showed more than 95% drug content which was comparable to innovator.

 

 

Table 2: Precompression parameters

S. No.	Formulation Code	Bulk Density (gm/cc)	Tapped Density (gm/cc)	Hausner Ratio	Compressibility index (%)
1.	F1	0.612	0.819	1.338	25.27
2.	F2	0.611	0.817	1.337	25.20
3.	F3	0.607	0.814	1.344	25.42
4.	F4	0.606	0.815	1.344	25.62
5.	F5	0.607	0.816	1.345	25.61
6.	F6	0.608	0.827	1.360	26.58
7.	F7	0.425	0.509	1.197	16.50
8.	F8	0.433	0.515	1.189	15.92

 

 

 

Table 3: Precompression parameters

Code	Thickness (mm)	Hardness (Kg/cm2)	Friability (%)	weight variation(mg)	Disintegration Time (sec)	Drug content uniformity (%)
F1	7.62	7.5	0.25	209.2	3’22’’	89.2
F2	7.53	8	0.28	210.2	5’13’’	90.3
F3	9.52	10.5	0.18	208.3	3’22’’	91.2
F4	9.63	10	0.27	209.5	3’29’’	92.5
F5	9.66	10.5	0.32	208.2	3’33’’	94.6
F6	9.59	9.5	0.18	209.8	3’25’’	95.7
F7	9.52	10.0	0.25	210.1	3’18’’	99.12
F8	9.56	10.5	0.28	209.9	5’22’’	99.78

 

The disintegration time (DT) of the different formulations (F1 to F10) is shown in Table 3. The effect of disintegrants and mode of incorporation of disintegrants were examined. It was shown that DT time ranged between 3.18 sec. to 5.22 sec., the least DT was taken by the formulation F7 (3.18 sec.) and maximum DT by F8 (5.22 sec.). There was no significant difference in DT observed between F1 and F3 (P>0.05) as they contain equal proportion of sodium starch glycolate (SSG). However comparison of F1 and F2 with F3 to F6 in respect of DT indicated that, the process of incorporation of SSG appeared to increase the DT. DT of F8 (5’22’’ sec.) was higher than that of F7 (3’18’’ sec.) [P<0.001], though the process of incorporation of disintegrant was same in these two formulations.

 

In vitro dissolution studies:

The release profile for formulations F1 to F8 was carried out at pH 6.8 phosphate buffer medium. Each experiment was done three times (Table 4 and Figure 1). The release study was limited to the above formulations based on the acceptable limit for drug content 100 to 101% with reference to innovator. The similarity factor f2 was applied to compare dissolution profile of formulations F5 to F8 with marketed product (innovator) in pH 6.8 phosphate buffer medium. It was observed that the dissolution profile of the above formulations were similar to that of innovator (f2 = 50-100), however the highest f2 value was obtained with formulation F8 (71) based on f2 value it can be suggested that sodium starch glycolate seems to be an ideal disintegrant for achieving faster dissolution of Bosentan.

 

Table 4: Comparative % release profile of F5 to F8 at ph 6.8 phosphate buffer

Time in minutes	Innovator	F5	F6	F7	F8
5	45± 0.94	46±1.1	46±1.2	46±1.2	46±1.2
10	82±1.64	75±1.1	76±1.2	76±1.2	76±1.2
15	98±0.54	87±0.6	89±0.6	89±0.6	89±0.6
20	99±0.48	98±1.6	99±1.6	99±1.6	99±1.6
30	100±0.29	98±0.6	100±0.68	100±068	100±0.6
45	100±0.29	100±1.4	101±1.5	101±1.44	101. ±1.4
60	100±0.29	100±1.3	101±1.8	101±1.2	101±1.2

 

 

Figure 1: Comparative % release profile of formulation F5 to F8 with innovator

 

 

DISCUSSION:

Dissolution is essential for a drug to be absorbed through biological membrane into systemic circulation for therapeutic efficacy. Conventional tablet formulations generally required rapid disintegration to aid dissolution. Super disintegrations are added to oral dosage formulations to facilitate disintegration. Commonly used disintegrants such as pregelatinised starch, and sodium starch glycolate are highly efficient at low concentration levels (2–5 w/w %) in the tablet formulation for facilitating the rate and extent of tablet disintegration. Different approaches have been followed for the preparation of immediate release tablet formulations. They are dry, wet granulation and fluidized bed granulation methods. Commercial literature reports suggests that more often dry or wet granulation method have been employed for the manufacturing of immediate release tablet formulation of Bosentan. Fluidized bed granulation is another approach which yields products of high quality like uniformity of drug contents, high percentage yield, and least batch to batch variation. However it is considered that fluidized bed granulation approach may not be cost effective as compared to dry or wet granulation methods. In this study immediate release tablet formulation of Bosentan monohydrate was developed by direct compression, wet granulation and fluidized bed granulation methods using varying proportion of disintegrants such as pregelatinised and SSG. The effect of processing method and disintegrants on physico-chemical and in vitro release characteristic of Bosentan was also examined.  The formulations F1-F8 were made with starch, pregelatinised starch, Sodium Starch glycolate and Povidone. F1-F2 was designed by direct compression method. F3-F6 was designed by wet granulation process, F7- F8 were made fluid bed process. The above formulations were evaluated in comparison with the parameters of the innovator product and it was noted that formulation F8 which was designed by fluid bed process possess optimum value of evaluation parameters that superimposed on the parameters of innovator. The formulation F6 were subjected to process changed after at various developmental stages of formulation at lab scale batches, because the blend exhibits the poor flow characteristics. The Formulation F7 was developed with the fluid bed process to get the good flow characteristics. The granules obtained by the fluid bed process exhibit the good flow characteristics,. So the process change was recommended.  The film coating also carried out for the tablets for taste masking and glossy appearance. The physico-chemical characteristics like bulk density, Carr’s index, Hausner’s ratio were studied. The release profile of all formulations (F7 to F8) prepared by fluidized bed granulator indicate that the drug dissolution rate was not significantly influenced by type of disintegrants and mode of incorporation. However, analyzing similarity factor f2 to compare dissolution profile of these formulations showed that the highest f2 value was found in F8 formulation that indicated sodium starch glycolate as the best disintegrant for achieving faster dissolution of Bosentan. Immediate release tablet formulation of Bosentan can be developed by proper selection of disintegrants in order to achieve faster dissolution of characteristics of the drug. More importantly fluidized bed granulation method appears promising for development of immediate release tablet formulation of Bosentan with higher drug content suitable for reaching therapeutic efficacy of drug as compared to wet granulation or direct compression. The mode of addition of disintegrants or other excipients did not seem to affect the physico-chemical and in vitro release characteristic of Bosentan.

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Received on 03.08.2017       Accepted on 18.10.2017     

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