Design, Development and Evaluation of Solifenacin Succinate Tablets

R. K.V. Naga Sudha¹*, V. Sai Kishore¹, CH. Venu Babu¹, E. Jitendranath²

¹Bapatla College of Pharmacy, Bapatla -522101,Guntur (District), Andhra Pradesh (state), India.

²AKRG College of Pharmacy, Vijayawada, A.P

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

pharmacistvenu@gmail.com, ejitendranath@gmail.com.

ABSTRACT:

Solifenacin Succinate is used in the treatment of over active bladder with symptoms of urge urinary incontinence, urgency, and increased urinary frequency, and anti spasmodic. Solifenacin Succinate was launched in 2005 and has been shown in both short and long term clinical trials to fulfill these requirements. Solifenacin is a competitive M3 receptor antagonist with a long half-life (45-68 hours). It is available in two dosage strengths namely a 5 or 10 mg once-daily tablet. Ten different trial batches were carried out using different concentrations of excipients like binder (Methocel E5 premium LV), super disintegrant (sodium starch glycolate, cross carmellose sodium, cross povidone), lubricant (Magnesium stearate), glidant (Aerosil) by direct compression technique. The pre-compression parameters and post compression parameters of Solifenacin Succinate tablets were evaluated. The tablets were evaluated for in-vitro drug release studies. Based on similarity factor f2 cross povidone (1.17%), Methocel E5 premium LV (3%), Magnesium starate (1.47%), Aerosil (0.529%) was selected.

KEYWORDS: Solifenacin Succinate, Urinary incontinence, Overactive bladder, Muscarinic receptor antagonist, Direct compression.

INTRODUCTION:

The goal of any drug delivery system is to provide a therapeutic amount of drug in the proper site in the body to achieve promptly and then to maintain the desired drug concentration. That is, the drug delivery system should deliver drug at a rate dedicated by the needs of the body over a specified period of treatment. For many drug substances, conventional immediate-release formulations provide clinically effective therapy while maintaining the required balance of pharmacokinetic and pharmacodynamic profiles with an acceptable level of safety to the patient. During the development process it under gone the Pre formulation studies, formulating the product, optimizing the formula and comparing the in vitro dissolution profile of final formula.

Oral drug delivery is the most desirable and preferred method of administering therapeutic agents for their systemic effects and oral route of drug administration have wide acceptance up to 50-60% of total dosage forms. Solid dosage forms are popular because of ease of administration, accurate dosage, self-medication, pain avoidance and most importantly patient compliance. The most popular solid dosage forms are tablets and capsules. But the important drawback of these dosage forms is the difficulty to swallow. Oral dosage form is the most popular route for drug therapy. Over 80% of the drugs formulated to produce systemic effects in the United States are produced as oral dosage forms. Compared to other oral dosage forms, tablets are the manufacturer’s dosage form of choice because of their relatively low cost of manufacture, package^1-6. Solifenacin Succinate (Sol-if-en-ass-in suck-sin-ate) is a muscarinic receptor antagonist, used in the treatment of over active bladder with symptoms of urge urinary incontinence, urgency, and increased urinary frequency, and anti spasmodic. After intake of Vesicare tablets, maximum Solifenacin plasma concentrations (C_max) are reached after 3 to 8 hours and at steady state ranged from 32.3 to 69.9 ng/ml for 5 and 10 mg Vesicare tablets, respectively. Absolute bioavailability is approximately 90%. Solifenacin is extensively metabolized in the liver. The common side effects (likely to affect more than 1 in 10 patients) of drug are blurred vision, constipation, nausea, and heartburn (dyspepsia), stomach discomfort^7,8. Tablets are prepared by direct compression, wet granulation, and drug in base granules technique, by using these excipients like lactose monohydrate as diluents, maize starch is used as disintegrant, hypromellose as binder, in different concentrations. Supertab 11SD is used as diluent, crosscaramellose sodium is used as super disintegrant, aerosil as glidant and magnesium stereate is used as lubricant.

MATERIALS AND METHODS:

Solifenacin Succinate was obtained as a gift sample from Megafine Pharma (P) Ltd, Maize starch, Cross caramallose sodium, Lactose monohydrate (pharmatose 200M) was procured from Signet. Sodium starch glycolate, cross povidone and Magnesium stearate was purchased from Healthy Life Pharma Pvt. Ltd, Mumbai. Supertab 11 SD from DFE Pharma. Aerosil from Evonik industrials. All materials used in the study complied with pharmaceutical and analytical standards.

EVALUATION PARAMETERS:

Pre-formulation Studies

Drug - Excipient Compatibility Studies

Compatibility studies are carried out to study the possible interactions between Solifenacin Succinate and other inactive ingredients (Table 1).The compatibility studies are carried out by taking a mixture of drug and excipients at the ratio in which they are expected to be present in the innovator product. A part of mixture can be exposed to different storage conditions like 40⁰ c / 75 % RH (30), 40⁰ c /75 % RH (15), 60 ⁰ C, RT, Initial. Then respective ratios of mixture of API and Excipients were dispensed and passed through 40 # and manually blended and transferred into vials according to the protocol ratios. They are tested with respect to their physical and chemical aspects. The prepared drug and excipients mixtures were evaluated at various intervals (2^nd week, 4^th week) for related substances by HPLC as per the conditions and time intervals.

Pre-Compression Parameters⁹: Pre compression parameters were shown in table 2.

a) Bulk density (g/cc): 25 g of blend containing the drug and the excipients 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

a) Tapped density (g/cc): 25g of blend containing the drug along with the excipients was weighed and transferred to a measuring cylinder and then it was subjected to 500 tapings. The tapped volume was noted. The tapped density was calculated by the formula

Tapped density= Mass/ Tapped volume.

b) Angle of Repose: It is defined as, the maximum angle possible between the surface of the pile of the powder and the horizontal plane. The angle of repose was determined by the funnel method suggested by Newman. Angle of repose is determined by the following formula

Tan θ = h/r

Therefore θ = Tan -1 h/r

Where, θ = Angle of repose

h = height of the cone

r = Radius of the cone base.

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.

Preparation of Solifenacin Succinate tablets:

The Rotary tablet compression machine was used for the preparation of the tablets from the blend which was passed from sieve #40. Solifenacin Succinate tablets were prepared by direct compression. All the raw materials were dispensed as per the formula given in table no. 3. Above materials were taken into double poly bag. Sifted the drug, Lactose monohydrate (Pharmatose 200 M), Maize starch, Avicel PH 102, Methocel E5 Premium LV, Ac-Di-Sol, and aerosil was sifted through # 40 mesh, Magnesium stearate was sifted through # 80 mesh separately. Sifted materials were loaded into 2L bin blender and mixed for 15 minutes. Lubrication was done with magnesium stearate for 5 minutes. Then compression of the blend was done using the rotary tablet press to obtain tablets of diameter 7.5 mm.

Formulation of tablets by direct compression technique having different concentrations of cross povidone (super disintegrant), Methocel E5 premium LV (Binder), Magnesium stearate (lubricant), Aerosil (glidant).

Table 1: Drug Excipient Compatibility Study

S.No	Name of Excipient	Ratio of API/ excipient	Initial description	Final Descriptions 40^0C/75%RH		Conclusion
				2^ndweek	4^th week
1.	API (Solifinacin Succinate )	--	White powder	White	White	Compatible
2.	API +Microcrystalline cellulose	1:20	White powder	White	White	Compatible
3.	API + Lactose monohydrate	1:20	White powder	White	White	Compatible
4.	API + Lactose monohydrate	1:20	White powder	White	White	Compatible
5.	API + Methocel E5 premium	1:1	White powder	White	White	Compatible
6.	API + povidone	1:1	White powder	White	White	Compatible
7.	API + Maize starch	1:20	White powder	White	White	Compatible
8.	API + SSG	1:2	White powder	White	White	Compatible
9.	API + Cross carmallose sodium	1:2	White powder	White	White	Compatible
10.	API + Magnesium stearate	1:1	White powder	White	White	Compatible
11.	API + Colloidal silicon dioxide	1:1	White powder	White	White	Compatible
12.	API + opadry pink	1:1	Pink powder	White	White	Compatible

Table.2: Pre compression parameters data

Lubricated Blend Parameters:

Formulation code	Angle of repose	Bulk density g/ml	Tapped density g/ml	Compressibility index	Hausner’s ratio	LOD (%L)
F1	43.12	0.459	0.601	23.62	1.309	1.73
F2	42.35	0.491	0.611	19.63	1.244	1.75
F3	32.23	0.462	0.566	18.37	1.225	1.65
F4	35.33	0.521	0.619	15.83	1.18	1.69
F5	31.75	0.532	0.59	10.16	1.13	1.67
F6	28.36	0.521	0.55	9.83	1.055	1.71
F7	26.84	0.458	0.526	12.92	1.148	1.73
F8	28.50	0.53	0.58	8.62	1.09	1.72
F9	26.62	0.502	0.561	10.51	1.117	1.76
F10	27.55	0.54	0.59	8.47	1.09	1.72

Post Compression Parameters¹⁰:

The following post compression parameters were evaluated (Table 4)

% 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

Estimation of drug content:

Ten tablets were powdered, and 10 mg equivalent weight of Solifenacin tablet powder was accurately weighed and transferred into a 100 ml with 0.1N HCl. The solution in the volumetric flask was filtered, diluted suitably and analyzed spectrophotometrically at 220 nm.

Hardness test:

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

Friability test:

This determination was carried out using the friabilator. Randomly selected tablets about 6.5 g were weighed and placed in the friabilator. The friabilator was operated for 4 min at 25 rpm (100 revolutions). The tablets were de 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 time¹¹:

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 (table no.5, figure 1)

Table: 3. Composition of tablets by direct compression technique.

Ingredients	F1 Qty/Tab (mg)	F2 Qty/Tab (mg)	F3 Qty/Tab (mg)	F4 Qty/Tab (mg)	F5 Qty/Tab (mg)
Solifenacin Succinate	10	10	10	10	10
Lactose monohydrate (Pharmatose 200 M)	113.5	113.5	111.5	111.8	111.8
Maize starch B	20.1	20.1	18.1	18.1	18.1
Methocel E5 Premium LV	3.4	3.4	3.4 (2%)	5.1 (3%)	5.1
Aerosil	0.5	0.5	0.5	0.5	0.5
Magnesium stearate	1.5	1.5	1.5	1.5	1.5
Cross povidone	5	5	5(2.95%)	5(2.95%)	4(2.35%)
Sepertab 11SD	20	20	20	20	20
Total tablet weight (mg)	170	170	170	170	170

Table 3 continued

Ingredients	F6 Qty/Tab (mg)	F7 Qty/Tab (mg)	F8 Qty/Tab (mg)	F9 Qty/Tab (mg)	F10 Qty/Tab (mg)
Solifenacin Succinate	10	10	10	10	10
Lactose monohydrate (Pharmatose 200 M)	91.4	92.4	91.9	91.35	100.55
Maize starch B	18.1	18.1	18.1	18.1	18.1
Methocel E5 Premium LV	5.1	5.1	5.1	5.1	5.1
Aerosil	0.5	0.5	0.5	0.5 (0.29%)	0.9 (0.529)
Magnesium stearate	1.5	1.5 (0.88%)	2.0 (1.17%)	2.55 (1.47%)	2.55
Cross povidone	3(1.76%)	2(1.17%)	2	2	2
Sepertab 11SD	40.4	40.4	40.4	40.4	30.8
Total tablet weight (mg)	170	170	170	170	170

In vitro dissolution characterization¹²:

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 60 min at 50 rpm using 900ml of 0.1 N HCl as dissolute ion 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 220 nm against blank using UV double beam spectrophotometer to determine the amount of drug released from the tablets.

Table: 4 Post compression parameters data (Evaluation parameters of developed formulationJ

Formulation code	Average weight (mg)	Thickness (mm)	Hardness (kp)	Friability (%)	Disintegration time (min-sec)	Drug content (%)
F1	170 ± 0.10	3.51±0.02	6.5±0.11	0.8	8-30	98.5±0.18
F2	170 ± 0.12	3.52±0.05	6.2±0.12	1.2	10-15	98.1±0.15
F3	171 ± 0.10	3.56±0.09	5.8±0.31	1.0	8 -10	97.9±0.16
F4	171 ± 0.09	3.49±0.07	5.9±0.21	0.21	8-50	98.2±0.21
F5	169 ± 0.32	3.50±0.10	6.1±0.15	0.20	7-25	98.9±0.30
F6	170 ± 0.18	3.48±0.04	6.2±0.11	0.26	6-10	97.5±0.08
F7	171 ± 0.12	3.49±0.02	6.0±0.21	0.24	5 -30	98.5±0.15
F8	170 ± 0.91	3.10±0.04	4.2±0.30	0.52	4-26	97.9±0.32
F9	171 ± 0.70	3.52±0.05	6.3 ±0.25	0.60	3-50	98.5±0.16
F10	170 ± 0.50	3.53±0.09	6.5 ±0.13	0.23	3-30	98.9±0.03
Innovator product	170 ± 0.20	3.55±0.06	6.5 ± 0.16	0.21	3-50	99.1±0.02

Table.5: In vitro dissolution parameters for Solifenacin Succinate tablets (F1 to F10)

S.NO	Formulation code	T50 (min)	T90 (min)	K1 (min^-1)	Correlation coefficient (r) of first order	Similarity factor f2 value
1	F1	10.5	30.5	0.0125	0.991	47.00
2	F2	8.4	27.6	0.0137	0.981	42.19
3	F3	7.9	26.2	0.0988	0.987	43.91
4	F4	8.6	28.5	0.0808	0.986	46.48
5	F5	8.3	27.5	0.0839	0.955	55.19
6	F6	8.2	27.3	0.0843	0.968	54.79
7	F7	8.6	28.5	0.0807	0.951	58.90
8	F8	9.5	31.4	0.0733	0.942	65.29
9	F9	8.4	28.1	0.0821	0.896	93.78
10	F10	8.5	28.1	0.082	0.895	97.52

Table 6: XRD data for Solifenacin Succinate tablets:

Standard 2q values	2q Results
	Initial	40^0c/75%RH – 3 MONTHS
3.9	3.702	3.806
7.6	7.382	7.504
11.2	11.851	11.207
14.3	14.124	14.007
18.8	18.633	18.736
19.3	19.164	19.345
21.1	21.226	21.031
23.2	22.979	23.249
25.2	25.085	25.181

Figure.1: Comparative studies of disintegration time for different formulations (F1 to F10).

Figure.2: Comparative Dissolution profile for reference product of Solifenacin succinate tablets.

Figure. 3: XRD of Solifenacin Succinate coated tablets.

Table: 7. Stability studies of best formulation (F10) according to ICH guidelines.

S.NO	Time (hrs.)	% Drug release (mg)
		25±5^oC/60% RH
		Initial	1^st month		2^nd month		3^rd month
			15 days	30 days	15 days	30 days	15 days	30 days
1	10	43.27 ±0.11	43.15 ±0.13	43.11 ±0.11	43.02 ±0.03	42.90 ±0.05	42.50 ±0.07	42.55 ±0.09
2	15	52.82 ±0.05	52.80 ±0.11	52.76 ±0.09	52.64 ±0.05	52.50 ±0.04	52.41 ±0.06	52.20 ±0.03
3	30	74.94 ±0.09	74.93 ±0.09	74.91 ±0.08	74.84 ±0.02	74.77 ±0.08	74.60 ±0.04	74.20 ±0.06
4	45	91.08 ±0.04	91.05 ±0.05	91.00 ±0.07	90.95 ±0.02	90.80 ±0.04	90.65 ±0.08	90.40 ±0.07
5	60	99.86 ±0.05	99.82 ±0.03	99.75 ±0.07	99.64 ±0.04	99.55 ±0.09	99.40 ±0.01	99.15 ±0.05

Table 7 continued

S.NO	Time (hrs.)	% Drug release (mg)
		40±5^oC/75% RH
		Initial	1^st month		2^nd month		3rd month
			15 days	30 days	15 days	30 days	15 days	30 days
1	10	43.27 ±0.11	43.11 ±0.02	43.02 ±0.07	42.85 ±0.06	42.69 ±0.05	42.34 ±0.03	42.27 ±0.04
2	15	52.82 ±0.05	52.75 ±0.04	52.60 ±0.03	52.55 ±0.07	52.41 ±0.05	52.27 ±0.08	52.11 ±0.05
3	30	74.94 ±0.09	74.90 ±0.06	74.72 ±0.05	74.65 ±0.02	74.44 ±0.05	74.30 ±0.03	74.12 ±0.08
4	45	91.08 ±0.04	91.04 ±0.04	90.91 ±0.06	90.76 ±0.05	90.61 ±0.04	90.43 ±0.05	90.15 ±0.02
5	60	99.86 ±0.05	99.80 ±0.05	99.69 ±0.03	99.51 ±0.01	99.43 ±0.08	99.21 ±0.07	99.02 ±0.06

RESULTS AND DISCUSSION:

The research work is aimed to prepare and evaluate conventional tablets of Solifenacin Succinate having dissolution profile on par with the innovator product (Vesicare 10 mg). The objective of the study is to formulate and evaluate conventional immediate release tablets of Solifenacin succinate. Used in the treatment of over active bladder disorder with symptoms of urge urinary incontinence, urgency and urinary frequency. Pre formulation studies like organoleptic properties, solubility studies were carried out for API, and the drug excipients compatibility studies were performed by physical observation. The results obtained from these studies indicated that absence of any physical interactions among both active components and excipients. Tablets were prepared by direct compression. Ten different trial batches were carried out using different concentrations of excipients (binder, super disintegrant, lubricant, glidant). Pre compression parameters (micromeritics properties) were carried out for final blend such as angle of repose, bulk density, true density, compressibility index and hausner’s ratio etc. All the batches micromeritic properties were found to be satisfied and it is good to excellent. Ten different trial batches were carried out using different concentrations of excipients (binder, super disintegrant, lubricant, glidant) and tablets obtained from these batches were evaluated by physical parameters of tablet and in vitro dissolution studies (table 6, 7. Figure 2, 3) based on analysis of innovator product (Vasicare 10 mg). The drug release rate from all the formulation followed first order kinetics. From the results 1.17% (Among 2.95, 2.35, 1.76%) superdesintegrant (crosscarmellose sodium), 3% (Among 3, 5%) binder (Methocel E5 premium LV), 1.47% (Among 0.88, 1.17, 1.47 %) lubricant (Magnesium stearate), 0.529% (Among 0.29, 0.529%) glidant (Aerosil) was selected. Based on physical properties, dissolution efficiency etc. Concentration of excipients were selected. From the dissolution stusies % drug release was calculated, from that similarity factor was calculated. Among all the formulations, formulation F10 shown satisfactory results when compared with innovator product. Stability studies were carried out for optimized formulation (F10) at 25⁰C/60% RH, 40⁰C/75% RH in stability chamber as per ICH requirements. No significant change was observed in trial (F10) after three months at 40⁰ C/75% RH. There is no change in polymorphic form of the formulation it was concluded from the XRD studies. From the XRD studies 2q values was calculated. There is no change in 2q values of formulation F10 when comparing with the 2q values of API of Solifenacin Succinate, lubricated granules, placebo blend, core tablets, and coated tablets. As per above XRD data of Solifenacin succinate tablets, no change was observed in polymorphic form of Solifenacin succinate drug substance during the stability of film coated tablets.

CONCLUSION:

From the results obtained, conclusions were found to be the drug excipients compatibility studies showed that the excipients used in the formulations have no interaction with the drug. The excipients were compatible with API. Evaluation of physicochemical parameters like hardness, friability, dissolution and assay indicated that the tablet were mechanically stable and complied with necessary specifications and comparable to innovator product. Stability studies were carried out for optimized formulation at 25⁰C/60% RH, 40⁰C/75% RH in stability chamber as per ICH requirements. No significant change was observed in trial (F10) after three months at 25⁰C/ge with respect to parameters such as assay, impurities, drug release pattern that indicates, the stability of the finished product. Finally, it is concluded that the process adopted for the manufacturing provides a product predetermined specification and quality characteristics. The process would imbibe reproducibility and robustness in the formulation.

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Received on 21.11.2014 Modified on 25.11.2014

Accepted on 02.12.2014 ©A&V Publications All right reserved

Res. J. Pharm. Dosage Form. & Tech. 7(2): April-June, 2015; Page 111-117

DOI: 10.5958/0975-4377.2015.00016.6