1. INTRODUCTION:

Dissolution provides measurements of the bioavailability of a drug as well as can demonstrate bioequivalence from different batches of the finished pharmaceutical product. Dissolution is a requirement for getting approval from regulator for product marketing and is a vital component of the overall quality control program ^[12]. Chemically brivaracetam is (S)-2-((R)-2-Oxo-4-propylpyrrolidin-1-yl) butanamide.

Brivaracetam is a racetam derivative of levetiracetam which is used in the treatment of epileptic seizures. It binds with Synaptic vesicle glycoprotein 2A modulator with 20 times higher affinity than levetiracetam^[1-2]. Briviact received FDA approval in February 2016. It is available under the brand name Briviact made by Union ChimiqueBelge (UCB), a multinational biopharmaceutical company headquartered in Brussels, Belgium.

Literature survey reveals no analytical method is available for dissolution of brivaracetam tablet, which forms the need to develop method of analysis for dissolution of brivaracetam tablet. Rationale behind proposed study is to optimize analytical method for dissolution of finished pharmaceutical product which is used throughout the development life-cycle for product release and stability testing. Dissolution is a pivotal analytical test used for detecting physical changes in an active pharmaceutical ingredient and formulated product.Pharmacokinetics and metabolism of¹⁴C-brivaracetam, metabolism studies of brivaracetam and gemfibrozil, clinical trials of adjunctive brivaracetam for refractory partial onset seizures, identification of drug metabolites in human plasma or serum integrating metabolite prediction, by LC-HRMS methods arealso reported for the drug^{[3-7,10,12,18]}.We have developed a rapid, selective and sensitive HPLC method for dissolution study. Analytical method for dissolution test has been validated as per ICH Q2 (R1) guidelines.^[8-9,11]

According to WHO survey epilepsy accounts for 1% of the global burden of diseases. India alone has approximately 8-10 million people suffering from epilepsy.^[20] Epilepsy is a chronic noncommunicable disorder of the brain that affects people of all ages. Around 50 million people worldwide have epilepsy.^[21] Epileptic seizures are a sign of cerebral dysfunction.^[22] Epilepsy is the common serious neurological disorder and is one of the world’s most prevalent known communicable diseases.^[23] Generalized Tonic Clonic type of Epilepsy was the commonest type of epilepsy with Sodium valproate being the most common Antiepileptic drug prescribed.^[24] The effects of curcumin on the brain monoaminergic system are of particular interest, since it has been suggested that monoamines are of great clinical significance in the treatment of seizures and memory disorders.^[25] hydro-alcoholic extract of Erythrina fuscaLour. Barks possess antiepileptic effect against the animal models of epilepsy.^[26] Many research studies have shown that family is the important influential factor in a person’s psychosocial adjustment. Most research done thus far has shown that increased self-efficacy and social support positively affect the self-management of epilepsy.^[27] Using the EEG signals, the epileptic seizures can be analyzed because it aids in the recording, diagnosing and for treating other neurological disorders.^[28] In patients who presents with recurrent seizures, depressions tends to have a stronger association with the quality of life. Patients with epilepsy have a higher concordance to develop depressive symptoms and disorders when compared to a normal population.^[29]

Figure 1: Chemical structure of Brivaracetam (C₁₁H₂₀N₂O₂)

2. METHODOLOGY:

2.1 Material and methods:

The chromatography consisted of a Agilent 1200 HPLC system with quaternary pump, diode array detector and variable wavelength detector, autosampler and vacuum degasser. Data were evaluated by Chromeleon software. Sample for brivaracetam (tablets) was procured from UCB Pharma. All the chemicals i.e. trifluoroacetic acid, acetonitrile and potassium dihydrogen phosphatewere used are of analytical reagent grade, purchased from Merck chemicals limited, Mumbai, India. Water used for analysis purpose was of HPLC grade (filtered through ELGA purelab classic water purification system). The dissolution apparatus (Type II) was of Electrolab (TDT-08L). In addition an electronic balance (Sartorius), digital pH meter (LabIndia Pico+), ultrasonicator (Trans-O-Sonic) were used in this study. All the glass apparatus were used in this study was of Borosil.

2.2 Preparation of Phosphate Buffer pH 6.4 (Dissolution medium):

Dissolve about 6.8g of Potassium Dihydrogen Phosphate into 1000ml of water, Adjust the pH 6.4 with 10% w/v Sodium Hydroxide solution.

2.3 Optimization of method:

Planned way of method development with the aim of drug analysis is critical to success for fast and effective analytical method development.^[19]In initial method development trial, elution carried out by using nucleosil C18, 150mm x 4.6mm, 5µ HPLC column, using acetonitrile and water (50:50) as mobile phase with the flow rate of 1.2ml/min, but, fronting for brivaractem was observed (tailing factor was found to be 0.92), which needs to develop analytical methods more with respect to the better system suitability for brivaracetam. Finally, Optimum chromatographic conditions has been achieved using mobile phase containing a mixture of 0.1%v/v trifluoroacetic acid solution in water and acetonitrile (60:40 v/v), given system suitability within acceptance criteria. HPLC analysis has been conducted at column oven temperature of 30°C.Phosphate buffer pH 6.4 were used as a dissolution medium to determine % drug release from Brivaracetam tablets of strength 10mg and 100mg.

2.4 Detector and detection wavelength selection:

For selection of target wavelength, solution containing Brivaracetam was scanned from 200nm to 400nm with the help of UV-Visible spectrophotometer. Maximum absorption of drug was found at 210nm as shown in UV Spectra (Figure 2). Therefore wavelength 210nm was selected for estimation purpose.

Figure 2: UV Spectrum for Brivaracetam

2.5 Preparation of Standard Solution:

Accurately weighed 55mg Brivaracetamworking standard and transfer to100ml volumetric flask, to this added 70ml dissolution medium, sonicated to dissolve; and volume made upto 100ml by dissolution medium. For 10mg strength: 5ml of Stock solution has been diluted to 250ml with dissolution medium and for 100mg strength: 5ml of Stock solution has been diluted to 25ml with dissolution medium.

2.6 Test preparation (Dissolution sample preparation):

Transferred 900ml of dissolution medium in dissolution flask carefully and allowed medium to equilibrate to a temperature of 37±0.5ºC. Total six vessels taken and placed one tablet in each vessel and operated the apparatus at 75rpm for 45 minutes. Withdrawn 10 ml of sample (dissolution aliquote) from each dissolution vessel through 10µm filter of instrument from each dissolution vessel and filtered through 0.45µ PVDF filter or 0.45µ Nylon filter.

Note: Test Preparation was found to be stable up to 24 hours at 25°C.

2.7 Evaluation of System Suitability:

a. % RSD for 5 replicate injections of standard should not be more than 2.0%.

b. The tailing factor for Brivaracetam should not be more than 2.0.

3. ANALYTICAL METHOD VALIDATION:^[13-17]

3.1 System precision:

Six replicate injections of standard solution were injected into HPLC system. The mean, SD and %RSD for peak areas of Brivaracetam were calculated. The results are tabulated in Table 1. Acceptance criteria was %RSD for peak areas of Brivaracetam should not be more than 2.0. The %RSD value indicates an acceptable level of precision of the analytical system for the dissolution of Brivaracetam tablets of strength10mg and 100mg.

Table 1: System Precision

Sr. No.	Peak areas of Brivaracetam
Sr. No.	(10mg Strength)	(100mg Strength)
1	191512	1969714
2	191120	1976965
3	184981	1974387
4	187095	1959208
5	186042	1962281
6	188883	1972214
Mean	188272	1969128
SD	2689.6	6989.0
% RSD	1.43	0.35

3.2 Method precision:

Dissolution was performed on six tablets of each10mg and 100mgstrength;analysed as per test method. The % of drug dissolved was calculated and also calculated the %RSD for % dissolution of six samples. The results were tabulated in Table 2. Acceptance criteria was % RSD for % dissolution of Brivaracetam should not be more than 10.0%. The %RSD value indicates an acceptable level of precision of the analytical system for the dissolution of Brivaracetam tabletsof strength 10mg and 100mg.

Table2: Method Precision

Sr. No.	% Dissolution
Sr. No.	(10mg Strength)	(100mg Strength)
1	101.7	102.2
2	96.5	103.0
3	99.5	102.7
4	99.2	102.0
5	100.0	102.0
6	101.6	102.7
Mean	99.8	102.4
SD	1.910	0.420
% RSD	1.91	0.41

3.3 Intermediate precision (Ruggedness study):

Ruggedness of the method was verified by performing dissolution on six tablets of 100mg Strength. In ruggedness study, samples (which were used for method precision) analysed as per test method by different analyst using different dissolution apparatus, different HPLC and different column on different day. Calculated the % RSD of % dissolution and calculated the overall % RSD for above six results and method precision results. The results are tabulated in Table 3. Acceptance criteriawas; the % relative standard deviation (%RSD) for % dissolution of the six samples should not be more than 10.0 and also the overall % RSD should not be more than 10.0. %RSD indicates an acceptable level of intermediate precision for the dissolution of Brivaracetam tablets of strength 10mg and 100mg.

Table 3: Intermediate Precision (Ruggedness Study)

Sr. No.	Analyst-I (Day-1)	Analyst-II (Day-2)
HPLC (Make)	Agilent 1260 Series	Shimadzu Corporation
Dissolution Instrument (Make)	Electrolab EDT-08LX	Distek Inc.
1	102.2	100.1
2	103.0	101.3
3	102.7	101.0
4	102.0	101.6
5	102.0	101.5
6	102.7	101.5
Mean	102.4	101.2
SD	0.42	0.56
% RSD	0.41	0.55
Over all Mean	101.8
Over all SD	0.81
Over all %RSD	0.80

3.4 Specificity:

Blank, Placebo (in triplicate preparation), sample and standard solutions were injected into the HPLC system. There was no interference of the blank and placebo at the retention time of Brivaracetam peak. The retention time of Brivaracetam obtained from standard and sample solutions were tabulated in Table 4. No peak was found at the retention time of Brivaracetam peak in blank and placebo. The method was found to be specific for the dissolution of Brivaracetam tablets of strength 10mg and 100mg.

Table 4: Specificity Study

Peak name	Sample type	Retention time (Minutes)
Brivaracetam	Standard	3.300
Brivaracetam	Sample	3.299

3.5 Linearity study (for dissolution method):

The linearity of Brivaracetam was performed using standard solution in the range of 1.106mcg/ml to 143.785mcg/ml of Brivaracetam (about 1%-130% of test concentration as Brivaracetam i.e. 111.11mcg/ml of Brivaracetam as 100% test concentration). A graph was plotted with concentration (in mcg/ml) on x-axis and peak areas on y-axis. Slope, y-intercept, correlation coefficient (r-value) and residual sum of squares (RSS) were determined. The results are tabulated in table – 5 and graphically represented in Figure 1. The detector response of Brivaracetamwas found to be directly proportional to concentration ranging from 1% to 130% of test concentration i.e. 1.106mcg/ml to 143.785mcg/ml of Brivaracetam (i.e. 111.11mcg/ml of Brivaracetam as 100% test concentration). Refer Figure 3 for linearity graph.

Table 5: Linearity Study

(%) Linearity level	Concentration (mcg/ml)	Peak area
1	1.106	21158
5	8.295	150655
10	16.591	295471
25	27.651	489199
50	55.302	970769
100	110.604	1918818
130	143.785	2472754
Slope	17192
y-intercept	10337
r-value	0.99997
RSS	317828303

Figure 3: Linearity plot for Brivaracetam

3.6 Accuracy (Recovery by standard addition method):

Placebo was spiked with known amount of Brivaracetam at 5%, 25%, 50%, 100% and 130% of test concentration (i.e. 111.11mcg/ml of Brivaracetam as 100% test concentration). Amount of Brivaracetamwas quantified as per test method. Percentage recovery was calculated from the amount found and actual amount of Brivaracetam added. The results were tabulated in Table6.The analytical method meets the pre-established acceptance criteria for accuracy. Hence the method has found to be accurate for estimation of Brivaracetam tablets of strength 10mg and 100mg.

Table 6: Accuracy (Recovery study)

Recovery level (%)	Actual Amount of Brivaracetam added in mcg/ml	Amount of Brivaracetam found in mcg/ml	%Recovery	Mean	SD	% RSD
Level – 1 (5%)	5.554	5.706	102.7	103.1	1.54	1.49
	5.554	5.820	104.8
	5.554	5.652	101.8
Level – 2 (25%)	24.97	25.79	103.3	102.6	0.62	0.60
	25.04	25.57	102.1
	25.07	25.66	102.4
Level – 3 (50%)	49.85	50.60	101.5	101.5	0.06	0.06
	49.96	50.71	101.5
	49.98	50.77	101.6
Level – 4 (100%)	99.90	100.28	100.4	100.3	0.06	0.06
	99.94	100.27	100.3
	99.97	100.23	100.3
Level – 5 (130%)	129.89	128.40	98.9	98.8	0.12	0.12
	129.93	128.30	98.7
	129.94	128.31	98.7
Over all Mean			101.3
Over all SD			1.7
Over all % RSD			1.7

3.7 Range:

Range inferred from the data of linearity, accuracy and precision experiments.The method was found to be linear in the range of 1% to 130% of test concentration i.e. 1.106mcg/ml to 143.785mcg/ml of Brivaracetam. The method was found to be accurate in the range of 5% to 130% of test concentration of Brivaracetam. (i.e. 111.11mcg/ml of Brivaracetam as 100% test concentration).

3.8Stability in analytical solution:

Stability of Brivaracetam in analytical solution was verified by analysing the sample solution of 100mg strength and standard solution using method initially and also at different time intervals as mentioned below by storing in sample compartment of HPLC instrument at 25°C. Calculated the % dissolution of sample solution and % assay of standard solution. The results are tabulated in Table 7a and Table 7b.Acceptance criteria was; the solution should be considered as stable if the differences in the dissolution/assay are not more than 2.0 at each time interval. The difference in the results in both standard and sample solutions was within acceptance criteria, hence it was concluded that standard solution and sample solution is stable up to 24 hours at 25°C.

Table 7a: Solution Stabilityfor Standard Solution

Time in Hours	% Assay	Difference
Initial	100.6	-
1	100.5	0.10
3	100.6	0.00
5	100.0	0.60
7	100.5	0.10
9	100.4	0.20
11	99.9	0.70
13	100.6	0.00
15	100.3	0.30
17	100.8	0.20
19	100.5	0.10
21	100.5	0.10
22	100.5	0.10
24	100.7	0.10

Table7b: Solution Stabilityfor Sample Solution

Time in Hours	% Dissolution	Difference
Initial	102.2	-
1	101.7	0.50
3	102.1	0.10
5	101.8	0.40
7	101.7	0.50
9	102.3	0.10
11	101.6	0.60
13	102.1	0.10
15	101.8	0.40
17	102.2	0.00
19	101.7	0.50
21	101.4	0.80
22	102.0	0.20
24	102.2	0.00

3.9 Filter paper selection study:

Filter paper selection was evaluated by performing dissolution on 3 tablets of 100mg strength. Filtered the sample solution through 0.45µm PVDF, 0.45µm Nylon and 10µm instrument filters, centrifuged a portion of sample. The % dissolution was calculated and also calculated % dissolution difference between centrifuged and filtered samples. Results are tabulated in Table8. Hence it was concluded that, 0.45µm PVDF filter, 10µm instrument filter and 0.45µ Nylon filters are suitable for filtering sample solution of dissolution ofBrivaracetam tablets.

Table 8: Filter Paper Selection Study

Preparation Details	Sample	% Dissolution	Difference
Centrifuged Sample	1	101.9	NA
	2	103.0	NA
	3	102.8	NA
0.45µm PVDF Filter	1	102.2	0.30
	2	103.0	0.00
	3	102.7	0.10
0.45µm Nylon Filter	1	102.2	0.30
	2	102.6	0.40
	3	102.7	0.10
10µm Instrument Filter	1	101.8	0.10
	2	102.5	0.50
	3	102.3	0.50

4.0 Robustness study:

Robustness of the method was performed on 100mg strength tablets and verified by deliberately varying the following instrumental conditions.

a. By changing the flow rate (in chromatographic conditions) by ± 10%.

b. By changing the column oven temperature (in chromatographic conditions) by ± 5°C.

c. By changing organic content of mobile phase by ± 2% absolute.

d. By changing the RPM (in dissolution parameters) by ±5.

System suitability was evaluated for each condition and sample was analysed in triplicate. Results were compared with method precision and tabulated in table-9a and 9b; system suitability parameters are tabulated in table 10a and 10b. An acceptance criterion was; overall %RSD for %dissolution of above result with method precision result should not be more than 10. Method is robust for change in column oven temperature, flow rate, Organic content and RPM for estimation of the drug release of Brivaracetam in Brivaracetam tablets of strength 10mg and 100mg.

Table 9a: Robustness

Sr. No	I	II	III	IV	V	VI	VII	VIII	IX
1	102.2	101.2	101.3	101.6	101.3	100.3	100.0	101.3	100.7
2	103.0	102.0	102.3	102.7	102.6	101.7	101.2	100.9	102.1
3	102.7	101.2	102.3	102.2	101.8	100.8	101.1	100.2	101.8
4	102.0	NA	NA	NA	NA	NA	NA	NA	NA
5	102.0	NA	NA	NA	NA	NA	NA	NA	NA
6	102.7	NA	NA	NA	NA	NA	NA	NA	NA
Overall Mean		102.1	102.3	102.3	102.3	101.9	101.9	101.9	102.1
Overall SD		0.63	0.50	0.45	0.54	0.89	0.96	0.93	0.67
Overall %RSD		0.62	0.49	0.44	0.53	0.87	0.94	0.91	0.66

Table 9b: Robustness Experimental Conditions

Parameter details
Sr.No.	Experiment (Actual Value)
I	Method Precision data
II	Minus flow rate of Mobile Phase (0.9 ml/min)
III	Plus flow of Mobile Phase (1.1 ml/min)
IV	Minus column oven temperature (25°C)
V	Plus column oven temperature (35°C)
VI	Minus Organic Content in Mobile Phase (+2% absolute)
VII	Plus Organic Content in Mobile Phase (-2% absolute)
VIII	Minus RPM (Dissolution at speed of 70 RPM)
IX	Plus RPM (Dissolution at speed of 80 RPM)

5.0 Summary of system suitability:

System suitability was evaluated by injecting standard solution during various days of validation. The Tailing factor for the first standard injection and % relative standard deviation for the peak areas of Brivaracetam from five replicate injections of standard solution were verified at every stage. The results are tabulated in table -10a and 10b.Refer Figure 4, 5 and 6 for representative HPLC chromatogram for blank, standard and sample respectively.

Table 10a: Summaryof System Suitability (100 mg Strength)

Sr. No.	Name of Experiment	Tailing Factor	% RSD
1	System Precision, Method Precision, Filter Study, Solution Stability	0.9	0.39
2	Specificity	1.0	0.10
3	Robustness (Minus Flow)	1.0	0.19
4	Robustness (Plus Flow)	1.0	0.21
5	Robustness (Minus Column Temperature)	0.9	0.24
6	Robustness (Plus Column Temperature)	1.0	0.21
7	Ruggedness, Robustness (Minus RPM), (Plus RPM)	1.2	0.09
8	Linearity	1.2	0.08
9	Robustness (Minus Organic)	1.0	0.26
10	Robustness (Plus Organic)	1.0	0.21
11	Recovery	1.2	0.07

Table 10b: Summary of System Suitability (10 mg Strength)

Sr. No.	Name of Experiment	Tailing Factor	% RSD
1	System Precision, Method Precision.	0.9	1.59

6. Ethical consideration:

The present study not required any investigations/interventions to be conducted on the human subjects/patients; project does not involve any drug trial on animals. Ethical consideration has been completely observed by the authors with respect to the research.

7. CONFLICT OF INTEREST:

There is no conflict of interest among the authors.

8. CONCLUSION:

It is found that the developed HPLC method for dissolution of Brivaracetam tablets is quite simple, authentic, reproducible, definite sensitive, favourable, economical and specific. It can become efficient analytical tool for routine quality control of brivaracetamin its pharmaceutical dosage forms.The proposed dissolution methodology was validated as per ICH guidelines. The standard deviation, %RSD and standard error calculated for the method were low, indicating a high degree of precision of the method. The results of the recovery studies performed show a high degree of accuracy of the optimized dissolution method of analysis. Statistical tests indicate that the proposed methodology appear to be suitable for routine determination of brivaracetam.Hence, it can be concluded that the proposed method of analysis is accurate, precise, and selective and can be employed successfully to calculate % drug release from Brivaracetam tablets of strength 10mg and 100mg.

9.ACKNOWLEDGEMENT:

The authorsare thankful to UCB Pharma SA, Brussels, Belgium, for providing the sample for Brivaracetam.

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Received on 11.10.2020 Revised on 31.10.2020

Asian J. Pharm. Ana. 2021; 11(1):1-8.

DOI: 10.5958/2231-5675.2021.00001.6