Formulation Development and Evaluation of Sodium Valproate and Valproic acid Extended Release Tablets

 

K. Vanitha*, Prasanna Kumar Desu

Department of Pharmaceutics, Vishnu Institute of Pharmaceutical Education and Research, Vishnupur, Narsapur, Medak (dt), Telangana, India – 502313

 

ABSTRACT:

The objective of the present study was to formulate and develop extended release drug delivery system of anti-epileptic drug Sodium valproate (VAS) and Valproic acid (VA) in the ratio of 70:30 with extended release profile. Preliminary studies with different polymers such as HPMC K15M, PVP K90, Ethyl cellulose N50, Carbopol were performed. The results of in-vitro release data showed that HPMC K15M can sustain the drug release upto 24hr. From these studies HPMC K15M has been selected for further studies. HPMCK15M was used along with HEC 250HX to retard the drug release. VAS and VA extended release tablets were prepared by wet granulation method. The hardness of these extended release tablets was within the range between 5.63±0.42 to 6.92±0.33 kg/cm². The drug content was within the range, 97.23±0.25 to 102.03±2.45%. The in-vitro VAS and VA release from the tablets was found sustained over 24 hours with Higuchi kinetics of drug release and release pattern followed anomalous (Non-Fickian) diffusion. The Fourier transform Infrared spectroscopy analyses indicated that there was absence of chemical interaction between the drug and the excipients. The dissolution profiles of the developed formulation and the commercial tablet formulation, Encorate, were compared using the similarity factor (f₂) and difference factor (f₁).  The released profile of tablet containing 15% HPMC K15M and 15% HEC 250HX by weight was similar to that of Encorate^® providing the values of similarity factor (f₂) and difference factor (f₁) of 88.20 and 3.22 respectively.

 

 

 

INTRODUCTION:

Oral drug administration has been theImport route for drug delivery, during the past two decades, numerous oral delivery systems have been developed to act as drug reservoirs from which the active substance can be released over a defined period of time at a predetermined and controlled rate^1,.

 

 

Many drugs categorized as once-a-day delivery have been demonstrated to have suboptimal absorption due to dependence on the transit time of the dosage form, making traditional extended release development challenging. Therefore, a system designed for longer gastric retention will extend the time within which drug absorption can occur.

 

Sodium valproate (VAS) and Valproic acid (VA) are anti-convulsant agents that are widely used for simple and complex absence seizures^2,3 VAS and VA are used in combination because there are only minor differences in pharmacokinetics of the formulation and available in marketing. VAS and VA are available in different dosage forms; capsule, tablet, enteric-coated tablet, liquid, intravenous, suppository, and controlled release formulation⁴. Sustained release formulation of combination between VAS and VA can reduce the fluctuation in plasma drug concentrations, thus minimizing or preventing plasma peak- related adverse effects, and allows prolongation of dosing interval, thus allowing a once or twice daily administration⁵. VA is an oily solution thus tablet formulation is difficult to prepare. VA can be adsorbed onto colloidal silicon dioxide i.e. Aerosil which makes it possible to formulate into solid dosage form. In the present work VA was sprayed onto VAS powder causing adsorption of VA onto VAS powder which results in the formation of VAS and VA mixture (70:30). The extended release systems are the methods that can achieve therapeutically effective concentrations of drug in systemic circulation over an extended period of time. Numerous oral ER systems have been developed such as (a) insoluble, slowly eroding, or swelling matrices, (b) polymer coated tablets, pellets or granules and (c) osmotically driven systems⁶.

 

Hydroxypropylmethyl cellulose (HPMC) and HEC 250HX are the most important hydrophilic carrier material used in the preparation of oral controlled release dosage forms. One of the most important characteristics is the high swellability, which has significant effect on the release kinetics of incorporated drug⁷. Wet granulation techniques that require an organic solvent or a mixture of organic solvents and water are undesirable for environmental and health care reasons, whereas the use of pure water as granulation liquid for hydrophilic matrix compositions may give lump formation. On the other hand researchers have pointed out that water can be used as granulation liquid for hydrophilic based tablets⁸.

 

MATERIALS AND METHODS:

Sodium Valproate and Valproic acid was obtained as a gift sample from Inchem Labs. Hydroxy ethyl cellulose 250 HX, Hydroxy propyl methyl cellulose K15, K100, E15, Lactose monohydrate, Microcrystalline cellulose, PVP K 90, Ethyl cellulose N 50, Carbapol 974P were procured from Colorcon Asia Pvt Ltd. All reagents and chemicals used were of analytical grade.

 

Method of préparation of sodium valproate and Valproic acid Extended release tablets:

The tablets were prepared by wet granulation method. Sodium valproate and valproic acid mixture (70:30), HPMC K15M, HEC 250HX, Lactose monohydrate,  Microcrystalline cellulose(1^st part) were weighed and sieved through sieve no:20 and blended in a polybag for 10 min. Wet granules were prepared by adding Purified water into powder mixture. Simultaneously, Microcrystalline cellulose, Aerosil were passed through 20 mesh separately. Formed granules were blended to increase flow property. The powder was compressed into 350mg tablet using 11mm flat punches in a rotary tablet press. (Table-1).

 

Evaluation of tablet powder blends^{9 ,10,11}

Angle of repose:

The angle of repose of powder was determined by the funnel method. The accurately weighed powder was taken in a funnel. The height (h) of the funnel was adjusted in such a way that the tip of the funnel just touches the apex of the heap of the powder. The powder was allowed to flow through funnel freely onto the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation.                                                        

 

Tan θ = h/r

Where

‘h’ and ‘r’ are the height and radius of the powder cone, respectively.

 

Bulk density:

Both loose bulk density (LBD) and tapped bulk density (TBD) were determined. Powder from each formulation, previously lightly shaken to break any agglomerates formed was introduced into a 10 ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 sec intervals. The tapping was continued until no further change in volume was noted.

 

Bulk Density = Mass of powder / Bulk Volume of the powder

 

Table 1: Formulation of sodium valproate and valproic acid extended release tablets

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
VAS+VA (70:30)	193.5	193.5	193.5	193.5	193.5	193.5	193.5	193.5	193.5
HPMC K15	35.0	43.75	52	35.0	43.75	52	35.0	43.75	52
HEC 250HX	42.0	42.0	42.0	52.5	52.5	52.5	63	63	63
Lactose monohydrate	8.75	8.75	8.75	8.75	8.75	8.75	8.75	8.75	8.75
MCC	63.75	55.0	46.25	53.25	44.5	35.75	42.75	34.0	25.25
MCC	3.5	3.5	3.5	3.5	3.5	3.5	3.5	3.5	3.5
Aerosil	3.5	3.5	3.5	3.5	3.5	3.5	3.5	3.5	3.5
Purified water (mL)	0.066	0.066	0.066	0.066	0.066	0.066	0.066	0.066	0.066
Total weight (mg)	350	350	350	350	350	350	350	350	350

Tapped Bulk Density:

It was determined by placing a graduated cylinder, containing a known mass of drug-excipient blend. The cylinder was allowed to fall under its own weight onto a hard surface from the height of 10 cm at 2 second intervals. The tapping was continued until no further change in volume was noted.

 

Tapped density = Weight of powder / Tapped volume of the powder

 

Carr’s index:

It helps in measuring the force required to break the friction between the particles and the hopper. It is expressed in % and given by:-

 

CI = ρt - ρa / ρt = Va – Vt / Vt

 

Where ρt and ρa – tapped and poured bulk density; And

Vt and Va – tapped and poured bulk volume respectively.

 

Hausner’s Ratio:

It is the ratio of tapped density to untapped density. It is given by

 

H = Dt/Do

Where ‘Dt’ is the tapped density of powders

‘Do’ is the untapped density of powders.

 

EVALUATION OF EXTENDED RELEASE TABLETS^12,13:

All the batches of tablets were evaluated¹⁰ for various physical parameters like thickness, weight variation, friability, hardness, drug content and dissolution as per pharmacopoeial standards.

 

Thickness:

Thickness of tablets can vary with no change in weight because of the difference in the density of the granulation and the pressure applied to the tablets, as well as the speed of the compression machine. Ten tablets were randomly selected and thickness was measured using digital vernier calipers and recorded.

 

Weight Variation:

20 tablets were taken and weighed individually on a digital weighing balance. Average weight was calculated and the individual tablet weight was compared to the average. The tablet pass the U.S.P. test if no more that 2 tablets are outside the percentage limit and if no tablet differs by more than 2 times the percentage limit.

 

Hardness Test:

Tablet requires a certain amount of strength or hardness and resistance to friability to withstand mechanical shakes of handling in manufacture, packaging and shipping. Hardness generally measures the tablet crushing strength. Change in hardness results in differences in disintegration and dissolution characteristics. The crushing strength of the tablet was determined using Monsetto hardness tester.

 

Friability test:

Ten tablets from each batch were examined for friability using Roche Friabilator and the equipment was run for 4min at 25 revolutions per minute. The tablets were taken out, dedusted and reweighted and % friability was calculated. Tablet that lose less than 0.1-0.3% of the tablet weight were considered acceptable.

 

Assay:

Weigh accurately and transfer equivalent to 100mg of sodium valproate previously crushed tablets powder into a 100mL volumetric flask, add 70mL of methanol, sonicate for 60 minutes and make upto 100mL with methanol. Transfer 5mL of the above solution into 50mL volumetric flask and make upto volume with diluent (pH 2.0 buffer).

 

In-vitro dissolution¹⁴:

Dissolution testing was performed in compliance with USP using apparatus 2 with paddles with sinkers. A dissolution medium of 0.1N HCl was chosen for first 45minutes. A paddle speed of 50 rpm was selected with media volume of 500 mL. The medium was maintained at 37±0.5 ⁰C. The 1-L glass dissolution vessels were covered to minimize evaporation. After 45 minutes the media was replaced with 6.8 pH buffer with a volume of 900ml.  Samples were drawn at 3, 9, 12 and 24hr. 10mL of aliquots was collected at regular time intervals, and the same amount of fresh dissolution medium was replaced into dissolution vessel to maintain the sink condition throughout the experiment. The collected aliquots were filtered using Whatman filter No. 1, and further diluted suitably to analyze using HPLC method.

 

Kinetics Modelling Of Drug Dissolution Profile^15,16:

The dissolution profile of most satisfactory formulation was fitted to zero order, first order and Higuchi model to ascertain the kinetic modeling of the drug release. The methods were adopted for deciding the most appropriate model.

1.     Cumulative percent drug released versus time (Zero order kinetic model)

2.     Log cumulative percent drug remaining versus time (First order kinetic model)

3.     Cumulative percent drug released versus square root of time (Higuchi's model).

a)     Zero order: In many of the modified release dosage forms, particularly sustained or controlled release dosage forms (those dosage forms that release the drug in planned, predictable and slower than the normal manner) is zero order kinetic. The plot of cumulative percent drug released versus time is the linear.

b)    First order: Most conventional dosage forms exhibits this dissolution mechanism. Some modified release preparation, particularly prolonged release formulations, adheres to this type of dissolution pattern. It assumes that the drug molecules, diffuses out through a gel like layer formed around the drug during the dissolution process. A plot of log cumulative percent drug remaining versus time is the linear.

c)     Higuchi model: A large number of modified release dosage form contain some sort of matrix system. In such instances, the drug dissolves from the matrix. The dissolution pattern of the drug is dictated by water penetration rate (diffusion controlled). In Higuchi model, a plot of cumulative percent drug released versus square root of time is linear.

 

FT-IR analysis:

FT-IR was carried out to assess the interaction between drugs and tablet excipients. VAS, HPMCK15M, lactose monohydrate, HEC250HX, microcrystalline cellulose and prepared tablet mixture was taken in a ratio of 1:1 w/w and analyzed for functional groups by Fourier transform IR (FT-IR).One milligram of substance in solid state was ground  with 100mg of dry potassium bromide and scanned from 400-4000cm^-1 using FT-IR spectrophotometer¹⁷.

 

RESULTS AND DISCUSSION:

Micromeritic Properties:

Granules of all the formulations were subjected for various pre-compressional evaluations such as angle of repose, bulk and tapped density, compressibility index and Hausner’s ratio. Results of all the pre-compressional parameters performed on granules for formulations shown in Table2. The angle of repose was found to be ranging from 31^o 21’-34^o 17’ for the granules of all the formulations. Carr’s index was found to be ranging from 16.14 to 33.19 % for the granules of all the formulations. The results of Hausner’s ratio were found to be lesser than 1.25 which indicates better flow properties. The results of angle of repose (>30) indicates good flow properties of the powder. This was further supported by lower compressibility index values. The results were indicates that the prepared granules have good pre-compression properties. (Table-2).

 

Evaluation of prepared tablets

The results of physical evaluation of tablets were given in Table 3. The tablets of different batches were found uniform with respect to hardness within the range of 5.63±0.42 to 6.92± 0.33 kg/cm². Another measure of a tablet's strength is friability. Conventional compressed tablets that lose less than 1% of their weight are generally considered acceptable. Results of friability test were also has been found within limit. In weight variation test, all the tablets used in this study showed compliance within the official specifications (IP,1999) as none of the products deviated by up to 5% from their average weight. All the tablets contained sodium valproate and valproic acid within the range, 97.23±0.25 to 102.03 ± 2.45 %, These results clearly indicated that drug content in tablets of sodium valproate and valproic acid within 100 ± 10 %. Therefore, the drug content results ascertain the presence and compendia quality of sodium valproate and valproic acid in all tablets.

 

Table 2: Pre-compression studies of VAS and VA extended release tablets

Code	Angle of repose	Bulk density (g/cm3)	Tapped density (g/cm3)	Carr’s index (%)	Hausner’s ratio	Result
F1	31o 21’	0.58	0.72	19.22	1.23	Fair
F2	33o 16’	0.57	0.68	16.22	1.19	Fair
F3	32o 35’	0.56	0.67	16.14	1.19	Fair
F4	33o 45’	0.57	0.70	18.75	1.21	Fair
F5	31o 31’	0.58	0.72	19.97	1.24	Passable
F6	33o 43’	0.54	0.65	14.27	1.20	Good
F7	34o 17’	0.56	0.68	21.10	1.22	Passable
F8	33o 26’	0.56	0.68	30.88	1.20	Poor
F9	33o 43’	0.55	0.66	33.19	1.19	Very poor

 

 

Table 3: Weight variation, hardness, drug content, friability, thickness of VAS and VA tablets

Formulation code	Weight (mg) n = 20	Hardness± SD (kg/cm2) n=10	Drug content % + S.D. (n=3)	Friability (%)	Thickness (mm)
F1	350.54±1.28	5.63±0.42	98.25± 3.01	0.13	4.45±0.05
F2	350.05±1.12	5.85±0.65	102.03±2.45	0.12	4.67±0.02
F3	350.15±1.10	6.91±0.34	99.70±3.51	0.14	5.01±0.09
F4	349.59±1.29	6.58±0.49	100.81±0.72	0.13	4.71±0.10
F5	350.00±0.92	6.11±0.36	97.23± 0.25	0.16	4.13±0.03
F6	349.91±1.33	6.45±0.53	99.17± 1.42	0.12	4.50±0.07
F7	349.61±1.47	6.63±0.54	101.47±2.89	0.13	4.65±0.11
F8	351.35±1.37	6.63±0.43	100.01±3.01	0.15	4.35±0.08
F9	349.57±1.30	6.92±0.33	98.45±3.5	0.12	4.87±0.08

 

In-vitro Drug Release Studies:

The in-vitro release from sodium valproate and valproic acid tablets in 0.1 N HCl for first 45 minutes and then continued in 6.8 pH buffer for 24 hours is presented in Table.5 and Figure.1. The drug release was found sustained over a prolonged period (24hr). In these tablets HPMC K15M and HEC 250HX were used as release retardant materials. First 45minutes in 0.1N HCl causes the dissolution of film coat given to the tablets. In 6.8 pH buffer, upon contact with water HPMC K15M and HEC 250HX gets swelled and acts as a barrier to the drug release. This would retard the drug release rate from these tablets. In a parallel line, Siepmann and Peppas  suggested that the drug release from HPMC matrices is sequentially governed as follows: (i) At the beginning, steep water concentration gradients are formed at the polymer/water interface resulting in water imbibition into the matrix; (ii) Due to the imbibition of water, HPMC swells resulting in dramatic changes of polymer, drug concentrations and increasing dimensions of the system; (iii) Upon contact with water, the drug dissolves and diffuses out of the device due to concentration gradient; and (iv) With increasing water content, the diffusion coefficient of the drug increases substantially. The drug release kinetics was evaluated by using the linear regression method (Table.7.5). The best fit with the highest determination R² coefficients was shown by Higuchi which indicate the drug release follows the diffusion mechanism. The results of the in-vitro release data were fitted to the Korsemeyer- Peppas equation to analyze the release pattern of the drug from the polymeric system. The values of “n” were in the range of 0.32-0.62, indicating the drug release follows non-Fickian diffusion (both swelling and diffusion). The similarity and difference factor was estimated by using a software called as dd-solver. The similarity factor (f₂) values of drug release profile of optimized formulation was 88.20(50-100) and difference factor (f₁) values was 3.22(0-15) indicating the release was almost similar to that of marketed formulation.

 

Table.4: In- vitro release profile of sodium valproate and valproic acid for formulations F1-F9

Formulation	45 MIN (0.1N HCL)	6.8 pH BUFFER
		3 HR	9 HR	12 HR	24 HR
F1	3.25	41.34	59.11	76.04	80.21
F2	3.96	39.21	60.12	74.15	82.27
F3	4.35	37.35	64.98	70.28	78.14
F4	3.41	35.12	63.45	78.98	81.58
F5	4.41	32.78	58.72	64.64	79.46
F6	4.34	27.11	54.15	62.41	77.18
F7	3.61	32.10	59.34	74.71	84.71
F8	4.45	35.12	69.21	71.09	83.80
F9	5.68	37.30	62.78	75.76	79.02
Market formulation	3.18	29.47	55.39	61.18	78.53

 

 

 

Table.7.8: Comparitive profiles for similarity and difference factor of market and F6 formulation:

Time(hr)	Ref (F%)	Test (F%)
0	0.00	0.00
0.45	3.18	4.34
3	29.47	27.11
9	55.39	54.15
12	61.18	62.41
24	78.53	77.18

 

Figure.1: In-vitro drug release profile of VAS and VA film coated tablets of F1- F9 formulations

 

Figure.2: Zero Order drug release profile of Optimized Formulation

 

Figure.3: First Order drug release profile of Optimized Formulation

 

Figure.4: Higuchi drug release profile of Optimized Formulation

Figure.5: Korse meyer drug release profile of Optimized Formulation

 

Figure.6: Comparison of dissolution profiles for similarity and difference factor

 

 

FT-IR spectroscopy:

FT-IR spectra of pure sodium valproate and valproic acid mixture (70:30), sodium valproate and valproic acid tablets and other excipients were presented in Figure 7.20 to 7.29. The characteristic peaks of pure sodium valproate and valproic acid spectrum (1700, 3400 and 2900 cm^-1) were present in both the spectra of pure drug and in the blend of tablet composition without or with very minute shifting. The characteristic peaks 1700cm^-1 due to C=O present in both sodium valproate and valproic acid structure. 3400cm^-1 due to O-H group present in valproic acid. The peak at 2900cm^-1 was due to C-H. The splitting of the peak was due to the vibrational coupling due to AX₂ (CH₂) system. These phenomena indicate that there were absence of any chemical interaction between the drug and excipients.

 

 

Figure.7.20: FT-IR spectra of pure sodium valproate and valproic acid (70:30)

 

Figure.7.19: Combined FT-IR spectra of pure sodium valproate and valproic acid (70:30) mixture and its blend with other excipients

CONCLUSION:

In the present study VA and VAS extended release tablets were formulated using HPMC K15M and HEC 250HX as the polymers which prolong the drug release over 24hrs. Trials were performed to prepare the optimized formulation of VA and VAS in the concentration of HPMC K15M (10, 12.5, 15%) and HEC250HX (12, 15, 18%). The drug content of tablets was evaluated and revealed that the drug within the range, 97.23 ± 0.25 to 102.03 ± 2.45%. The weight variation for all the tablets showed compliance within the official specifications (USP, 2000; BP, 1998) as none of the products deviated by not more than 5% from their average weight. In addition, thickness of these tablets was found uniform. The hardness of these tablets was within the range between 5.63±0.42 to 6.92±0.33 kg/cm². The friability (%) of all formulated tablets was found within the range of 0.13 to 0.16. The drug release was sustained by HPMC and HEC based systems which could prolong drug release over 24hours. The in-vitro drug releases of formulation F1-F9 were found to be in the range of 77.18-84.71%. In-vitro drug release profile of F6 showed sustained release of 77.18% for 24hrs which is similar to extended rug release profile of Divalproex sodium (USP, 2000). So we selected F6 formulation for further studies. The best fit kinetic model of drug release is Higuchi’s kinetics and the mechanism of drug release was Non-Fickian (both diffusion and swelling controlled). The FT-IR analysis indicates that there were absence of any chemical interaction between the drug and excipients. The released profile of tablet containing 15% HPMC K15M and 15% HEC 250HX was similar to that of market sample (Encorate^®). The similarity factor (f₂) values of drug release profile of optimized formulation was 88.20(50-100) and difference factor (f₁) values was 3.22(0-15) indicating the release was almost similar to that of marketed formulation.

 

ACKNOWLEDGEMENT:

The author was very thankful to Principal and Management for giving support and facilities for conducting research work. Also thanksful to co-author for his supporting in carrying out this research work.

 

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Received on 25.10.2018         Modified on 05.12.2018

Accepted on 31.12.2018       ©A&V Publications All right reserved