Formulation, Design and In-Vitro Characterization of Clopidogrel Bisulphate Nanosponge Tablets for Oral Administration

 

Shweta S. Gedam¹*, Ganesh D. Basarkar²

¹Research Scholar, Department of Pharmaceutics, SNJBs Shriman Sureshdada Jain College of Pharmacy, Chandwad, Nashik, Maharashtra, India - 423101

²SNJBs Shriman Sureshdada Jain College of Pharmacy, Chandwad, Nashik, Maharashtra, India - 423101

 

ABSTRACT:

Poor bioavailability by the oral route is noticeable with the majority of new active pharmaceutical ingredients due to its dissolution rate limited absorption. A second-generation thienopyridine antiplatelet drug, though, it is BCS class II drug results in poor oral bioavailability. The present investigation was undertaken to prepare polymeric nanosponges to achieve improved solubility of clopidogrel bisulphate. Nanosponges using ethyl cellulose as a polymer and glutarldehyde as a cross-linker were prepared successfully by emulsion solvent diffusion method. Drug polymer compatibility study were performed by FTIR and DSC. To obtain optimized batch, 3² factorial designs were performed and all batches were evaluated. C1-C9 batches yields particle size (nm) between 87.28-183(nm), % drug content between 71.073±1.066 -88.663 ±0.549, % entrapment efficiency between 51.719±0.775- 81.765±0.506, % drug release 75.120±0.407-97.416±0.336. Optimized batch exhibited particle size 87.28nm, % drug content 88.663 ±0.549, % entrapment efficiency 81.765±0.506, % drug release 97.416±0.336. An SEM and TEM image of optimized batch shows spongy and spherical nature of nanosponges. The optimized nanosponge formulations were converted into tablets to achieve immediate release drug delivery for oral route. These tablets were prepared using crospovidone and pregelatinised starch. All nine tablet batches were evaluated and F3 batch shows good results i.e. hardness (kg/cm²) 3.71±0.04, in- vitro disintegration time (min) 3.21±0.025 and % drug release 99.18±1.38. In vitro dissolution studies indicate that percent cumulative drug release follows zero order kinetics. Accelerated and long term stability data revealed no significant change in drug content and drug release at the end of 6 months. In conclusion, nanosponges could be a newly emerging approach to enhance aqueous solubility of BCS Class II drugs.

 

 

 

 

1. INTRODUCTION:

The platelet is integral to the initiation of thrombosis. Drugs that affect platelet function are a fundamental part of primary and secondary management of atherosclerotic thrombotic disease. The indications for the use of antiplatelet drugs in the management of thrombotic diseases include stroke, acute myocardial infarction (AMI), acute coronary syndrome (ACS), coronary intervention (PCI), cardiac surgery, primary and secondary cardiovascular disease prevention, peripheral vascular disease, and thrombotic disorders such as atrial fibrillation¹ AMI, usually referred to in lay terms as a heart attack, is most often caused by a decrease or stoppage of blood flow to a portion of the heart, leading to necrosis of heart muscle. This is generally the result of a blood clot in the epicardial artery that supplies that territory of heart muscle. It is now recognized that, based on how AMI is defined, not all cases necessarily require a blood clot etiologically.²

 

Clopidogrel, is an antiplatelet agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It is a second-generation thienopyridine antiplatelet drug which exerts its effect by the inhibition of the platelet’s purinergic receptor P2Y12 preventing adenosine diphosphate (ADP) found on the membranes of platelet cells. It is BCS class II drug having low aqueous solubility and bioavailability due to extensive first pass hepatic metabolism and binding to plasma protein (98%).³

 

Advances in in vitro screening process of newly synthesized chemical moiety lead to the emergence of many challenging chemical components with noticeable therapeutic activity. However, about 40% of them are poorly water soluble drugs which have low oral bioavailability as their absorption is dissolution rate limited.⁴

 

Apart from this, major drawbacks of oral drug delivery of these drugs suffer from rapid metabolism, lack of steady state blood/plasma concentration of the drug, and inter individual variability.⁵

 

Oral delivery of poorly water soluble drugs in the form of nanosponge is a new and recent approach to overcome the aforementioned problems. A nanosponge contains microscopic particles of few nanometers wide cavities, in which a large variety of drug substances can be encapsulated. These microscopic particles are capable of carrying both hydrophilic and lipophilic substances and of enhancing the solubility of poorly water soluble molecules.⁶ Nanosponge shows a potential future in the coming years due to its variety of pharmaceutical applications like extended release, better product performance and elegance, improved physical, thermal and chemical stability of product, reduced irritation.⁷

 

2. MATERIALS AND METHODS:

2.1 MATERIALS:

Clopidogrel bisulphate was obtained as a generous gift sample from MSN Laboratories Ltd, Hyderabad. Ethyl cellulose, glutarldehyde and polyvinyl alcohol, lactose anhydrous, avicel 101, crospovidone, pregelatinised starch, magnesium stearate was purchased from Research-lab Fine Chem industries. All other chemicals and reagents used were of analytical reagent grade and were procured from commercial sources.

 

2.2 METHODOLOGY:

2.2.1. Calibration curve by U.V. Visible Spectrophotometric Method:

Calibration curve in methanol, 0.1N HCL were performed by U. V. Visible spectrophotometer (Agilent carry-60).⁸

 

2.2.2. Drug-polymer compatibility study:

2.2.2.1.Fourier-Transform Infrared Spectroscopy:

Fourier-transform infrared (FTIR) spectra were taken to access interaction, if any between drug and polymer in mixtures. The mixture was scanned by using an FTIR spectrophotometer (Perkin Elmer, Specrtum 2 FTIR).⁹

 

2.2.2.2. Differential Scanning Calorimetric:

Differential scanning calorimetric (DSC) studies was performed by Differential Scanning Calorimeter with thermal analyzer Metller Star SW 10.¹⁰

 

2.2.3. Preparation of nanosponges:

Nanosponges were prepared by emulsion solvent diffusion method by using two phases, i.e. organic and aqueous. Aqueous phase was prepared by dissolving definite amount of PVA in water by continuous stirring on water bath. After dissolving drug and polymer to suitable organic solvent, this phase was sonicated for a few minutes and added slowly to the aqueous phase under stirring. The resultant nanosponges were collected by filtration, washed with water and kept for drying in oven. The nanosponges was then packed and stored in airtight vials for further study.¹¹

 

2.2.4. Optimization of nanosponge formulation utilizing 3² factorial design:

A 3² full factorial design was constructed to study the effect of two independent variables i.e. Drug: polymer ratio (mg) (X1) and Volume of glutarldehyde (ml) (X2) at three levels Particle size (nm) (Y1), Drug content % (Y2) and In vitro drug release (%) (Y3). Analysis of variance (ANOVA) was performed to study the statistical significance of independent variables and their interaction term. Polynomial equations were calculated for responses. Design expert (version 8.0.4.1) was used for the statistical and mathematical analysis.^12,13

 

2.2.5. Evaluation of nanosponges:

2.2.5.1. Particle size and polydispersity:

The particle size and polydispersibility index (PDI) were determined by Malvern Zeta Sizer. PDI is an index of width or variation within the particle size distribution.¹⁴

 

 

Table 1: Formulation for Clopidogrel bisulphate nanosponges.

Batches	Drug: Ethyl cellulose ratio (mg)	PVA conc. (mg)	Glutaraldehyde (ml)	Distilled water (ml)
C1	1:1	0.3	05	100
C2	1:1.5	0.3	05	100
C3	1:2	0.3	05	100
C4	1:1	0.3	10	100
C5	1:1.5	0.3	10	100
C6	1:2	0.3	10	100
C7	1:1	0.3	15	100
C8	1:1.5	0.3	15	100
C9	1:2	0.3	15	100

 

2.2.5.2. Product yield:

The percent yield of nanosponges was calculated based on the amount of drug and polymer used for the formulation of nanosponges.¹⁵ The percentage yield was calculated from following equation,

 

 

2.2.5.3. Percent entrapment efficiency (%):

10 mg equivalent of Clopidogrel Bisulphate nanosponges was dissolved in 10 ml of methanol. The absorbance was measured by UV- visible spectrophotometer (Agilent carry-60) at 217nm. The % entrapment efficiency was followed,

 

 

2.2.5.4. Percent drug content:

To calculate the drug content, accurately weighed quantity of nanosponges (10mg) with 5 ml of methanol in a volumetric flask was shaken for 1min using a vortex mixer. The volume was made upto 10ml. Then the solution was filtered and diluted and the concentration of Clopidogrel Bisulphate was determined spectrometrically at 217nm.^{14, 15}

 

 

2.2.5.5. In Vitro Release Studies:

In vitro release studies were performed in triplicate using the USP Paddle method at 50RPM and 37±0.5^oC in 1000 ml of 0.1N HCL. Samples were taken at appropriate time intervals of 5min. for period of 30min.The filtered samples were analyzed spectrophotometrically at 270nm.

 

2.2.5.6. X-Ray Diffraction Studies:

XRD studies of drug Clopidogrel bisulphate and Clopidogrel bisulphate nanosponges were recorded using X-ray diffractometer (Make Bruker, Model D8 Advance, with X-ray source of Cu, Wavelength 1.5406 A0 and Si (Li) PSD detector) which was operated at the current and voltage of 40kV and 40mA respectively. The samples were smeared over low back ground sample holder and XRD patterns were recorded in the 2θ geometry and step 0.020 size at the speed of 5°/min.

 

2.2.5.7. Scanning and Transmission Electron Microscopy:

Nanosponges that showed the best results (F5) were subjected to scanning and transmission electron microscopy (SEM and TEM) studies. Images were recorded at the required magnification at an acceleration voltage of 20 KV using a scanning electron microscope.

 

2.2.6. Preparation of immediate release tablets using direct compression method:

The weighted quantity of nanosponges equivalent to 75mg of drug were taken. The excipients were passed through #60-sieve. All these ingredients except magnesium stearate were mixed in a double cone blender (Orchid, AP-01) for 10 min at 10 rpm. Sifted magnesium stearate was then added to the blend and mixed in the double cone blender for another 2 minutes. The blend was compressed using 12 station tablet press (Accura mini R and D model) using 8mm circular flat bevelled edge punches.¹⁶

 

Table 2: Formulation batches for Clopidogrel bisulphate nanosponge tablets.

Batches	Clopidogrel bisulphate nanosponges	Lactose anhyd. NF	Crospovidone IP	Pregelatinised starch (mg) IP	Talc IP	Magnesium stearate IP	Total weight (mg)
F1	85.08	51.92	4.5	4.5	2.5	1.5	150
F2	85.08	50.8	5.62	4.5	2.5	1.5	150
F3	85.08	49.67	6.75	4.5	2.5	1.5	150
F4	85.08	48.92	4.5	7.5	2.5	1.5	150
F5	85.08	47.8	5.62	7.5	2.5	1.5	150
F6	85.08	46.67	6.75	7.5	2.5	1.5	150
F7	85.08	45.92	4.5	10.5	2.5	1.5	150
F8	85.08	44.8	5.62	10.5	2.5	1.5	150
F9	85.08	43.67	6.75	10.5	2.5	1.5	150

 

2.2.7. Pre-Compression Evaluation of Powder:

Bulk and Tapped density, Carr’s index (%), Hausner’s ratio, Angle of repose were determine for powder blend.

 

2.2.8. Post compression evaluation of Clopidogrel bisulphate tablets:

All prepared tablets were evaluated for the following parameters:

Prepared tablets were evaluated for its weight variation, (%) friability, hardness, thickness, wetting time and water absorption ratio.^17,18

 

2.2.8.1. Drug Content:

To calculate drug content, accurately weighed quantity of crushed tablet (10mg) and 5ml of methanol in a volumetric flask was shaken for 1min using vortex mixer. The volume was made upto 10ml. then the prepared solution was filtered and diluted the concentration of Clopidogrel bisulphate was determined spectrometrically at 217 nm.¹⁹

 

 

2.2.8.2. In-vitro Disintegration:

In-vitro disintegration test was carried out with the help of disintegration apparatus. Tablet were placed in every tubes (six) of the basket containing 1000ml of 0.1N HCl, temperature of immersion fluid was maintained at 37^o ± 2^oC. Apparatus were operated till no residue of the unit under test remains on the screen of the apparatus.²⁰

 

2.2.9.3. In vitro Dissolution Study:

In vitro release studies were performed in triplicate using USP Paddle method at 100 rpm and 37±0.5^oC in 1000 ml of0.1N HCl. Samples were taken at appropriate time intervals of 5min. for period of 30min. The filtered samples were analyzed spectrophotometrically at 270nm.²⁰

 

2.2.9.4. Stability Studies:

Stability studies of prepared tablets were performed as per the standard protocol. The accelerated stability studies at 40˚C ± 2˚C/75% RH± 5 % RH for a period of 6 months were carried out. Samples were analyzed for (%) drug content and (%) in vitro drug release.²¹

 

3. RESULT AND DISCUSSION:

3.1. U.V. Visible Spectrophotometric study:

UV-spectra of pure Clopidogrel bisulphate in 0.1N HCl and methanol shows lambda max at 270nm and 217nm respectively.

 

3.2. Fourier transforms infrared spectroscopy (FT-IR) analysis:

All IR spectrum indicates that there is no physicochemical interaction in between the drug and polymer which suggest that the polymer is compatible with FTIR spectra of Clopidogrel bisulphate.

 

3.3. Differential Scanning Calorimetry:

DSC curve of Clopidogrel bisulphate shows a sharp peak at 180.29ºC. The pure polymer (Ethyl cellulose) exhibits a peak at 224.08ºC, referring to the relaxation that follows the glass transition. The DSC Thermogram of nanosponges shows broad peak with reduced intensity. The broad peak was observed because of glassy nature of polymer. Little shift in the melting point was observed due to formation of weak hydrogen bonding between drug and polymer. This phenomenon is responsible for the solubility enhancement.

 

Table 3: Evaluation of optimized batches of Clopidogrel bisulphate nanosponges.

Batches	Particle size (nm)	PDI	Product yield	Drug content	Entrapment efficiency (%)
C1	132.49	0.194	85.35	80.836± 0.664	68.993±0.566
C2	123.71	0.173	87.92	82.243±0.951	72.307±0.836
C3	143.45	0.212	83.13	77.581±0.403	64.493± 0.335
C4	102.23	0.116	90.26	85.409 ±0.791	77.090± 0.714
C5	87.28	0.101	92.22	88.663 ±0.549	81.765±0.506
C6	117.62	0.122	88.51	84.969±1.066	75.206± 0.943
C7	167.43	0.131	76.54	74.855±0.791	57.293± 0.605
C8	154.47	0.131	80.65	76.614±0.403	61.789±0.325
C9	183.31	0.107	72.77	71.073±1.066	51.719±0.775

 

The results of nanosponge evaluation are shown in Table no. 4 and 5. The particle size, drug content and % entrapment efficiency were within the normal acceptable range. Formulation C5 shows good results i.e. particle size and PDI was 87.28nm and 0.101 respectively, percent drug content (%), entrapment efficiency (%) shows good results i.e. 88.663 ±0.549 and 81.765±0.506 respectively. Optimized batch shows good percent in-vitro drug release 97.416±0.336.

 

3.7.3² Factorial design for optimization of Clopidogrel bisulphate nanosponges:

A.    For dependent variable – Particle size (Y1)

Final Equation in Terms of Coded Factors:

Particle size  =+89.53+7.04* A+17.59* B+1.23* A* B+19.27* A²+48.43* B²

Final Equation in Terms of Actual Factors:

Particle size =+538.05778-299.13667* Polymer Conc.-36.21200* Volume of glutarldehyde+0.49200* Polymer Conc.* Volume of glutarldehyde+77.07333* Polymer Conc.²+1.93733 * Volume of glutarldehyde²

 

B.    For dependent variable – Drug content (Y2)

Final Equation in Terms of Coded Factors:

Drug content  =+88.60-1.25 * A-3.02* B-0.13* A* B-3.39* A²-9.14* B²

Final Equation in Terms of Actual Factors:

Drug content =+7.80956+52.22933* Polymer Conc.+6.81447* Volume of glutarldehyde-0.052400* Polymer Conc.* Volume of glutarldehyde-13.54933* Polymer Conc.²-0.36569 * Volume of glutarldehyde²

 

C.For dependent variable – % drug release (Y3)

Final Equation for in Terms of Coded Factors:

Drug release =+96.63-1.37 * A-4.59* B+0.19*A* B-4.21*A²-11.92 * B²

Final Equation in Terms of Actual Factors:

Drug release =-2.28667+63.92667* Polymer Conc.+8.46467* Volume of glutarldehyde

+0.077000* Polymer Conc.* Volume of glutarldehyde-16.86000* Polymer Conc.²-0.47680

* Volume of glutarldehyde²

 

From the results of 3² factorial design, it was found that as polymer and crosslinking agent concentration increases, particle size decreases at some extent and then there is increase in particle size and it shows increase in % drug content and % drug release at some level and then decreases.

 

From above results, C5 batch was selected as optimized batch so, it was selected for tablet preparation.

 

3.8. Evaluation of Tablet Dosage form:

Table 4: Postcompression evaluation of tablet batches.

Batch Code	Weight variation (Average weight in (mg) ±SD(n=10))	Hardness(kg/cm2) ±SD (n=3)	Thickness (mm) ±SD(n=3)	Friability (%)	Drug Content Uniformity (%) ± SD(n=3)
F1	0.861±1.209	3.9±0.1	3.14±0.01	0.52	98.30±1.37
F2	1.088±0.860	3.83±0.05	3.15±0.005	0.47	98.96±1.00
F3	1.014± 1.284	3.71±0.04	3.17±0.01	0.54	99.18±1.38
F4	1.230 ±1.346	4.0±0.17	3.16±0.02	0.35	98.52±1.00
F5	1.417±1.356	3.9±0.1	3.163±0.03	0.496	98.96±0.76
F6	1.229±1.156	3.86±0.11	3.176±0.01	0.30	99.74±0.65
F7	0.980±0.999	4.16±0.05	3.15±0.005	0.44	99.18±0.38
F8	1.207±0.986	4.06±0.1	3.15±0.13	0.41	98.74±0.65
F9	1.765±1.193	3.96±0.057	3.15±0.02	0.50	97.86±1.37

 

Table 5: Postcompression evaluation of tablet batches.

Formulation Code	Wetting Time (n=3) Mean ±SD (sec)	Water Absorption ratio (n=3) Mean ±SD	In-vitro Disintegration Time (min.)
F1	48.33±1.15	53.70±1.55	4.76±0.152
F2	45.66±0.577	66.33±3.02	4.07±0.036
F3	40.33±1.52	77.25±1.62	3.21 ±0.025
F4	61±1	45.78±3.76	5.06±0.251
F5	57.33±1.52	48.65±0.88	4.57±0.015
F6	52±2	50.90±2.88	4.33±0.020
F7	71.66±0.577	40.50±2.61	5. 45±0.01
F8	68.66±1.154	44.16±3.41	5.27±0.020
F9	65.66±1.154	44.78±3.49	5.13±0.04

On basis of evaluation results shown above, F3 batch formulation was selected as best batch.

 

Kinetic treatment of dissolution data:

 

Fig. 1: Zero order kinetic plot

 

Fig. 2: First order kinetic plot

 

Fig. 3: Higuchi model plot

 

 

Fig. 4: Korsmeyerpeppas plot

 

 

Fig. 5: FTIR spectra of best batch

 

FTIR spectrum of F3 batch indicates that there is no physicochemical interaction in between the drug and excipients which suggest that they are compatible with each other.

 

3.9. Stability studies:

Accelerated stability studies of F3 batch formulation revealed no significant change in appearance and assay after storage at 40˚C ± 2˚C/75% RH± 5% RH. The percent drug content and percent drug release was 98.71±1.131and 98.53±0.941 respectively at the end of 6 months batch appearance was unchanged, indicating that the optimized formulation is fairly stable at accelerated storage condition.

 

4. CONCLUSION:

The nanosponges were successfully prepared by emulsion solvent diffusion method by using various concentrations of polymer to achieve improved solubility of Clopidogrel bisulphate. In vitro drug release studies revealed that, concentration of polymer in the nanosponges, volume of crosslinking agent and emulsion stabilizer concentration affect the in vitro drug release. C5 batch were selected as optimized batch. The formulation containing drug: polymer ratio i.e.1:1.5 and 10ml of glutarldehyde were selected for preparation of immediate release tablets. SEM image shows that the drug may be present in the bulk of the nanosponges and not surface associated. TEM photographs showed that nanosponges were spherical in shape.

 

Tablets containing 3.75% concentration of crospovidone and 5% conc. of pregelatinised starch shows good results. The formulation was found stable under accelerated condition for 6 months with respect to physical characteristics, drug content and drug release.  In conclusion, nanosponges could be a newly emerging approach to enhance aqueous solubility of BCS Class II drugs.

 

5. ACKNOWLEDGEMENT:

Authors are thankful to MSN Laboratories Ltd, Hyderabad for providing a gift sample of Clopidogrel bisulphate and to the management and Principal of  SNJBs Shriman Sureshdada Jain College of Pharmacy, Chandwad, Nashik for providing research facilities for carrying out this research and to APT research, Pune for performing pharmacokinetic studies.

 

6. CONFLICTS OF INTEREST:

There is no conflict of interest.

 

7. REFERENCES:

1.     Altman R. Risk factors in coronary atherosclerosis atheroinflammation: the meeting point, Thromb J. 2003; 1: 4-4.

2.     Bray PF. Platelet hyper-reactivity: predictive and intrinsic properties, Hematol/Oncol Clin North Am. 2007; 21: 633-6.

3.     Kumar K P, Subash V, Reddy NY. Clopidogrel - an overview, International Journal of Pharmacology Research. 2013;3(1): 1-7.

4.     Dahanand A, Haffman A. Rationalizing the selection of oral liquid based drug delivery systems by an in-vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs, Journal of Controlled Release. 008; 129(1): 1-10

5.     Chakraborty S, Shukla D, Singh S. Lipid an emerging platform for oral delivery of drugs with poor bioavailability, European Journal of Pharmaceutics and Biopharmaceutics. 2009; 73(1): 1-15.

6.     Subramanian S, Singireddy A, Krishnamoorthy K, Rajappan M. Nanosponges: a novel class of drug delivery system –Review, Journal of Pharm Pharmaceutical Sci. 2012; 5(1): 103-11.

7.     Jenny A, Merima P, Alberto F, Francesco T.  Role of β- cyclodextrin nanosponges in polypropylene Photooxidation, Carbohydrate Polymers. 2011; 86: 127-35.

8.     IP 2010, Volume II, Government of India, Ministry of Health and Family welfare, published by the Indian Pharmacopoeia Commission, Ghaziabad, 1119-20.

9.     Koradia V, Chawla G, Bansal A. Qualitative and quantitative analysis of clopidogrel bisulphate polymorphs, Acta Pharm. 2004; 54: 193–204.

10.  Lira LM, Lourenco AL, Neves GF, Sousa VPD, Rodrigues CR, Cabral LM.  Assessment of analytical techniques for characterization of crystalline clopidogrel forms in patent applications, Brazilian Journal of Pharmaceutical Sciences. 2014; 50(2): 229-242.  

11.  Bolmal UB, Manvi FV, Rajkumar K. Recent Advances in Nanosponges as Drug Delivery System, International Journal of Pharmaceutical Sciences and Nanotechnology. 2013;6(1):1934-1944.

12.  Gedam SS, Jadhav P, Talele SG, Jadhav A. Effect of crosslinking agent on development of gastroretentive mucoadhesive microspheres of risedronate sodium,  International Journal of Applied Pharmaceutics. 2018; 10(4): 134-140.

13.  Antonio Z, Antunes T, Saini G, Macgregor A. Factorial design used in optimization immediate release solid dosage ranitidine HCl, Estud. biol. 2006; 28: 17-25.

14.  Gedam SS, Basarkar GD. Nanosponges: An Attractive Strategy for Enhanced Therapeutic Profile, J. Pharm. Sci. and Res. 2019; 11(6): 2479-2487.

15.  Indian Pharmacopoeia 2010 Volume II, Govt. of India, Ministry of Health and Family welfare, published by the Indian Pharmacopoeia Commission, Ghaziabad. 1417-18.

16.  Hiremath SN, Raghavendra RK, Danki LS. Dissolution enhancement of gliclazide by preparation of inclusion complexes with β-cyclodextrin, Asian Journal of Pharmaceutics. 2014; 1: 73-76.

17.  Atram SC. Formulation and evaluation of immediate release tablet using response surface methodology, Asian Journal of Pharmaceutics. 2011; 1(1): 46-51.

18.  Pande V, Karale P, Goje P, Mahanavar S. An overview on emerging trends in immediate release tablet technologies, Austin Therapeutics. 2016; 3(1): 1-8.

19.  Lakka NS, Goswami N. Solubility and dissolution profile studies of gliclazide in pharmaceutical formulations by RP-HPLC, Int. Res. J. Ph. 2012; 3(6): 126-129.

20.  Jadhav SB, Mali Rajeghadage SH and Bathe RS. Formulation and evaluation of immediate release tablets of imipramine hydrochloride, International Journal of Biomedical and Advance Research. 2014; 5(11): 559- 565.

21.  Vamshi PV, Rao GC, Reddy DS, Reddy VP. The effect of different superdisintegrants and their concentrations on the dissolution of topiramate immediate release tablets. International Journal of Pharmaceutical Sciences and Nanotechnology 2009; 2(2): 531-536.

 

 

Received on 16.04.2020            Modified on 18.06.2020

Accepted on 22.07.2020         © RJPT All right reserved