INTRODUCTION:

In recent years, a variety of pharmaceutical research has been conducted to develop new dosage forms. Considering the quality of life, most of these efforts have been made on ease of medication. Among the various dosage forms created to improve the ease of administration, the mouth-dissolving tablet (MDT) is the most widely preferred commercial product.

Solid dosage forms are popular because of cost effectiveness, ease of administration, accurate dosage self-medication, pain avoidance, and most importantly patient compliance. The most popular solid dosage forms are tablets and capsules.^1,2,3 However in the case of dyspepsia in geriatric patients, the underdeveloped muscular and nervous system in young individuals, and the case of an uncooperative patient, many problems occur but swallowing is a common phenomenon that leads to poor patient compliance. To improve these drawbacks fast dissolving tablets or orally disintegrating tablets has immersed as alternative oral dosage forms.⁴ As a result of increased life expectancy, the elderly constitutes large portion of the worldwide population today.^5-6 A fast-dissolving drug delivery system, in most cases, is a tablet that dissolves or disintegrants in the oral cavity without the need for water or chewing.¹

Ivabradine hydrochloride is employed in the treatment of mild to severe chronic heart failure and also employed unstable angina pectoris which causes chest pain. Ivabradine is also called a heart rate-lowering agent.^7-10 Angina pectoris is a disease characterized by the improper supply of oxygen. An angina attack needs to be the quick balance of the oxygen supply so, as to diminish the chest pain. With some effective treatment, there should be a decrease in oxygen demand. Ivabradine Hydrochloride is the drug that decreases the oxygen demand and hence balances the oxygen supply demand.⁷

Hence the present work was aimed at increasing the onset of action of ivabradine hydrochloride thus providing a faster rate of absorption by adding potential superdisintegrants like Banana Powder and Guar Gum in different concentrations.

MATERIALS AND METHODS:

Ivabradine HCl was procured from Hetro Drug Limited (Unit-1), India, and Banana powder from the local market in Thane, Maharashtra, India. Microcrystalline Cellulose, Magnesium stearate, Talcum Powder, Sucralose, Guar gum, and Menthol flavor were procured from Research-Lab Fine Chem Industries, Mumbai, Maharashtra, India.

Preformulation Studies:

Organoleptic properties: Appearance and color were determined by visual inspection.^11,12

Melting point determination:

The melting point of Ivabradine Hydrochloride was determined by Thiele's Tube method. The glass capillary was sealed from one end and the drug was filled into it from another end. Then the capillary tube was tied to the thermometer and placed in Thiele's tube containing liquid paraffin. The tube was heated, and the melting point of the drug was determined by observing the temperature on the thermometer when the particles have just started to melt and when all the drug particles were melted.⁷

FTIR studies:

The FTIR spectrum of Ivabradine Hydrochloride was recorded using Shimadzu IR Affinity-IS. The drug sample was placed in an FTIR sample holder and scanned over the range of 400 to 4000 cm-1. The spectrum was confirmed by comparing it with the IR spectra of Ivabradine Hydrochloride.^7,13

Ultraviolet-Visible (UV-Vis) Spectrophotometry:

Determination of λ-max of Ivabradine Hydrochloride:

Accurately weighted 10mg Ivabradine Hydrochloride was transferred into 100ml of volumetric flask and volume was makeup with the help of methanol and was marked as stock solution 1mg/ml i.e., 100 parts per million (ppm). 1 ml was taken from a stock solution in another volumetric flask and diluted up to 10ml to give a stock solution of (10 ppm) and was examined between 200-400nm. The λ-max was observed to be 286nm. Similarly, λ-max was also determined in phosphate buffer pH-6.8 and methanol.⁷

Estimation of calibration Curve in 0.1 N HCl, Phosphate Buffer 6.8, and methanol:

From the above stock solution of 100ppm, dilutions of 2, 4, 6, 8, and 10ppm were prepared, and absorbance was measured at λ _max using a UV spectrophotometer.

Determination of solubility:

Solubility of Ivabradine Hydrochloride was determined in water, methanol, and Phosphate buffer (pH-6.8).⁷

Physical mixture:

The physical mixture was prepared by blending the drug and excipient in a mortar for ten minutes to obtain a homogeneous mixture. The resulting mixture was sieved through 60 mesh sieve and stored in an airtight container and placed in a desiccator for further evaluation.⁷

Preparation of immediate-release drug delivery system (mouth dissolving tablet):

Orodispersible tablets of Ivabradine HCl were prepared by direct compression method using; superdisintegrants in addition to combined approaches according to the formula given in Table 1. Ivabradine HCl 8.084mg was taken. In all formulations, microcrystalline cellulose was used as a diluent. The specified quantity of the drug and the other excipients were weighed accurately and passed through a 60 # screen before mixing. All the materials were transferred to mortar in geometrical order and co-grounded for 15min. The resulting powder mixture was compressed into tablets using a tablets compression machine (Riddhi trading company 10 stations D-tooling machine) using 6mm flat surface round punches. The compression force was adjusted to give tablet hardness in the pharmacopeial range of orodispersible tablets (2–4 kg/cm³).⁷

Pre-Compression Evaluation of Powder:

Bulk density, tap density, compressibility, angle of repose, and Hausner's ratio were used to study the flow property of solid formulation.

Bulk density:

Bulk density was determined by pouring the accurately weighed powder into a graduated cylinder. The bulk volume (Vb) and weight of powder (M) were determined.^14,15

The bulk density was calculated using the equation,

Bulk Density (BD) = Weight of powder (M)/Bulk volume (Vd)

Tapped density:

The 100ml measuring cylinder was filled with the sample powder. After that, a fixed number of taps (100) were applied to the cylinder. Record the final volume and by the following equation, the tapped density was calculated.^14,15

Tapped Density = Weight of powder/Tapped volume

Charr’s index:

Charr's index is one of the most important parameters to characterize the nature of powders and granules. From the following equation, it can be calculated and the category of Charr's Index is shown in the table¹⁶

Carr’s Index (I) = Tapped Density (TD) – Bulk density (BD)/Tapped Density (TD)

Angle of repose:

The funnel method was used to measure the angle of repose. The quantity of blend was taken in a funnel and height was calibrated in a way in which the apex of the heap just touches the tip of the funnel. The drug excipients blend was allowed to flow willingly onto the surface. The diameter of the cone of powder was measured and by using the given equation angle of repose was calculated. ^16,17

Angle of repose (θ)= tan^-1(h/r)

Where θ is the angle of repose; h is the height of the pile; r is the radius of the base pile

Hausner’s ratio:

Hausner's ratio is an index of the ease of flow of powder. Hausner's ratio of less than 1.25 indicates good flow. Hausner’s ratio can be calculated as:^[16,18]

Hausner’s ratio = Tapped Density / Bulk Density

Table no.01: Formulation of Ivabradine HCl mouth dissolving tablets (F1-F6)

Sr. No	Ingredients	F1	F2	F3	F4	F5	F6
1	Ivabradine HCl (mg)	8.084	8.084	8.084	8.084	8.084	8.084
2	Guar Gum(mg)	6	8	10	-	-	-
3	Banana Powder(mg)	-	-	-	6	8	10
4	Sucralose (mg)	0.88	0.88	0.88	0.88	0.88	0.88
5	Microcrystalline Cellulose (mg)	92.28	90.28	88.28	92.28	90.28	88.28
6	Magnesium stearate (mg)	0.99	0.99	0.99	0.99	0.99	0.99
7	Talc(mg)	1.1	1.1	1.1	1.1	1.1	1.1
8	Menthol (mg)	0.66	0.66	0.66	0.66	0.66	0.66
	TOTAL	110	110	110	110	110	110

Preparation of Optimized Batch by using different Super Disintegrant:

Post compression:

General Appearance:

The general appearance of a tablet, its visual identification, and overall 'elegance' is necessary for consumer acceptance. These involve the tablet's size, shape, color, presence or absence of an Odor, taste, surface texture, and physical flaws.¹¹

Hardness:

For the determination of the hardness Monsanto hardness tester was used. The tablet was inserted in contact between the plungers and the handle was pressed, the force of the fracture will be recorded. In this way, for each formulation, the hardness of 3 tablets was evaluated.^19,20,21

Thickness:

By using a digital Vernier scale the thickness of the tablet was measured. Thickness was expressed in mm.²²

Wetting time:

Wetting time was measured by the use of a piece of tissue paper (12cm x 10.75cm) folded twice and properly placed in a Petri dish (ID 9cm) containing 6ml phosphate buffer pH 6.8 equivalent to the saliva pH. After that, the wetting time was recorded.^23,24

Weight variation:

In Indian pharmacopeia procedure for uniformity of weight was followed, ten or twenty tablets were taken and their weight was founded individually and collectively on a digital weighing balance. Then the average weight of one tablet is required to be Determined from the collective weight. The weight variation test would be a satisfactory method of finding out the drug content uniformity.^25,26

Friability:

A Roche friabilator was used to determine the friability of the tablets. This device has a plastic chamber revolving at 25rpm and dropping a tablet at a height of 6 inches in each revolution subjects the tablet to the combined effect of abrasion and shock. The tablets are weighed before it is placed in the friabilator and is subjected to 100 revolutions. Tablets were de-dusted using a soft muslin cloth and reweighed. By the following formula, the friability (F%) is calculated.^27,28

F = (W _int. -W _fin) /W_int×100

Where, W_int = Initial Weight of tablets before friability;

W_fin = Final Weight of tablets after friability.

Drug content:

Weigh and powder 20 tablets. Calculate the tablet powder equivalent to 10mg of the drug and transfer it to a 100-volumetric flask. Add 60ml phosphate buffer pH 6.8. Shake for 15minutes and sonicate for 10minutes. Makeup volume with PBS 6.8. Filter this solution with Whatman filter paper no-1. (Ivabradine Hydrochloride -100mcg/ml). Then pipette out 1 ml of the above solution and dilute it in a 10ml volumetric flask with PBS pH 6.8. Measure the absorbance and calculate the drug content.^29,30

In vitro Dissolution:

The dissolution test was performed in the USP II dissolution testing apparatus (LABINDIA). 900 ml of phosphate buffer pH 6.8 was taken as the dissolution medium at 50pm and 37.7ºC±0.5ºC. Five milliliters of aliquots were periodically withdrawn, and the sample volume was replaced with an equal volume of fresh dissolution medium. The samples were analyzed spectrophotometrically at 286nm, and the percent drug release was calculated.^7,31

Comparison of optimized formulation with marketed formulation:

The in vitro drug release of optimized formulation was found to be observed and in vitro drug release of the marketed formulation was observed. The Comparison between the marketed formulation and the optimized formulation was done.⁷

Drug excipients compatibility study:

Stability study for optimized formulation:

The prepared mouth-dissolving tablet of the drug was packed in an aluminium strip and subjected to short-term stability studies at 40±2°C and 75±5° RH for 30 and 60 days in a humidity chamber. Sample withdrawn after 30 and 60 days observed a significant change in the appearance of tablets drug release CPR profile of stability studies are observed disintegration time, wetting time was observed, optimized batch drug release profile was observed. The results of short-term stability studies indicated that the formulation was stable or unstable on required storage conditions.³²

RESULTS AND DISCUSSION:

Preformulation Studies:

Organoleptic Analysis: Ivabradine Hydrochloride was evaluated for its organoleptic properties like Appearance it was found to be amorphous powder, color it was found yellowish white powder, and odor it was found odorless.

Melting point determination:

The melting point of the drug was determined by the capillary tube method. The melting point of Ivabradine Hydrochloride was observed between 195°C indicating that the drug obtained was pure without any impurities.

FTIR Spectroscopy:

The drug identity was confirmed by studying the IR spectra of Ivabradine Hydrochloride. The observed peaks of Ivabradine Hydrochloride were found to be in the range which confirmed that the drug obtained was not degraded and was suitable for the use of experiments and developing formulations.

FTIR spectra of drug:

Figure no. 1: FTIR Spectra of Ivabradine HCl drug

Figure no. 2: FTIR Spectra of Ivabradine HCl drug + Banana Powder + Excipients

Figure no. 3: FTIR Spectra of Ivabradine HCl drug + Guar Gum + Excipients

Evaluation:

Solubility Studies:

The solubility of all solid dispersions was found to be increased when compared with the pure drug. Out of all the formulation F6 batch showed well solubility increase and the second was the F5 batch thus both were considered for further tablet preparation.

The solubility of all batches in pH 6.8 phosphate buffer.

Evaluation of Tablets:

Pre-Compression Evaluation Results:

The tablet powder blend was evaluated for its flow properties.

Table no. 2: Pre-Compression Evaluation Results.

Sr. No	Bulk Density	Tapped Density	Carr’s Index (%)	Hausner’s ratio	Angle of Repose (θ)
1	0.2796	0.3495	20	1.25	30.9606
2	0.2793	0.3491	19.9942	1.2499	29.0516
3	0.2602	0.3013	13.6408	1.1579	28.9235
4	0.2696	0.3145	14.2766	1.1665	30.2533
5	0.2618	0.3031	13.6258	1.1577	27.1783
6	0.2676	0.2958	9.5334	1.1053	24.7726

Post-Compression Evaluation Results:

The prepared tablet batches were evaluated for post-compression parameters like physical appearance, hardness, friability, weight variation, disintegration time, and in-vitro dissolution studies. It was revealed that the post-compression parameters of all tablet batches were found under acceptable limits.

Physical appearance The physical appearance of all tablet batches showed that the tablets were Yellowish White in color.

In-vitro dissolution studies:

The dissolution studies for all tablet formulations were performed which revealed that the tablets having less disintegration time and improved solubility showed faster dissolution rates. As compared with all the formulations batch F6 showed faster dissolution and maximum drug release of 99.66% at the end of 15 mins.

Table no. 4: In-Vitro Drug Release of Optimized Ivabradine Hydrochloride Tablet (F6)

Sr. No.	Time (min)	F6 (%)
1	0	0
2	2	19.3018
3	4	36.84
4	6	61.74
5	8	67.41
6	10	75.339
7	12	94.01
8	15	98.66
9	20	97.62

Stability studies:

The stability studies of F6 tablets were carried out as per ICH guidelines and investigated the effect of aging on physicochemical parameters and dissolution rate of F6 tablets. The appearance, hardness, average tablet weight, friability, disintegration time, drug content, and dissolution rates were measured at one-month intervals. The results revealed that there was no significant difference between the initial and stored tablets evaluation parameters. The F6 tablets were stable at 40 ± 2°C/75±5% RH conditions.

CONCLUSIONS:

From the present research work, it is concluded that Mouth dissolving tablets of Ivabradine Hydrochloride can be successfully prepared by direct compression techniques using selected superdisintegrants for better patient compliance and effective therapy. The relative efficiency of these superdisintegrants to improve the disintegration and dissolution rate of tablets of Mouth Dissolving Tablet. The above studies lead to the following conclusions

· FTIR study indicated drug-carrier compatibility.

· All the solid dispersions showed improved solubility.

· The Mouth Dissolving tablets prepared were mechanically stable and free from chipping and chapping.

· The hardness of prepared tablets was found to be in the range of 2.7 to 3.5 kg/cm²

· The friability of all tablets was less than 1%

· The percentage drug content was uniform in all formulations

· According to in vitro dissolution profiles maximum drug release was obtained within 15 minutes by the F6 formulation. Other formulations also showed a considerable increase in dissolution rates.

· The stability study showed no significant changes in tablets after 3 months of study.

Based on the observations, it can be concluded that the formulated mouth dissolving tablets using super-disintegrants could exhibit all the properties of standard criteria of mouth dissolving tablets. They are thus showing faster bioavailability and faster therapeutic action. However, these approaches can be used for solubility and dissolution rate enhancement of another poorly soluble drug.

REFERENCES:

1. Savpure, G. C.; Shaikh, A. Z.; Tadavi, S. A.; Pawar, S. P. Review on Mouth Dissolving Tablet. World Journal of Pharmacy and Pharmaceutical Sciences. 2019; 8 (3): 1524–1537.

2. Bhowmik Debjit, B. Chiranjib, Kant Krishna, Pankaj, R. Margret Chandira: Fast Dissolving Tablet: An Overview. Journal of Chemical and Pharmaceutical Research, 2009; 1(1): 163-177.

3. Venkateswara Srikonda Sastry, Nyshadham Janaki Ram, Fix Joseph A.: Recent technological advances in oral drug delivery – a review. PSTT. 2000; 3: 139-144.

4. Sunita Kumari, Visht Sharad, Sharma Pramod Kumar, Yadav Rakesh Kumar, Fast dissolving Drug delivery system: Review Article. Journal of Pharmacy Research. 2010; 3(6): 1444-1449.

5. Kuchekar B. S, Badhan A.C, Mahajan, H.S, Mouth dissolving tablets: A novel drug delivery system, Pharma Times. 2003; 35: 7-9.

6. Ratnaparkhi M. P, Dr. Mohanta G. P, Dr. Upadhyay L, Review on Fast Dissolving Tablet. Journal of Pharmacy Research. 2009; 2(1): 5-12.

7. Patel, D. B.; Patel, K. J.; Bharadia, P. D. Formulation and Evaluation of Orodispersible Tablet of Ivabradine Hydrochloride. Pharmaceutical and Biological Evaluations. 2017; 4 (3): 162.

8. Doig C. Ivabradine: first of a new class of treatments for angina. Wily Online Library. 2009; 17(15):14-7.

9. Tripathi KD. Essential of medical pharmacology; 6th edition. Jaypee Brother's medical publishers (P) Ltd. 2008: 521-538.

10. Maheshwari S, Khandhar AP. Quantitative Determination and Validation of Ivabradine HCl by Stability Indicating RP-HPLC Method and Spectrophotometric Method in Solid Dosage Form. Eurasian J Anal Chem. 2010; 5(1):53-62.

11. Preeti, Vijay A, Abhinav A, An Overview on Mouth Dissolving Tablet: From Manufacturing and Patented Technique to Quality Control Test.Asian Journal of Pharmaceutical and Clinical Research. 2022; 15 (11):7-13

12. Ragade, S. M.; Bari, M. M.; Barhate, S. D. Formulation and Evaluation of Candesartan Cilexetil Mouth Dissolving Tablet by Using Natural Superdisintegrant. Asian Journal of Pharmaceutical Research 2018; 8 (3): 136. https://doi.org/10.5958/2231-5691.2018.00024.2.

13. Jeevana Jyothi B; Aparna J. Ivabradine Hydrochloride Directly Compressed Tablets Using Nano-Cellulose Extracted from Arachis Hypogaea Shells. Asian Journal of Pharmaceutical and Clinical Research. 2019; 115–123.

14. Chawla G and Jain N: Mouth Dissolving Tablets: An Overview. International Journal Pharmaceutical Science and Research. 3(9); 2919-2925.

15. Dholakiya RB, Akbari BV, Shiyani BG, Patel GF, Ramani GK, Vekariya NR. The Effect of Various Superdisintegrating Agents on Mouth Dissolving Tablet of Ranitidine HCl. Research J. Pharm. and Tech. 2010; 3(1): 175-178.

16. Raj, K.; Chandel, P.; Kapoor, A. Fast Dissolving Tablets: Needs to Enhance Bioavailability. International Research Journal of Pharmacy 2013, 4 (5), 51–58.

17. Morade, V. B.; Daga, V. R.; Malpure, P. R. Formulation and Evaluation of Mouth Dissolving Tablets of Zolmitriptan. Asian Journal of Pharmacy and Technology 2018; 8 (1): 35. https://doi.org/10.5958/2231-5713.2018.00006.5.

18. Swamivelmanickam, M.; Venkatesan, P.; Sangeetha, G. Preparation and Evaluation of Mouth Dissolving Tablets of Loratadine by Direct Compression Method. Research Journal of Pharmacy and Technology 2020; 13 (6): 2629. https://doi.org/10.5958/0974-360x.2020.00467.9.

19. Geetika S, Rupinder K, Sukhdev S, Ajay K; Shivani S; Ramandeep S; Yogesh K. Mouth dissolving tablets: A current review of scientific literature. International Journal of Pharmaceutical and Medicinal Research. 2013;1(2):73-84

20. Govind, A.; Menden, M. B.; Ravikumar; Simila; Mercy; Swamy, V. N. Formulation and Evaluation of Mouth Dissolving Tablets of Deflazacort. Asian Journal of Pharmacy and Technology. 2016; 6(2): 91. https://doi.org/10.5958/2231-5713.2016.00013.1.

21. Rao, K. S.; Khan, M.; Udgirkar, D.; Patil, P. S.; Biradar, K. V. Design and Evaluation of Meloxicam Mouth Dissolving Tablets. Research Journal of Pharmaceutical Dosage Forms and Technology. 2015; 7 (1): 44. https://doi.org/10.5958/0975-4377.2015.00007.5.

22. Akhtar MS. Formulation and evaluation of fast-dissolving tablets of antiepileptic drug. Universal Journal of Pharmaceutical Research. 2019; 4(6): 20-24.

23. Agrawal, Dr. D.; Goyal, Dr. R.; Bansal, Dr. M.; Sharma, A. K.; Khandelwal, M. Formulation, Development and Evaluation of Fast Dissolving Tablet of Meclofenamate Sodium by Using Natural Superdisintegrant (Banana Powder). International Journal of Pharmaceutical Sciences Review and Research. 2021; 69 (2): 219-224.

24. Joshi, P.; Manju; Fateh, M. V.; Rao, N. G. R. Review on Mouth Dissolving Tablet. Asian Journal of Pharmaceutical Research. 2019; 9 (1): 42. https://doi.org/10.5958/2231-5691.2019.00008.x.

25. C Haranath, P Muralidhar, P Harish, et al. Comparative Study of Natural and Synthetic Superdisintegrating Agents in the Formulation of Oral Dispersible Tablets of Escitalopram-IP. Inventi Rapid: Novel Excipients. 2016; (3):1-8, 2016.

26. Jain, A. A.; Barhate, S. D. Formulation Optimization and Evaluation of Mouth Dissolving Tablet of Rizatriptan Benzoate by Using Natural Superdisintegrant. Asian Journal of Research in Pharmaceutical Science. 2019; 9(4): 245. https://doi.org/10.5958/2231-5659.2019.00038.9.

27. Raj, A. R. U. N. R. Comparative Evaluation of Potato Starch and Banana Powder as Disintegrating Agents in Aceclofenac Tablet Formulation. International Journal of Pharmacy and Pharmaceutical Sciences. 2013; 5 (2): 204–207.

28. Haque, I.; Kumar, R.; Narayanaswamy, V.; Hoque, M. Formulation and Evaluation of Montelukast Sodium Fast Dissolving Tablets. Asian Journal of Pharmaceutical Research. 2016; 6 (3): 159. https://doi.org/10.5958/2231-5691.2016.00023.x.

29. Kumari, B.; Soni, A.; Singla, S.; Goyal, S.; Thakur, S.; Mahant, S. Formulation and Evaluation of Mouth Dissolving Tablets Containing Losartan Potassium Using Natural Superdisinigrants. International Journal of Pharmaceutical Sciences and Drug Research. 2017; 9 (05): 210-215.

30. K. V. Sri, R. H. K. Reddy and R. Mahesh. Diphendramine Hydrochloride Oral Dispersible Tablets: Preparation and Evaluation. Asian J. Pharm. Res. 2014; 4(3): 123-128

31. Bhargava, V. H.; Sable, P. S.; Kulkarni, D. A.; Darekar, G. P. Formulation and Evaluation of Mouth Dissolving Tablet of Benazepril Hydrochloride. Research Journal of Pharmacy and Technology. 2021: 3161–3166. https://doi.org/10.52711/0974-360x.2021.00551.

32. Jha, A.; Chetia, D. Development of Natural Gum Based Fast Disintegrating Tablets of Glipizide. Asian Journal of Pharmaceutics. 2012; 6 (4):282.

Received on 12.06.2023 Modified on 03.07.2023

Res. J. Pharma. Dosage Forms and Tech.2023; 15(4):247-252.

DOI: 10.52711/0975-4377.2023.00040

Sr. No	Average tablet weight (mg)	Hardness (kg/cm²)	Friability (%)	Wetting Time (sec)	Disintegration time (sec)	Drug Content (%)
1	110	2.7	0.12	32	23 sec	97.32
2	110	3.2	0.07	29	19 sec	97.95
3	110	3.4	0.04	24	16 sec	99.19
4	110	2.8	0.09	28	18 sec	98.57
5	110	3.4	0.02	18	14 sec	99.15
6	110	3.5	0.01	16	11 sec	99.40