INTRODUCTION:

Chronopharmaceutics And Chronotherapy:

“The study of drug delivery systems that release a bioactive agent at a rhythm that exactly matches the biological requirements of treating a certain disease is the focus of the discipline of pharmaceutics known as chrono-pharmaceutics.

Chronobiology of disease and pharmacological agents make up the majority of chrono-pharmaceutics. Chronobiology primarily covers the study of biological rhythms and mechanisms.

The idea behind Chrono therapy:

The concept of chrono-therapeutics was first inspired by the discovery that the principal disease conditions, such as heart disease, throat infection, inflammatory disease, and respiratory disease, follow rhythmic patterns, for example, of symptom eruption. The development of chronotherapeutic delivery systems aims to generate the most efficient treatment plans that are based on the objectively reassuring highest possible drug concentration at the beginning of symptoms. According to recent research, a lot of emphasis has been put on drug delivery systems with sustained zero-order drug release profiles. Sustained release preparations keep medication release within a therapeutic window for a longer period of time, which lowers peak-to-trough variations and, in turn, minimizes adverse effects and dosage frequency. To treat chronotherapeutic disorders, when pulsatile drug administration is required and drug release may occur after a lag phase at predefined time intervals, zero-order drug release is not optimal. In some circumstances, obtaining a sigmoidal medication release profile is the research's goal. The formulation's key feature is achieving a predetermined lag time profile, which should be followed by a pulse-type drug release that releases the active concentration.

ADVANTAGES AND DISADVANTAGES:^10,11,12

Advantages:

1. The developed system has a very short resident time and is of a reproducible type.

2. Variability between individuals is reduced.

3. This system improves bioavailability.

4. It reduces a drug's molecule's adverse drug reaction.

5. Body parts experience less irritation.

6. There is no drug dumping issue in the GI tract.

7. The development of possible approaches.

8. Formulation stability is increased

9. The patient compliance is improved by these formulations.

10. Each drug release profile differs from each other.

11. These techniques can be utilized for extending a patent.

Disadvantages:

1. A problem with reproducibility and manufacturing efficiency was found.

2. Variations in the manufacturing process were noticed.

3. Multiple stages are taken in the production process.

4. High production costs.

5. It requires sophisticated methods.

6. Skilled workers are needed for production.

OBJECTIVE:

1. To do the Preformulation research for the selected medication.

2. To formulate and design a compressed tablet of an elected medication.

3. To assess the physiochemical properties of the synthesized dosage form, such as hardness, friability, weight variation, dissolution, and disintegration taste.

4. To create and produce the best possible and reliable dosage form.

5. To use a particular dosage form with lesser frequency than a different one.

6. Developing a dosage form that adapts to a disease's or the body's circadian rhythm.

7. The primary goal of this work was to design and test a time-controlled single unit oral pulsatile tablet.

MATERIALS AND EQUIPMENTS:

Sr. No	Materials	Manufacturer
1	Tramadol HCL	Cipla Ltd. Mumbai
2	HPMCK4M	Color con Asia Ltd. Goa
3	Ethyl Cellulose	SDF in e chemical, Mumbai
4	Croscarmellose	Signet Chem, Mumbai
5	Magnesium Stearate	SDF in e chemical, Mumbai
6	Talc	SDF in e chemical, Mumbai
7	Lactose	SDF in e chemical, Mumbai

Table1: List of Chemicals Used

PREFORMULATION STUDY¹³

Determination of melting point:

Melting point analysis was used as the primary method of medication authentication. The capillary method was used to determine the drug's melting temperature.

Solubility:

Tramadol hydrochloride's solubility in distilled water and methanol was determined. Tramadol hydrochloride was used in excess for solubility tests in various beakers using the solvents.

Determination of Absorption Maxima (λ_max):

Tramadol HCL's absorption maximum was found by scanning a 10g/ml solution sample of the medication at wavelengths between 200 and 400nm using a UV double beam spectrophotometer. The outcomes are shown in figure no. 1

Drug Excipient Compatibility study:

For the purpose of identifying any potential chemical interactions between the medication and the polymer, infrared spectra matching was used. A 1:1 physical combination of the medication and polymer was made and combined with the appropriate amount of potassium bromide. Using a hydraulic press, the mixture was squeezed into a clear pellet. It was scanned using a Shimadzu 8400 DRS FTIR spectrophotometer from 400 to 4000 cm-1. In order to identify any peak appearance or disappearance, the IR spectrum of the physical mixture was compared with those of pure drugs and polymers.

Preparation of Standard Calibration Curve of Tramadol HCL:

To make stock solution I, 100mg of tramadol hydrochloride was properly weighed into a 100ml volumetric flask, dissolved in phosphate buffer solution, and the remaining volume was made up with phosphate buffer. A 100ml volumetric flask was filled with phosphate buffer and 1ml of the previously mentioned solution was pipette out into it to create stock solution II. Sample material was taken from the stock solution II and appropriately diluted with phosphate buffer to provide a concentration range of 1g/ml to 10g/ml. Using phosphate buffer as a blank, the absorbance of these solutions was measured at 270.50nm.

Preparation of Core Tablets of Tramadol HCl:

The direct compression process was used to prepare the core tablets. Table 1 displayed the tablet's chemical make-up. The sieve number 30 was used to filter out all the excipients. The necessary elements were precisely measured, completely mixed, and dry blended for five minutes with talc and magnesium stearate. The obtained blends were compacted using an 8 mm flat face punch with a multi station tablet punching machine and subjected to micromeritic characteristics.

Table 2: Formulation of Tramadol HCl Core Tablets:

Sr. No.	Ingredients	Formula
Sr. No.	Ingredients	F1	F2	F3
1	Tramadol HCl (mg)	50	50	50
2	Croscarmellose Sodium (mg)	3	4.5	6
3	Magnesium stearate(mg)	1.5	1.5	1.5
4	Talc(mg)	1.5	1.5	1.5
5	Lactose(mg)	94	92.5	91
6	Total Wt. (mg)	150	150	150

Formulation of Press Coated Pulsatile Tablet of Tramadol HCl:

Each item was precisely weighed, passed through sieve number 70, and carefully combined for five minutes. A powder bed with a level surface was created by first filling a die with a half-quantity of the combination of two polymers (hydrophilic HPMC and ethyl cellulose) with a variable weight ratio. The center of the powder bed was then carefully positioned with the core pill there. The remaining coating slurry was poured into the die, and the powder bed was immediately squeezed using a 12mm flat punch to create the appropriate press-coated tablets. Table 1 displays the press coated tablet formulations. The hardness, thickness, content uniformity, friability, and duration of dissolving of the press-coated tablets were also assessed.⁶¹

Table 3: Composition of Press Coated Tablets

Sr. No.	Ingredients	Formula
Sr. No.	Ingredients	F1	F2	F3	F4	F5
1	Core Tablet	150	150	150	150	150
2	HPMCK4M	200	150	100	50	-
3	Ethyl Cellulose	-	50	100	150	200
4	Total Wt.(mg)	350	350	350	350	350

EVALUATION:

Evaluation of Powder Blend^14-18

Bulk Density:

Bulk density is defined as the ratio of mass of powder to bulk volume. It is calculated using the following quation:

Bulk density=weight of sample taken/volume noted

The graduated cylinder was carefully filled with the number of granules (W) that had been precisely weighed, and the volume (v o) was then calculated. The cylinder was then dropped three times from a height of one inch, at intervals of two seconds, onto a hard hardwood platform. Bulk density was estimated once the volume was measured.

Tap Density:

The graduated cylinder was carefully filled with the number of granules (W) that had been precisely weighed, and the volume (v o) was then calculated. After carefully smoothing the surface, the volume was calculated. From a height of six inches, the final volume (V f) after 50 taps on a wooden surface was measured to determine the tap density, which is given in g/cm3.

Bulk density = W/Vo

Tapped density= W/V f

Were,

Vo = initial volume

Vf=final volume.

Compressibility Index and Hausner Ratio:

The Hausner ratio and Compressibility index are indicators of a powder's susceptibility to be compressed. They serve as indicators of the relative significance of particle interactions. Such interactions are typically less important in a free-flowing powder, and the values of the bulk and tapped densities will be closer. There are usually stronger particle interactions and a greater difference between the bulk and tapped densities in inferior moving materials. The Compressibility Index and the Hausner Ratio both reflect these variations.

The compressibility index and Hausner ratio can be calculated using measured values forbulkdensity( ρ _bulk) and tapped density(ρ_tapped) as follows.

Compressibility index = (ρ_tapped - ρ _bulk) × 100 / ρ_tapped

Hausner ratio = ρ_tapped / ρ _bulk

Angle of Repose:

The angle of repose is used to measure the flow properties. Frictional forces between the particles cause improper powder flow. The angle of repose is used to measure these frictional forces. The maximum angle that can be formed between a pile of powder's surface and the horizontal plane is known as the angle of repose.

tan θ = h/r

θ = tan^-1h/r

Where

h = Height of pile

r = Radius of the base of the pile

θ = Angle of repose

Evaluation of Core and Press Coated Pulsatile Tablets^19-23

Thickness:

Control over a tablet's physical characteristics, such as thickness, is essential for consumer acceptance and uniformity. Using Vernier calipers, the tablet's thickness was determined. It has a millimeter scale.

Hardness:

The hardness of the pill was assessed using the Monsanto hardness tester. Between a fixed and movable jaw, the tablet was being held. The load was steadily increased until the tablet shattered when the scale was set to zero. The amount of force there provides a measurement of the tablet's hardness. The unit of hardness was Kg/cm²_.

Friability:

The strength of a tablet is measured by its friability. The following approach was done to test the friability using the Roche Friabilator. Twenty tablets were precisely weighed and put in the plastic container, which rotates at 25 rpm for four minutes, dropping the tablets six inches at a time. The tablets were reweighed after 100 revolutions to determine the % weight loss.

%F= {1-(Wo/W)} ×100

Were,

% F = Friability in percentage

Wo = Initial weight of tablet

W = Weight of tablets after revolution

Weight Variation Test:

To verify that a tablet contains the right amount of medication, the weight of the tablet being manufactured is frequently measured. 20 tablets were weighed individually for the IP weight variation test, the average weight was calculated, and the individual weights were compared to the average. If no tablet differs by more than twice the percentage limitations and no more than two tablets are beyond the limitations, the tablet passes the IP test.

Table4: Standard limit value in weight variation test (asper IP)

Average weight of a tablet	Percentage Deviation
80mgorless	±10
>80and <250mg	±7.5
250mgor more	±5

Uniformity of drug content:

Ten different-formulated tablets were separately weighed and pulverized. A UV/Visible Spectrophotometer was used to measure the absorbance at 270.50nm following appropriate dilution of a powder comparable to the average weight of tablets. The drug concentration was then calculated.

Dis integration Test:

The process of a tablet disintegrating is crucial to the drug's absorption. The USP disintegration test apparatus was used to conduct the disintegration test. At the base of the basket rack assembly, it consists of 6 glass tubes that are 3 inches long, open at the top, and pressed up against a 10-mesh screen. One tablet was placed in each tube and the basket rack was placed in a 1-liter beaker filled with 6.8 phosphate buffer solution at 37°C 1°C so that the tablet stays 2.5cm below the surface of the liquid in order to test the disintegration period of core tablets. It was noticed how long it took the tablets to completely dissolve.

In Vitro Drug Release Studies:

Utilizing U.S.P. II (type II) dissolving rate test equipment, the drug release of the manufactured core and press coated pulsatile tablets was assessed. As a dissolving media, 900ml of phosphate buffer with a pH of 6.8 was utilized. Throughout the experiment, the temperature of 37±0.5℃ and the paddle's rotational speed of 50rpm were held constant. At certain intervals, 1ml samples were taken out and replaced with the equal volume of fresh dissolving medium. On a double beam UV/Visible spectrophotometer set to a maximum wavelength of 270.50nm, the samples were spectrophotometrically analyzed. The data were calculated as a cumulative medication release percentage.

Stability Studies:

According to ICH recommendations for an optimized formulation, the accelerated stability studies have been carried out. The formulation was packaged in a strip of aluminum foil and kept in a stability chamber set to Zone III conditions—40°C and 75% relative humidity—for a month. The tablet's appearance, hardness, drug content, and in vitro release were all assessed before and after three months.

RESULT:

Pre formulation study:

Determination of Melting Point:

Tramadol HCL's melting point was established using the capillary technique. Tramadol HCL's melting point has been found to be between 180 and 181 ℃, which satisfies IP criteria and proves the medicine sample's purity.9.1.2 Tramadol hydrochloride was shown to be quickly soluble in methanol and water.

Figure 1: UV Spectra of Tramadol Hydrochloride

Determination of Absorption Maxima (λ _max) With the aid of an appropriate blank, a solution with the right amount of the drug was made and scanned in a UV spectrophotometer from 200 to 400nm. The drug's highest absorption was at 270.50n min wavelength. There is a spectrum in figure 1.

1.1.1 Drug Excipient Compatibility Studies (FTIR):

Study is done on the IR spectrum of pure drugs and polymers. We found that there is no chemical reaction between tramadol hydrochloride and polymer in the current study. Because of some bond formation between drug and polymer, it was noticed that the primary peak in the IR spectra of the drug and polymer mixture did not change, indicating that there was no physical interaction.

Figure 2: FTIR Spectra of pure drug Tramadol hydrochloride

Figure3: FTIR Spectra of Tramadol hydrochloride and HPMC

Figure4: FTIR Spectra of Tramadol hydrochloride and Ethyl Cellulose

Standard calibration curve of Tramadol HCl:

At concentrations ranging from 1g/ml to 10g/ml, the medication responded linearly. Figure 5 depicts the results of treating the calibration curve with linear regression analysis after visualizing the absorbance versus concentration data.

Table5: StandardcalibrationcurveofBosentaninphosphatebufferpH6.8

Sr. No.	Concentration (µg/ml)	Absorbance
1	1	0.32
2	2	0.65
3	3	0.94
4	4	1.21
5	5	1.54
6	6	1.86
7	7	2.12
8	8	2.4
9	9	2.76
10	10	2.97

Concentration (µg/ml

Figure5: Calibration Curve of Tramadol HCl in Phosphate Buffer pH 6.8

Correlation Coefficient (R) = 0.9992

Equation for regression line: y = 0.2988x + 0.0305 Where, X = Value of Concentration

Y = Regressed value of Absorbance 0.0305 = Slope of regressed line 0.2988 = y intercept

EVALUATION:

Pre-Compression Para meters:

Table6: Micromeritics properties of powder blend of core tablets for mulation

Formula	Bulk density (g/cc)	Tapped density (g/cc)	Compressibility Index (%)	Hauser’s Ratio	Angle of Repose (Ѳ)
F1	0.435	0.550	14.15	1.19	25.32
F2	0.471	0.552	15.24	1.24	27.62
F3	0.421	0.512	15.44	1.21	28.50

Table 3 displays the micromeritic characteristics data. Bulk density values were obtained for all formulations in the range of 0.421 to 0.471gm/cc, and the tapped density measurements ranged from 0.512 to 0.552g/cc. The compressibility index ranged from 14.15 to 15.44, the angle of repose ranged between (25.32-28.50), and Hausner's ratio was between (1.19-1.24), all of which supported the powder blend's favorable flow properties. Thus, the powder had improved its flow properties and was not aggregated.

Post Compression parameters:

Table7: Post Compression parameters of Core Tablets Formulation(F1toF3)

Formula	Weight Variation	Hardness (Kg/cm2)	Friability (%)	Thickness(mm)	Drug Content (%)	Dis integration Time(sec)
F1	150±1.4	3.5±0.35	0.94	3.2±0.50	95.66	45± 1.12
F2	151±1.2	3±0.47	0.98	3.1±0.34	96.12	40± 1.51
F3	150±1.2	3.5± 0.52	0.92	3.2±0.31	96.72	30± 0.74

(SD± Mean of n=3)

The result of evaluation parameter had been showed in Table 7. The post-compression parameter forallformulation F1 to F3 found within acceptable limit.

Weight Variation:

All formulation batch F1 to F3 tablet weights were approved and confirmed to be compliant with pharmacopoeial standards.

Hardness:

For formulations F1 to F3, the hardness of the tablets was determined to be optimal and suggest tablets withstanding mechanical shock in the range of 3 to 3.5kg/cm2.

Friability:

All tablet batch formulations F1 through F3 had friability values that were less than 1%, which indicates that the tablets had a satisfactory mechanical strength.

Drug Content:

Within and between the various types of tablet formulations, there was good medication content uniformity. Between 95.65 and 96.72% were the values.

Thickness:

For formulations F1 to F3, it ranges from 3.1 to 3.2, which is determined to be ideal and indicates good dispersion of pure medication.

Disintegration Time:

Disintegration times for formulations were determined to be within pharmacopoeial guidelines, falling between 30 and 45 seconds. Due to the increased concentration and wicking action of the disintegrating agent, croscarmellose sodium, FormulaF3 had the shortest disintegration time of 30 seconds when compared to other formulations.

In Vitro Drug release of Core Tablets of Tramadol HCl:

In phosphate buffer pH 6.8, rapid core tablet in vitro drug release tests were conducted.

Table8: In Vitro Drug release of Core Tablets of Tramadol HCL

Time(min)	F1	F2	F3
5	31.15	42.26	44.72
10	48.33	50.24	54.75
15	62.21	66.84	70.02
20	80.20	84.37	87.62
30	92.32	95.41	98.61

At 60 minutes, 92.32% of the medication was released from core formulations containing F1 that were made with 2% croscarmellose sodium. At the end of 60 minutes, formulation F2 made with 3% croscarmellose sodium released 95.41% of the medication, while formulation F3 made with 4% croscarmellose sodium released 98.61%. Because croscarmellose sodium, a super dissolving agent, was present in every formulation, the medicine was released quickly. In comparison to other formulations, formulaF3 showed the fastest drug release. The outcomes showed that the medication release increased as the concentration of super disintegrant increased.

Evaluation of Press Coated Pulsatile Tablet of Tramadol HCl:

Using various concentrations of the hydrophilic polymer HPMC K4M and the hydrophobic polymer ethyl cellulose, press coated pulsatile tramadol tablets were created. Table 3 displays the formulations' makeup. In terms of formulations, formula F3 was chosen for press coating in order to generate pulsatile tablets because it had a quicker drug release and disintegration time. The direct compression approach was used to create the tablets. Tramadol HCl pulsatile tablets undergone post compression analysis.

Utilizing a Monsanto Hardness tester, the hardness of the tablets made utilizing the direct compression method was determined. Indicating good crushing strength, the mean hardness of coated tablets was determined to be in the range of 5.8 0.32 to 6.3 0.36kg/cm2.

For the pulsatile tablets, the mean thickness of coated tablets was determined to be between 4.50mm and 4.53mm.

All formulations' drug content uniformity was tested, and it was found to be between 96.30% and 98.42%, which is within acceptable limits.

All tablet batch formulations F1 through F5 completed the test and had weight variations that were within the pharmacopoeia's acceptable range. All formula of tablets passed the friability test with less than 1%, indicate good mechanical strength.

Formula F1 made with HPMC K4M alone showed 0 hours of lag time, which may be related to the hydrophilic character of the polymer. The lag time of the press coated tablets was determined by determining the time for which there is no release of medication. Formula F2, F3, F4, and F5 revealed lag times of 1 hour, 4 hours, 3 hours, and 4 hours, respectively. The Formula F3 and F5 displayed the maximum 4-hour lag time. Table 9 displays evaluation data for coated tablets.

Table 9: Evaluation of Press Coated Pulsatile Tablets (F1 to F5)

Formulation Code	Parameter	Before storage (0month)	After storage (3Momths)
F3	Hardness (kg/cm2)	6	5.8
	Drug content	98.42	96.16
	%Drug release	96.6	96.23

(SD±Mean of n=3)

In Vitro Drug release of Press Coated Pulsatile Tablets:

Tablets were dissolved in phosphate buffer at a pH of 6.8. Understanding the impact of various polymers and their increasing concentrations was the goal of the dissolving investigation of these formulations. The formulation was improved based on the intended lag time and dissolving profile values. formula F1, created only with HPMC, displayed a lag time of 0 hours and an 8-hour drug release of 92.7%. After eight hours, the drug release from formulas F2, F3, and F4 made with various amounts of HPMC and EC was 90.26%, 96.60%, and 86.825 respectively. The hydrophobic character of the EC polymer may be the cause of the formula F5's significant lag time and poor drug release, which revealed lag times of 4 hours and 41.32% in 8 hours, respectively. Formula F3 is the best formulation among the others since it provides an adequate lag time and optimal drug release. Table 8 displays data on the percent cumulative drug release over time for all formulation formulas,

Stability studies:

For stability testing, a pulsatile tablet formulation with the best lag time and drug release was chosen. In accordance with ICH recommendations, optimized formulations F3 were kept at a temperature of 400°C and a relative humidity (RH) of 75% for three months. The formulation's appearance, hardness, drug content, and in vitro release were all assessed. At the end of three months, there was no discernible alteration in the hardness, drug content, or in vitro drug release. According to the results of the stability investigation, press coated pulsatile tablet formulation F3 was discovered to be stable.

Formula	Weight Variation	Hardness (Kg/cm²)	Friability (%)	Thickness (mm)	Drug Content (%)	Lag Time (Hr.)
F1	351 ± 0.23	6 ± 0.42	0.62	4.51± 0.52	97.61	0
F2	353± 0.41	5.8 ± 0.32	0.51	4.53± 0.33	98.12	1
F3	351± 0.57	6 ± 0.57	0.46	4.50± 0.35	98.42	4
F4	349±0.22	6.2 ±0.21	0.52	4.52±47	97.36	3
F5	352±0.25	6.3 ±0.36	0.54	4.51±64	96.30	4

Table10: Stability data of optimized formulationF3

DISCUSSION:

All the batches were formulated and evaluated successfully in which we found that that the formula F1 to F3 shows the optimized result according to standards.

CONCLUSION:

The findings of the current investigation led to the following observations:

· Tramadol Hydrochloride pulsatile tablets can be made using the direct compression method and a polymer such as ethyl cellulose and HPMC.

· All of the prepared formulas produced outcomes that were satisfactory.

· Studies using IR spectroscopy show that there is no drug-excipient interaction during formulation.

· Formulation F2, which has a lag time of 4 hours and an 8-hour drug release of 96.6%, was regarded as the optimal formulation.

· Future thorough research is necessary to determine the pulsatile tablet of tramadol hydrochloride's in vivo effectiveness, and a long-term stability study is necessary to prove the tablet's stability.

ACKNOWLEDGMENT:

Authors are thankful to Cipla Ltd. Mumbai for providing gift sample of drug.

CONFLICTS OF INTEREST:

The authors have no known conflict of interest concerning the present article.

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Received on 24.06.2023 Modified on 23.01.2024

Research J. Science and Tech. 2024; 16(3):193-202.

DOI: 10.52711/2349-2988.2024.00029