INTRODUCTION:

The prim aim of present research is to fabricate the bilayer tablets for sustain release of Metoclopramide HCl and Tramadol HCl using various synthetic and natural polymers. The model of Double-layer tablet (DLT) formulation is exploited to design continuous release and instant release formulation in a single tablet for a single and combination drugs. DLT had higher significance in certain circumstances such as the maintenance of constant drug levels, reduce dose, side effects, intensification to deliver safe and potent drugs to produce better patient compliance.¹A synthetic opioid analgesics Tramadol used to inhibit pain transmission in the spinal cord through the antagonizing of serotonin reuptake in the CNS. Tramadol HCl possesses squat biological half-life (5-7hrs.), due to that patient necessary to take three doses in a day which might be produced dosage missing and accumulation of drug to the patient. To troubleshoot this problem, bilayer Tramadol HCl sustained release dosage forms are designed and evaluated using multiple analyses methodology. Tramadol HCl which is used as an analgesic is formulated as sustain single layer of bilayer tablet. The Metoclopramide HCl coated as first layer intended to reduce stomach and esophageal problems caused by the tramadol. It is generally used to treat emptying of the stomach in people with delayed stomach emptying, nausea, vomiting, and help to reduce gastro esophageal reflex disease.²

MATERIALS AND METHODS:

Metoclopramide HCl and Tramadol hydrochloride, obtained from sicho biotech pharma research solutions, Hyderabad, all other excipients purchased from Loba and SD Fine Chemicals Limited, Mumbai.

Estimation of Metoclopramide HCl and Tramadol HCl by UV spectral analysis:

A stock solution of Metoclopramide HCl in 0.1M HCl solutions (100mg in 100mL) was prepared to identify the λ_maxof tramadol. The Solution 20µg/ml taken from a stock solution of Tramadol was prepared in 6.8 phosphate buffer solution and scanned between 200-400nm for absorption maxima identification.³

Fabrication of immediate release layer:

Direct Compression Method:

The direct compression procedure was applied to form the one layer of Metoclopramide HCl (Table 1). All the excipients include the amalgamation of drug stood sieved through sieve no. 40 to eliminate outsized pellets and blended for 10 min. Consequently, a sufficient amount of the talc intermingled with powder mixture for 5 min and this mixture was directly compressed. The ultimate mass of instant release layer of metoclopramide fixed to 60mg.⁴

Table 1: Composition of the IR layer of Double-layer tablets prepared by Direct Compression technique

S. No	Materials	Composition (mg)
1	Metoclopramide HCl	30
2	Sodium starch glycolate	15
3	PEG	9
4	Talc	2
5	Magnesium stearate	2
6	Ethyl cellulose	2
7	Total weight	60

Fabrication of constant release layer:

Wet Granulation process:

Drug and additional materials stood sifted through sieve no. 40, blended homogenously and granulated with the starch solution (10%) as a granulating vehicle (Table 2). The wet mass remained prepared then passed over and done with sieve no. 12. The granules were air-dried for 10 minsand again passed through sieve no.24 Lubrication through an adequate amount of talc stood done in addition to compressed into tablets. Ethyl cellulose was added between two layers. The final mass of sustained-release layer fixed to 156mg. 2mg of Ethyl cellulose was added between two layers of tablet.⁵

RESULTS:

Compatibility studies between drug and excipient:

These study emphases on a double mixture of drug material besides particular carefully chosen ingredients in a perpetual ratio. The combination kept in the storage condition of 75% RH at higher temperatures as 40^oC, 60% RH at temperatures as 55^oC in plugged vials. The consequence of the active drug and added ingredients was resolute using IR spectral analysis. A (Bruker FTIR) spectrophotometer was used for the IR spectrum. The sample was recorded using the standard KBr pellet technique. With a resolution of about 4cm^-1, samples were scanned in the area from 4000 to 400 cm^-1and it was found is drug is compatible with polymers.⁶

Preformulation analysis:

Color and nature of ingredients were analyzed by shifted small amount of powder and spread on a white surface and then visually observed. Further the taste and odor. Similarly, the minimum amount of Tramadol HCl stood used to identify the taste.⁷

Table 2: Composition of continuous delivery of Double layer Tablets manufactured by Wet Granulation technique

S. No	Formulation	F₁	F₂	F₃	F₄	F₅	F₆	F₇	F₈	F₉	F₁₀
S. No	Formulation	mg
1	Tramadol HCl	100
2	Gum gum	50	-	-	-	25	-	-	25	-	25
3	Xanthan gum	-	50	-	-	-	25	-	-	25	25
4	HPMC	-	-	50	-	25	25	25	-	-	-
5	NACMC	-	-	-	50	-	-	25	25	25	-
6	Starch (10%)	Quantity sufficient
7	Mg stearate	3
8	Talc	3
9	Total weight	156

Properties of pre-compression blend and in process quality assurance test for bilayer tablet:

Pre-compressional specifications of Double layered tablets such as Bulk density and true density for the present design remained in the assortment of 0.32- 0.39 gm./ml and 0.40 - 0.49gm./ml.^12-14The angle of repose for the formulations was found to be in the range of 24.47^o to 32.38^o. Compressibility index and Hauser’s ratio stayed in the range of 10.61 to 13.72% and 1.12 to 1.23. specified that granules prepared by the wet granulation process stood free-flowing. The Assessment of Double-layer tablets such as friability, hardness, thickness, weight variation, drug content, time of disintegration remained inside the standard approved IP limits.⁸

Dissolution Studies of bilayer tablet using In- vitro methods:

The instant metoclopramide release layer of the dissolution (of 900ml of 0.1N HCl solutions) is considered with the help of USP Type-I device by setting at the 75rpm. The solution upholds at the temperature of 37±0.5°C, and with drawn of 5ml of dissolution medium at every 15 min interval carried out to measure the absorbance by UV spectrophotometric technique at 272nm and then the concentration of the Metoclopramide is estimated from the regular calibration curve. The capacity of the dissolution solution stood accustomed to 900ml at every sampling time by interchanging 5ml with the same dissolution medium.^21-23In the dissolution device release of bilayer drug from the tablet was confirmed by the measurements of 10 hr. by the approach of basket-type tablet dissolution device (USP Type-I) having 900 ml of buffer medium. The conservational condition fixed at 37±0.5ºC and 75rpm speed of movement.⁹

Cumulative percent drug release data for bilayer tablets of instant release:

The In-vitro cumulative percent of drug release for instant release was done by using USP Type-I dissolution apparatus and it was found to be all the formulations release the drug within two hours.¹⁰

Cumulative percent drug release for continuous release:

The consequences of in-vitro drug release outline of Double layered tablets illustrates that amalgamations of natural gums performs a significant part in the impedance and optimization of the drug delivery and enhance the delay of drug delivery from the continuous layer of a Double layered tablet.¹¹ Whole preparations stood prepared for instant delivery layer by means of sodium starch glycolate, PEG, Talc; the percentage drug delivery expressions formulations (F1-F10) in the series of 98.102% to 99.897% for F8 and F3 was tabulated in (Table 3).

Invitro drug release kinetics:

The erosion model stood smeared to in vitro delivery records; the linearity stood detected with r value in addition similarly Hixon-Crowell cube root model exhibited great. r² value of 0.942 to 0.999 was tabulated in (Table 4-5) recommended that the geometrical shape of tablet lessened proportionality due to erosion of the hydrophilic gel layer. To discover the delivery configuration, results of the in-vitro dissolution records stood fitted to the Korsmeyer-Peppas equation, which describes the delivery mechanism. The value of delivery exponent (n) for whole preparations remained in concerning 0.427 to 0.669 directs the non fickian transport or irregular diffusion it refers to an amalgam of jointly diffusion and erosion rate release.¹²

Table 3: Cumulative percent drug release data for bilayer tablet for Continuous release

S. no	Time (Hr.)	F1 G	F2 X	F3 H	F4 N	F5 (G+H)	F6 (X+H)	F7 (H+N)	F8 (G+N)	F9 (X+N)	F10 (G+X)
1	0.5	25.34	22.11	33.969	35.476	27.874	27.75	34.571	30.589	29.865	22.11
2	1	33.666	24.12	41.406	46.698	35.838	35.684	40.725	36.924	38.734	24.135
3	1.5	34.571	31.356	49.647	59.006	42.354	42.532	48.689	43.078	48.508	27.135
4	2	46.155	40.401	60.702	75.115	51.947	49.199	53.938	46.979	52.128	33.768
5	2.5	53.576	49.446	71.556	86.88	59.549	56.227	59.549	51.766	58.101	41.808
6	3	59.73	57.285	80.802	95.568	69.142	57.669	67.513	59.766	62.264	47.258
7	3.5	69.142	63.114	88.641	97.016	76.02	64.156	73.486	68.599	68.056	51.225
8	4	77.106	76.179	91.656	99.369	80.907	68.120	81.812	77.468	72.038	53.265
9	4.5	86.518	82.209	96.279		85.251	70.102	86.699	83.079	74.029	59.898
10	5	93.396	85.626	99.897		87.321	72.445	94.301	86.699	79.278	66.933
11	5.5	95.93	93.063			89.957	76.049	97.921	89.957	82.536	70.725
12	6	99.188	95.676			95.749	81.815	98.645	93.034	87.423	75.174
13	6.5		97.083			97.921	84.879		95.568	90.138	78.792
14	7		99.095			98.826	89.744		98.102	91.948	82.611
15	7.5						92.627			93.396	85.827
16	8						95.330			95.568	89.455
17	8.5						98.295			97.921	93.465
18	9						99.295			99.331	96.078
19	9.5										98.289
20	10										99.596

Table 4: In-vitro Drug Release Kinetics for Bilayer Tablets R²Values.

S. No	Formu lation	Zero-order (R)²	First-order (R)²	Higuchi (R)²	Peppas (R)²	Hixson crowel (R)²
1	F1	0988	0.831	0.969	0.671	0.942
2	F2	0.971	0.898	0.975	0.735	0.986
3	F3	0.971	0.732	0.985	0.479	0.965
4	F4	0.940	0.932	0.973	0.451	0.989
5	F5	0.951	0.431	0.987	0.508	0.986
6	F6	0.977	0.830	0.996	0.500	0.954
7	F7	0.991	0.866	0.981	0.481	0.965
8	F8	0.975	0.924	0.976	0.813	0.985
9	F9	0.960	0.940	0.996	0.785	0.990
10	F10	0.985	0.807	0.985	0.635	0.961

Table 5: In-vitro Drug Release Kinetics for Bilayer Tablets.

S. no	Formulation	Zero-order	First-order		Higuchi	Peppas		Hixoncrowel
S. no	Formulation	Slope (k)	Slope	(k)	Slope (k)	Slope (n)	(k)	Slope	(k)
1	F1	14.8	-0.280	0.6650	42.60	0.600	32.1025	0.563	0.1213
2	F2	13.5	-0.268	0.7000	42.01	0.669	27.9254	0.521	0.1122
3	F3	19.52	-0.399	1.0061	46.09	0.512	44.2588	-0.727	0.1566
4	F4	24.00	-0.500	1.1988	52.96	0.540	49.773	-0.939	0.2023
5	F5	13.55	-0.260	0.5622	39.13	0.520	37.4110	-0.481	0.1036
6	F6	9.12	-0.195	0.6522	32.54	0.454	36.2242	-0.353	0.07605
7	F7	9.550	-0.180	0.3999	33.81	0.584	25.6448	-0.343	0.0739
8	F8	12.89	-0.200	0.5000	38.134	0.491	37.4196	-0.447	0.0963
9	F9	9.66	-0.199	0.4563	32.49	0.427	39.6278	-0.364	0.0784
10	F10	9.258	-0.650	0.4125	34.55	0.600	24.9999	-0.355	0.0258

Molecular simulations studies:

Software:

To study the adsorption between the tramadol and various polymers Materials Studio platform (DEMO) used which predict and understand the relationships of a material’s atomic level interaction energies with its properties and behavior.¹³

Blends

The binding energy was measured to find the energy interaction between the polymer and tramadol. In this study initially, COMPASS II force field was applied and geometrically optimized the coordinates of the components. Further, tramadol used as a base and four different polymers used as a screen to analyses the compatibility energy.¹⁴

Adsorption Locator:

This adsorption Locator module simulates a substrate loaded with tramadol in a fixed composition. It finds low energy adsorption sites of the polymer where tramadol binds with higher stability to make a stable composition. Monte Carlo searches identify the possible adsorption configurations in the chemical space of the substrate-adsorbate system rendering to a simulated annealing protocol was represented in (Table 6) and (Fig. 1-2)¹⁵

Table 6: Blends binding energies between tramadol and Polymers

Energies	Ebb avg (298 K)	Ebs avg (298 K)	Ess avg (298 K)
Tremadol_ Xanthan	-4.7963	-5.93538	-9.14678
Tremadol_HPMC	-4.7963	-20.0316	-25.6125
Tremadol_Guar Gum	-4.7963	-2.9821	-1.93962
Tremadol_CMC	-4.7963	-22.3303	-115.399

Fig. 1: Adsoption location and the binding energy graph of tramadol and xanthone polymer.

Fig. 2: Adsoption location and the binding energy graph of tramadol and Guar Gum polymer.

DISCUSSION:

Tramadol HCL shows virtuous straightly indicative of choice of UV-spectrophotometry system for assessment of tramadol is accurate.^16-20 The resulting limits of Double layered tablets stood within standard authorized IP limits Pre-compressional specifications of Double layered tablets such as Bulk density and true density for the present design remained in the assortment of 0.32- 0.39 gm. /ml and 0.40 - 0.49gm./ml. The angle of repose for the formulations was found to be in the range of 24.47^o to 32.38^o. Compressibility index and Hauser’s ratio stayed in the range of 10.61 to 13.72% and 1.12 to 1.23. specified that granules prepared by the wet granulation process stood free-flowing. The Assessment of Double-layer tablets such as friability, hardness, thickness, weight variation, drug content, time of disintegration remained inside the standard approved IP limits.^21-23 The Grade A Design of Double-layer tablets stood selected for FTIR process did not display any interaction amongst the Gums and pure drug. The degree and process of delivery of Tramadol HCL from the processed double-layered tablets stood estimated by decent the dissolution data into the zero-order, First order, Higuchi, Korsmeyer-Peppas and Hixson Crowell equations. Entirely the Preparations (F1-F10) show the Zero-order release process. Higuchi plots for entire preparations straight representing the drug delivery by diffusion controlled.^24-26Next layer is a continuous delivery layer to sustain stable state concentrations of drug in the systemic circulation. The present investigation is to Design and evaluates a perfect double layer matrix tablet of the continuous delivery outline by using appropriate systems by means of improved synthetic and natural gums.^27-28The erosion model stood smeared to in vitro delivery records, the linearity stood detected with r value in addition similarly Hixon-Crowell cube root model exhibited great r² value of 0.942 to 0.999 (Table. 4) recommended that the geometrical shape of tablet lessened proportionality due to erosion of the hydrophilic gel layer. To discover the delivery configuration, results of the in-vitro dissolution records stood fitted to the Korsmeyer-Peppas equation, which describes the delivery mechanism. The value of delivery exponent (n) for whole preparations remained in concerning 0.427 to 0.669 directs the non fickian transport or irregular diffusion it refers to an amalgam of jointly diffusion and erosion rate release (Table. 5).^29-30 Blends binding energy results showed that the tramadol mixed with the polymers in the order of Xanthan> Guar gum> HPMC> CMC. The binding energies for the three components in the simulated boundary such as base-base (E_bb), base-screen (E_bs), and screen-screen (E_ss) combinations found equal distributions which indicate the polymers are well compatible with the drug in the above order. The charts, shown below, indicate that Xanthan and tramadol bind well and the energy distribution (Table 6) is good. Also, the adsorption locator module result showed that the Xanthan possible to absorb the tramadol in two sites (Fig. 1 and 2) with the low energies which make the stable combination and longtime release compare to other mixtures.³¹The fragment pyran and the aliphatic oxygen formed the interaction with the aliphatic hydrogen and N-CH₃ atoms of Xanthan gum (Fig. 1). Guar Gum formed the two hydrophobic interactions with the rings of tramadol (Fig.2). Other two polymers not formed proper orientation with the tramadol which leads to the faster release compare to the xanthane and guar gum. ³²

CONCLUSION:

The present research stood conceded out to progress bilayer Continuous deliver tablets of Metoclopramide Hydrochloride Instant deliver layer by direct compression method which is use full for the management of Gastro reflex diseases and Tramadol HCl hydrophilic polymers for sustain release layer by wet granulation process. Established that, double-layer tablet processes can remain effectively smeared for Tramadol HCl by means of gums like HPMC K 100, NACMC, Xanthan gum, Guar gum can be utilized as rate monitoring natural Gums by an applicable assortment of the capacity of natural gums in the matrix tablets. Molecular simulation studies the adsorption locator module result showed that the Xanthan possible to adsorbs the tramadol in two sites with the low energies which make the stable combination and longtime release compare to other mixtures. Finally, this research found to be optimized batch F10 by bilayer drug delivery design and provide healthier disease in pain and gastritis management and also provides patient compliance.

CONFLICTS OF INTEREST:

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the manuscript.

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Received on 08.10.2020 Modified on 26.02.2021

Research J. Pharm.and Tech 2022; 15(2):529-534.

DOI: 10.52711/0974-360X.2022.00085