Physicochemical Characterization of Bi-Layered Terbutaline Sulfate Tablets for Chronotherapeutic Pulsatile Drug Delivery Design Based on Natural and Synthetic Polymer using Direct Compression Technique

 

Prasanta Kumar Mohapatra1*, Janki Manohar2, Pankaj Singh Patel 1, Mandeep Kumar Gupta1, Bibhuti Prasad Rath3

1Moradabad Educational Trust Group of Institutions Faculty of Pharmacy, Moradabad,

Uttar Pradesh - 244001, India.

2Lydia College of Pharmacy, Ravulapalem, Andhra Pradesh - 533238, India.

3Gayatri Institute of Science and Technology, Rayagada, Odisha- 765022, India.

*Corresponding Author E-mail: mohapatra.kjr@gmail.com

 

ABSTRACT:

The aim of the strategy to formulate the pulsatile drug delivery system using terbutaline sulfate by direct compression technique and evaluate the effects of formulation and dissolution medium on the behavior of drug release, and to clarify the drug release mechanism based on acquiring results. Pulsatile release tablets include a drug and disintegrating agent-containing core and swellable external layers for slow down drug release, then rupturing the nearby surrounding outer layer for fast release. Core tablets prepared using disintegrating agent by direct compression method and coated with polymers like HPMC K100M, ethyl cellulose, karaya gum in different quantities. Several physical parameters of the tablets evaluated such as stiffness, thickness, friability, weight variation, disintegration, drug content and dissolution test. Terbutaline sulfate released from bi-layered tablets with pulsatile behaviors. In-vitro drug release rate readings showed that F3 and F6 are best based on the less quantity of drug release during the lag time (11% and 14% in 5 h). So, from the result, the F6 has nominated the best formulation. Thus, by the direct compression method prepared, coated tablets before drug release with an obvious lag time is possibly useful preparation for the medication of osteoarthritis, rheumatoid arthritis, dysmenorrhea, asthma which follows a circadian rhythm. It confirmed that eroding, diffusion, and swelling mechanisms were responsible for drug release. Ultimate pulsatile release activities may be done by modifying polymeric membrane quantities and proportions to meet the condition of pulsatile activities.

 

KEYWORDS: Terbutaline sulfate, Pulsatile drug release, Lag time, Direct compression, FTIR.

 

 


INTRODUCTION:

The pharmaceutical industry is increasing the cost of successful drug discovery and development and kept pressure to keep prices down1. For the improvement of a novel drug delivery system (NDDS) and chronomodulated drug delivery system (ChrDSS) the time and average cost needed is 3 to 4 y and $20-$50 million. To improve a new chemical object the which 60% metabolized by the liver in an average cost needed is more than the 10-12 y and approximate $500 million.

 

 

A current drug molecule can acquire a fresh life and grow its market value and extend patent life and competitiveness2. Nowadays, the interest is increasing has turned to systems intended to achieve a site-specific and time-specific (delayed, pulsatile) release of drugs as compared to modified-release oral dosage forms. For this mostly, systems for delayed-release will deliver the drug over a planned period following administration3. Subsequently, ChrDSS constructs a quite innovative class of DSS, the importance of which is essentially connected with the current improvements in chronopharmacology4,5,6. The number of drugs pharmacokinetics and pharmacodynamics property follows temporal rhythms, frequently resulting in variations in circadian along with the symptomatology of numerous pathologies. The possibility of utilizing delayed-release to implement chronotherapy is quite interesting for some diseases. The symptoms of which returned mostly at night-time or in the early morning, for example, bronchial asthma, angina pectoris, and rheumatoid arthritis7. The postponement in the onset of action has reached through hydrophilic or hydrophobic layers, osmotic mechanisms, covering a drug-loaded core and swell-able or erodible masses coating a drug comprising an insoluble capsule body8,9,10,11. The drug release pattern of the conventional drug delivery system fluctuates or in a sustaining release case, a constant release rate observed, but it is not always ideal12,13. Due to this reason, the latest release pattern of drug delivery developed, and that fulfilled by a pulsatile drug delivery system (PDDS). From the maximum DSS, the controlled release DSS, and the conventional oral DSS, the drug releases in a constant pattern or fluctuating pattern14. In a pulsatile release the drug release rate characterized by a (lag time) time of very slow release rates, afterward, a rapid and complete drug release wherein the method controls the lag time independent of body environmental influences like GI motility, pH, enzymes15,16. The system designed and demand for a time-programmed therapeutic arrangement, releasing the correct quantity of the drug at the correct time. The requirement of this pattern of release achieved by a PDDS, which described by a lag time that is an interval of a smaller amount of drug release afterward the drug releases speedily15,17. The PDDS is necessary for a verity of diseases similar to asthma, cancer, diabetes, duodenal ulcer, neurological disorders, hypercholesterolemia, arthritis, colonic transport, and diseases like cardiovascular18. One of the diseases is asthma, where the PDDS can be suitable and circadian fluctuations, observed in common lung function, airway resistance rises in asthmatic patients gradually at night18,19,20. A potent β-adrenoreceptor agonist terbutaline sulfate is usually used in the treatment of asthma21,22,23. The drug terbutaline sulfate absorption from the gastrointestinal tract is inconstant and absorbed only 33-50% of the total administered an oral dose and apart from which 60% is metabolized by the liver under the first-pass metabolism24. Not only this, but the drug also undergoes metabolism by the gut wall25. For these reasons, 15% of the oral bioavailability of the drug is found from the total administered dose26. And also, the drug is having a small half-life 3-4 h needs repeated administration27. Thus, evaluation and improvement of ChrDSS of terbutaline sulfate have been undertaken, but also the benefits of this system also consist of the improved utilization of drugs having small half-life with expansive first-pass metabolism thereby producing a better therapeutic result for nocturnal asthma28.

 

MATERIALS:

The pure drug terbutaline sulfate bigheartedly provided by Matrix Laboratory Limited, Hyderabad, India. Crospovidone and ethyl cellulose obtained as a gift sample from S.D. Fine Chemicals, Mumbai, India. Mannitol and HPMC K100M purchased from Rankem Lab, Hyderabad, India. Karaya gum and magnesium stearate were generously supplied by Otto Chemicals, Pvt Ltd, Mumbai and NR chemicals, Chennai, India. The obtained analytical grade other reagents and chemicals were from S.D. Fine Chemicals, Mumbai25,28,29.

 

METHODS:

Formulation of the core tablet:

The terbutaline sulfate core tablets mass-produced through direct compression procedure. The powdered ingredients like drug terbutaline sulfate and crospovidone were dry mixed for 20 min afterward, magnesium stearate added, and the formula shown in Table I. The powder blends then additionally blended for 10 min and from the subsequent powder blend 50 mg manually compressed by 16 station rotary tablet punch instrument comprising 6 mm circular die and punch for the core tablet formulation16,18,30.


 

Table 1: Composition of core tablets

Ingredients (mg)

C1

C2

C3

C4

C5

C6

Terbutaline sulfate

5 mg

5 mg

5 mg

5 mg

5 mg

5 mg

Crospovidone

5 mg

5 mg

5 mg

5 mg

5 mg

5 mg

Mannitol

39.25 mg

39.25 mg

39.25 mg

39.25 mg

39.25 mg

39.25 mg

Magnesium stearate

0.75 mg

0.75 mg

0.75 mg

0.75 mg

0.75 mg

0.75 mg

Total weight

50 mg

50 mg

50 mg

50 mg

50 mg

50 mg

 

Table 2: Composition of press coat tablets

Ingredients (mg)

F1

F2

F3

F4

F5

F6

Magnesium stearate

0.75 mg

0.75 mg

0.75 mg

0.75 mg

0.75 mg

0.75 mg

HPMC K100M

200 mg

300 mg

100 mg

-

-

-

Ethyl cellulose

200 mg

100 mg

300 mg

200 mg

300 mg

100 mg

Karaya gum

-

-

-

200 mg

100 mg

300 mg

Total weight

450 mg

450 mg

450 mg

450 mg

450 mg

450 mg

Note: (-) the particular excipient not utilized in the formulation

 

 


Formulation of press-coated tablet:

The formulations weighed and dry blended around 10 min having compositions ethyl cellulose and HPMC K100M. The core tablets were press-coated and which contain around 50mg of weight and specified in Table II. The accurate weight containing outer layer material 200 mg measured thereafter shifted to 12 mm diameter die afterward the core tablet was by hand situated at the center. The residual barrier layer material, exactly 200 mg added into the same die and compressed16,31,32,33.

 

Experimental design layout:

Experimental design utilized in the current investigation for the optimization of excipients concentration, such as the concentration of HPMC K100M, ethyl cellulose, and karaya gum taken as X1, X2, and X3 and formulae for all the experimental batches represented in Table II. Three levels for the concentration of polymers selected and coded as (-1=100mg, 0=200mg, +1=300mg). Table III summarizes a record of the six-formulation examined, their factor combinations, and the coded levels to the experimental units utilized during the study6,8,29.

 

Table 3: Experimental design layout

Coded factors and units

Coded levels

Low level

Middle level

High level

 

-1

0

+1

HPMC K100M

100

200

300

Ethyl cellulose

100

200

300

Karaya gum

100

200

300

Formulation code

Coded factors and their levels

Coded factors and their actual values

X1

X2

X3

X1

X2

X3

F1

0

0

-

200

200

-

F2

+1

-1

-

300

100

-

F3

-1

+1

-

100

300

-

F4

-

0

0

-

200

200

F5

-

+1

-1

-

300

100

F6

-

-1

+1

-

100

300

Note: (-) the particular excipient not utilized in the formulation

 

Evaluation parameters for the pre-compression tablet:

Bulk density:

Pharmaceutical ingredients or particulate matter and the granules property, powders, and divided solids determined by bulk density. It represented a substantial mass divided by occupied total volume. The total volume of a substance defined as the addition of inter and intra-particle void volume to true volume. The bulk density determined by dividing the powder sample volume concerning a known mass in a graduated cylinder18,22,34.

Where,

ρb= Bulk density

M = Mass of the powder

V0 = Bulk volume of the powder

 

Limits-The bulk density results having less than 1.2 g/cm3 indicating decent packing and result from over 1.5 g/cm3 specifies poor packing.

 

Tapped density:

The well-known powder mass poured into a transparent graduated cylinder and the volume of the powder mass known as V0. A density determination apparatus fixed to the cylinder and the cylinder which contains granules/powder tapped for 500 times than reading detected. With the help of a measuring cylinder containing the granules/powder sample, the density achieved by mechanically tapped18,22,34.

Where,

ρt= Tapped density

M = Mass of the granules/powder

Vt = Tapped final volume of the granules/powder

 

Compressibility index:

Carr’s index calculated based on bulk density and tapped density values. Carr’s index equation represented below22,33,35.

Where,

ρt = Tapped density

ρb = Bulk density

 

Hausner’s ratio:

The flow properties of the powder specified by Hausner’s ratio and estimated by taking a ratio of tapped density to the bulk density of the powder or blend18,22.

 

Angle of repose:

The knowledge about the flow property of the particles or powder estimated by the angle of repose. This represented as the maximum angle achieved between the powder pile surface concerning the horizontal plane18,22,33.

Where,

θ = Angle of repose

h = Height of a pile (2 cm)

r = Radius of pile base

 

Evaluation parameters for the press-coated tablet:

Thickness and Diameter:

The 10 core tablets, as well as press-coated tablets thickness and diameters, noted by using a Vernier caliper18,22.

Weight variation test:

This is a quality control and in-process quality control test to confirm that the manufacturers control each compressed tablet comprises the proper amount of drug, different pharmacopeias stated these weight variation tests. First, randomly selected 20 tablets average weight calculated then the same 20 tablets individual weight calculated with the help of the analytical balance. Afterward, the ±% limit of average weight compared to an individual tablet. The ±% average weight limits of uncoated compressed tablets provided by the USP16,30,36.

 

Hardness:

The hardness of a tablet influenced by its particle-particle bonding and tablet resistance power to capping, breakage during transportation, and handling. Hardness, which called crushing strength and it can be regulated by pressure modification of tablet machine. A too-hard tablet may not disintegrate in the appropriate time, so onset time will be more and too soft tablet not be able to withstand the stress like transportation, handling, coating and packaging, and easily break. It is the measurement of strength needed to break the tablet when the force applied by diametrical direction to the tablet. The in terms of kg/cm2 average hardness was calculated30,36,37.

 

Friability:

Friability test carried out by using 20 tablets. Randomly from each tablet formulation 20 tablets collected and weighed by using an analytical balance. The same tablets kept in a rotary drum and rotated at 25 rpm for 4 min means a total of 100 revolutions. After 100 revolutions, the tablets removed from the rotary drum and weighed. The percentage of weight loss calculated using the following equation. During transportation, the tablet got stress like friction and shock and for this reason, the tablets may chip, break. To appraise the capacity of the tablet to withstand abrasion during packaging, handling, and transportation, the friability test led. A weight loss, an extreme percentage of 20 tablets must not be over 1% and measured by the apparatus Roche friabilator16,18,22,37.

 

Disintegration test:

As described in Indian Pharmacopoeia the disintegration apparatus was used to determine the disintegration time of the compact mass (tablet). In it, 2 basket assembly located, and each basket contains 6 glass tubes having 3 inches long is present in a beaker having 1000 ml capacity. The tubular upper part is open and the lower part fixed with 10 no mesh. Into each tube, one tablet kept and pH 7.4 phosphate buffer solvent system used at temp 37±0.5°C. The time required to disintegrate the tablet (particles completely pass from the tube into the beaker through no 10 mesh) was noted18,30,36.

 

Uniformity of content:

The test uniformity of content is used to confirm that each tablet comprises the quantity of drug substance design with little deviation among tablets within a batch. The content uniformity test has added to the monographs due to the need for better-quality awareness of the physiological availability of entire dosage forms coated and uncoated tablets plus capsules proposed for the administration of oral dosage form.

 

Method:

In this test, randomly selected 30 tablets from the batch, from that 10 tablets randomly selected and according to the official assay method, 10 of them assayed individually. Nine of the 10 tablets must have the strength within ±15% of the labeled drug content. Only one tablet may be within the limit of ±25%. If two tablets within the limit of ±25%, then the remaining 20 tablets drug content must be estimated individually and none may fall outside ±15% of the labeled content16,30,36.

 

Drug excipients compatibility:

In all pharmaceutical dosage forms, the excipients behave as a dynamic element. To formulate an effective and stable solid dosage form, it is highly necessary to select appropriate excipients that should have no interaction property between them. Which has helped with easy administration, facilitate prolong release as well as maintain the bioavailability in the body and to protect from decline? One of the most exact analytical techniques to detect functional groups of a drug is FTIR (FT/IR 4100, Jasco, MD, USA) spectroscopy thus the pure drug and their formulations subjected to FTIR studies taken in the range of 4000-500 cm-1. In the ongoing study, the conducted technique was a potassium bromide disc (pellet) technique21,22,25.

 

In-vitro dissolution of the press-coated tablet:

The pulsatile delivery press-coated tablets of the terbutaline sulfate drug release study performed in the USP Type-II (paddle) dissolution apparatus. The dissolution medium of pulsatile tablets contains 900 ml of pH 1.2 for the initial 2 hrs afterward pH 7.4 phosphate buffer at 37±0.5 °C at 50 rpm rotating speed of the paddle, the dissolution studies performed. During the study, 5 ml of the filtrate drug solution withdrawn from the dissolution basket at a specified time interval and replaced with the same volume of fresh buffer solution. The collected dissolution samples absorbance checked at 276 nm in the UV-Visible spectrophotometer. Each formulation lag time and percentage release determined, and the graph was plotted18,31,38.

 

Drug release kinetics:

To look into the drug release mechanism from the microspheres, the in-vitro release data were gone into various kinetic models like zero order, first order, Higuchi’s equations. Further, the drug release mechanism also analyzed by the Korsmeyer-Peppas equation39,40.

 

RESULTS:

Pre-compression parameters:

Formerly continuing to direct compression method drug (terbutaline sulfate) along with excipients estimated for bulk density, tap density, angle of repose, compressibility index and Hausner’s ratio. The prominent physical parameters are in Table IV and they are the bulk density 0.306±0.06 to 0.510±0.02, tap density 0.353±0.05 to 0.583±0.02, angle of repose: 22.68±0.31 to 26.89±0.92, Compressibility record: 12.46±0.9 to 14.54±1.1, Hausner’s proportion: 1.13±0.02 to 1.17±0.05 determining the tasteful outcome18,30.


 

Table 4: Precompression parameters for formulation batches

Formulations

Angle of repose (θ)*

Bulk density (g/cm3)*

Tapped density

(g/cm3)*

% Compressibility

index*

Hausner’s ratio*

 F1

 22.68 ± 0.31

 0.510 ± 0.02

 0.583 ± 0.02

 12.52 ± 0.8

 1.13 ± 0.02

 F2

 23.73 ± 0.76

 0.416 ± 0.04

 0.482 ± 0.04

 13.69 ± 0.92

 1.15 ± 0.03

 F3

 23.58 ± 0.61

 0.423 ± 0.05

 0.495 ± 0.03

 12.46 ± 0.9

 1.14 ± 0.04

 F4

 25.16 ± 0.56

 0.309 ± 0.04

 0.353 ± 0.05

 13.80 ± 1.6

 1.16 ± 0.06

 F5

 26.89 ± 0.92

 0.306 ± 0.06

 0.355 ± 0.04

 14.54 ± 1.1

 1.17 ± 0.05

 F6

 24.65 ± 0.48

 0.322 ± 0.09

 0.376 ± 0.03

 14.36 ± 1.2

 1.16 ± 0.03

*Values were expressed in mean ±SD (n = 3)

 


 

Figure 1: 3D Plot shows the compressibility index

 

Post-compression parameters:

In the tablet's production, the important parameters according to official specifications for thickness, hardness, friability, weight variation, drug content, and in-vitro disintegration time measured and reported in Table V and VI18,29,30.

 

Thickness:

The average thickness of the core and press-coated tablets (n=3) of batches F1to F6 varied from 1.38±0.13 mm to 1.55±0.15mm and 4.20±0.6mm to 4.51±0.2mm. The standard deviation values indicated that all the formulations were within the range.

 

Weight variation test:

All the tablets fell out of the weight variation test, i.e., the average percentage weight variation found within the pharmacopeia limits of ±5%.

 

Hardness:

All the formulations hardness or crushing strength of core tablet hardness varied from 3.6±0.3kg/cm2 to 4.1±0.2kg/cm2, and for press-coated tablets, the hardness varied from 6.5 kg/cm2 to 7.4 kg/cm2 possessed satisfactory mechanical strength with adequate hardness.

 

Friability:

Core and press-coated tablets friability values from F1 to F6 varied from 0.328±0.2, to 0.611±0.12, and from 0.398±0.19 to 0.711±0.21 respectively. The obtained outcomes found to be fit within the approved range (<1%) in all the manufactured formulations. The friability test of all the batches passed.

 

Disintegration test:

Core tablets in-vitro disintegration time from F1 to F6 achieved at pH 7.4 it was from 197±2.3 Sec to 655±1.9 Sec. The least disintegration time displayed in batch F5, and F6 tabulated in Table V.

 

Uniformity of content:

The core tablets exhibited drug content in the range from 97.11±0.76 to 100.1±0.85, and similarly press coat tablets drug content from range 98.11±0.66 to 102.1±0.55. As specified in pharmacopeia the results were within the limit (±15%).


Table 5: Physical evaluation parameters of core tablets

Formulations

Hardness (kg/cm2)*

Weight uniformity (mg)*

Friability (%)*

Thickness (mm)*

Uniformity of content (mg)*

Disintegration time (sec)*

 F1

 3.6 ± 0.3

 50.52 ± 0.1

 0.557 ± 0.2

 1.51 ± 0.15

 99.77 ± 0.73

 432 ± 1.7

 F2

 3.8 ± 0.4

 51.26 ± 0.3

 0.435 ± 0.16

 1.49 ± 0.083

 97.11 ± 0.76

 566 ± 2.2

 F3

 3.9 ± 0.5

 49.64 ± 0.4

 0.469 ± 0.23

 1.38 ± 0.13

 99.10 ± 0.89

 655 ± 1.9

 F4

 4.0 ± 0.6

 50.36 ± 0.3

 0.611 ± 0.12

 1.40 ± 0.14

 100.1 ± 0.85

 368 ± 2.5

 F5

 4.1 ± 0.2

 48.92 ± 0.6

 0.328 ± 0.2

 1.55 ± 0.15

 98.77 ± 0.81

 298 ± 2.7

 F6

 3.9 ± 0.3

 49.50 ± 0.2

 0.551 ± 0.17

 1.39 ± 0.13

 100.1 ± 0.78

 197 ± 2.3

*Values were expressed in mean ± SD (n = 3)

 

Table 6: Physical evaluation parameters of press coat tablets

Formulations

Hardness (kg/cm2)*

Weight uniformity (mg)*

Friability (%)*

Thickness (mm)*

Uniformity of content (mg)*

 F1

 7.2 ± 0.4

 142 ± 0.6

 0.552 ± 0.1

 4.51 ± 0.2

 99.77 ± 0.73

 F2

 6.9 ± 0.6

 146 ± 0.8

 0.645 ± 0.2

 4.49 ± 0.5

 98.11 ± 0.66

 F3

 7.4 ± 0.7

 144 ± 0.4

 0.549 ± 0.15

 4.38 ± 0.4

 99.10 ± 0.89

 F4

 6.5 ± 0.2

 143 ± 0.5

 0.711 ± 0.21

 4.20 ± 0.6

 102.1 ± 0.55

 F5

 6.8 ± 0.3

 147 ± 0.3

 0.398 ± 0.19

 4.42 ± 0.3

 98.77 ± 0.81

 F6

 7.2 ± 0.6

 145 ± 0.2

 0.551 ± 0.22

 4.33 ± 0.4

 100.1 ± 0.78

*Values were expressed in mean ±SD (n = 3)

 


 

Figure 2: FTIR graph of terbutaline sulfate pure drug (a) and optimized formulation (b)

 

 

Figure 3: In-vitro drug release of terbutaline sulfate from formulation

 

Figure 4: Release kinetics of best formulation F6

 

DISCUSSION:

Drug excipients compatibility:

The solid pure drug terbutaline sulfate and drug-excipients mixture compatibility study performed in FTIR and spectra represented in (Fig. 2). FTIR spectrum of pure terbutaline sulfate shows prominent peaks at 2845.34 cm-1, 1316.31 cm-1, 1158.94 cm-1, 1037.01 cm-1 corresponds to CH alkanes, CH3 alkanes, S=O sulfonates, C-N alkyl, stretching respectively. These peaks may be reflected as characteristic peaks of terbutaline sulfate were not unnatural and observed in the FTIR spectra of terbutaline sulfate along with excipients, which indicated that the interaction between drug and excipients was not observed21,36.

 

In-vitro release studies:

The pulsatile release drug delivery dissolution studies conducted at pH 1.2 standard buffer 900ml for the initial 2 hrs, afterward phosphate buffer pH 7.4 used dissolution medium for press-coated tablets6,41. From the dissolution data, it concluded that F3 and F6 both selected based on the drug release pattern because of, the drug release delayed for 5 h and then the drug released rapidly within 2 h in F3 and 3 h in F6 respectively and both formulations follow the zero-order kinetic drug release pattern. It observed that the burst release may be in F3 due to the use of a 1:3 ratio of HPMC K100M: ethyl cellulose mixture used as the external layer as well as ethyl cellulose is a hydrophobic polymer porous creation in the external layer and the effect of the super disintegrant. In F6, burst release arises because of 1:3 ratio of ethyl cellulose: karaya gum mixtures in which, as soon as karaya gum dissolves within 5 h, the drug releases very quickly detailed in (Fig. 3). In F3 ethyl cellulose mixed with HPMC K100M and in F6 ethyl cellulose mixed with karaya gum to modulate the lag time and hence control the disintegration. HPMC K100M and karaya gum forms a firm gel, but does not hydrate quickly while ethyl cellulose is a hydrophobic polymer and shows erosion type of mechanism. Therefore, the drug instantly released from the core tablet as soon as a breakdown of the surrounding external layer. In the pulsatile tablet, the burst release carried out as a result of pressure escalation within a system. This escalation of pressure might be imputed to the inflow of the dissolution medium by the erosion effect as a result of the existence of ethyl cellulose in the external layer. This theory advises that in the external layer ethyl cellulose might behave as a pore-forming agent instead of as a gelling agent, therefore enhancing the penetration of water before rupturing the surrounding external layer5,28,42.

 

In-vitro release kinetic studies:

In Table VII the release exponent values are shown, representing that the dominant mechanism of drug release through F3 and F6 types of tablets was due to swelling and erosion which continually associated with a diffusion mechanism. The first-order release kinetics followed by formulation F1, whereas residual F2 to F6 followed a zero-order release mechanism. From the slope, the release exponent ‘n’ value calculated, and it describes the mechanism of drug release. The ‘n’ value obtained for formulations F1, F2, F3, and F6 tablet was in between (> 0.45 and < 0.89) and recommended that the drug release monitored non-Fickian anomalous diffusion because of the hydrophilic polymers have a greater attraction to water. But the ‘n’ value of formulation F4 and F5 is greater than > 0.89 so, the release following the super case II transport mechanism43,44.


 

Table 7: In-vitro drug release kinetic studies of different formulations

Formulations

Zero-order

First-order

Higuchi

Hixon Crowell

Release exponent

(n)

 (R2)

F1

0.881

0.892

0.888

0.888

0.875

F2

0.968

0.907

0.939

0.936

0.680

F3

0.691

0.589

0.586

0.642

0.516

F4

0.963

0.918

0.895

0.936

0.961

F5

0.923

0.87

0.836

0.89

0.996

F6

0.819

0.687

0.724

0.768

0.782

(R2 = regression coefficient), (n = release exponent).

 


 

CONCLUSION:

The FTIR spectra of the pure drug (terbutaline sulfate) along with excipients evaluated and form the characteristic peak of the drug with a physical mixture of the drug and excipients no other suspicious effects found, and it indicated that the characteristic peak of the drug has looked in the spectra deprived of any alteration in the position, henceforth between drug and excipient, no interaction observed. The conducted all the properties of micromeritics results were found satisfactory. From the observed report concluded, the flow property found excellent, and it proved through bulk density, tapped density, the angle of repose, Hausner’s ratio, and Carr’s index. The chronomodulated tablets were inspected for quality control tests along with appearance, thickness, weight variation, hardness, friability, uniformity of content, and indicated that all are within the limits. Among all core tablets, formulation F3 and F6, press coat tablets nominated as optimized formulation. From the directly above results, it displayed that formulation F6 is the best. From the outcomes, it verified that the PDDS containing terbutaline sulfate is appropriate for formulating by direct compression technique in the treatment of nocturnal asthma.

 

ACKNOWLEDGEMENTS:

The authors are like acknowledging Matrix Laboratory Limited, Hyderabad, India for providing the gift sample drug terbutaline sulfate.

 

AUTHORS CONTRIBUTIONS:

All the authors have contributed equally.

 

CONFLICTS OF INTERESTS:

The authors declared a conflict of interest none.

 

STATEMENT OF HUMAN AND ANIMAL RIGHTS:

This clause does not contain any studies with human or animal subjects performed by any of the writers.

 

REFERENCES:

1.      Hemalatha V, Kumar PPS, Naidu MRL, Priyanka et al. Formulation and evaluation of pulsatile drug delivery system of Celecoxib. World Journal of Pharmaceutical Research. 2016; 5(2): 1110-1119.

2.      Hochhaus G, Mollmann H. Pharmacokinetic/pharmacodynamic characteristics of the beta-2-agonists Terbutaline, Salbutamol and Fenoterol. International journal of clinical pharmacology, therapy, and toxicology. 1992; 30(9): 342-362.

3.      Naik VV, Ankarao A, Anil Babu K, Neelima P.V.A, Anil Babu G et al. Formulation and evaluation of Valsartan pulsincap drug delivery system. International Journal of Pharmacy and Analytical Research. 2015; 4(1): 41-47.

4.      Jain D, Raturi R, Jain V, Bansal P, Singh R. Recent technologies in pulsatile drug delivery systems. Biomatter. 2011; 1(1): 57-65.

5.      Nabin K, Biswajit B, Patel J, Patel KM et al. Preparation and evaluation of pulsatile drug delivery system containing Terbutaline sulphate. International Research Journal of Pharmacy. 2011; 2(2): 113-119.

6.      Nandedkar S.Y, Wagh RD, Bauskar MD et al.  Formulation design and optimization of pulsatile release tablet of Acebrophylline with swelling and erodiable layers for treatment of nocturnal bronchial asthma. International Journal of Pharmaceutical Sciences and Research. 2011; 2(12): 3100-3108.

7.      Baghel P, Roy A, Chandrakar S, Bahadur S. Pulsatile drug delivery system: A promising delivery system. Research Journal of Pharmaceutical Dosage Forms and Technology. 2013; 5(3): 111-114.

8.      Mahajan AN, Shah DA, Patel KT et al. Studies in formulation development of chronotherapeutics dosage of model drug. Scholars Research Library. 2011; 3(4): 227-240.

9.      Fatima SN, Mohammed S et al. Formulation and in-vitro evaluation of meloxicam pulsin cap for pulsatile drug delivery. International Journal of Innovative Pharmaceutical Sciences and Research. 2017; 5(8): 126-138.

10.    Vijaya Vani Ch.S, Rao MV.U, Bhavani D et al. Formulation and evaluation of Montelukast sodium pulsatile drug delivery system by core in cup method. International Journal of Pharmacy Review and Research. 2015; 5(1): 15-23.

11.    Sudhamani T, Radhakrishnan M, Mallela D, and Ganesan V. Chronotherapeutic floating pulsatile drug delivery: An approach for time-specific and site-specific absorption of drugs. Research Journal of Pharmacy and Technology. 2011; 4(5): 685-690.

12.    Gajanan N.P, Borate S, Ranpise A, Mandage Y, Thanki K, Rao M et al. Design, evaluation and comparative study of pulsatile release from tablet and capsule dosage forms. Iranian Journal of Pharmaceutical Sciences. 2009; 5(3): 119-128.

13.    Gohel MC, Parikh RK, Patel LD, Patel VP Gami SV et al. Design and evaluation study of pulsatile release tablets of Metoprolol succinate. Pharma Science Monitor-An International Journal Pharmaceutical Sciences. 2012; 3(2): 171-181.

14.    Jadhav TS, Thombre NA, Kshirsagar SJ. Pulsatile drug delivery system using core-in-cup approach: a review, Pharmaceutical and Biological Evaluations. 2016; 3(3): 1-9.

15.    Seidler FJ, Rahman AA, Tate CA, Nyska A, Rincavage Hl, Slotkin TA, Rhodes MC et al. Terbutaline is a developmental neurotoxicant: effects on neuroproteins and morphology in cerebellum, hippocampus, and somatosensory cortex. The Journal of Pharmacology and Experimental Therapeutics. 2004; 308(2): 529-537.

16.    Thakare VM, Gandhi BR, Tekade BW, Sadaphal KP et al. Formulation and evaluation of pulsatile drug delivery system for chronobiological disorder: asthma. International Journal of Drug Delivery. 2011; 3: 348-356.

17.    Dharmamoorthy G, Nandhakumar. Chronotherapeutics: a range of newer drug delivery approaches for better patient compliance, International Journal of Applied Biology and Pharmaceutical Technology. 2011; 2(4): 110-120.

18.    Vishnu PP, Sharma JVC, Avinash A et al. Formulation and evaluation of Terbutaline sulphate by pulsatile drug delivery system. International Journal of Biopharmaceutics. 2016; 7(1): 7-12.

19.    Kumar A, Sonam R. Pulsatile drug delivery system: method and technology review, International Journal of Drug Development and Research. 2012; 4(4): 95-107.

20.    Hamed Md.M, Rafiq M, Ali N, Sayeed A et al. Pulsatile drug delivery systems: recent technology. International Journal of Pharmaceutical Sciences and Research. 2013; 4(3): 960-969.

21.    Mahajan AN, Pancholi SS. Formulation and evaluation of timed delayed capsule device for chronotherapeutic delivery of terbutaline sulphate. ARS Pharmaceutica. 2010; 50(4): 215-223.

22.    Rao NGR, Panchal H, Hadi MA. Formulation and evaluation of biphasic drug delivery system of Terbutaline sulphate for chronotherapy. International Journal of Pharma and Bio Sciences. 2012; 3(3): 626-637.

23.    Singh HN, Saxena S, Singh S, Yadav AK. Pulsatile drug delivery system: Drugs used in the pulsatile formulations. Research Journal of Pharmaceutical Dosage Forms and Technology. 2013; 5(3): 115-121.

24.    Emami J, Boushehri MAS, Varshosaz J, Eisaei A. Preparation and characterization of a sustained release buccoadhesive system for delivery of Terbutaline sulphate. Research in Pharmaceutical Sciences. 2013; 8(4): 219-231.

25.    Ramani Nd, Kumar Pb, Kola R et al. Formulation and in-vitro evaluation of Terbutaline sulphate sustained release tablets. Indian Journal of Research in Pharmacy and Biotechnology. 2013; 1(5): 621-624.

26.    Kumar TMP, Kumar HGS. Novel core in cup buccoadhesive systems and films of Terbutaline sulphate development and in-vitro evaluation. Asian Journal of Pharmaceutical Sciences. (2006) 1(3-4):175-187.

27.    Gobade NG, Koland M, Harish KH. Asymmetric membrane osmotic capsules for Terbutaline sulphate. Indian Journal of Pharmaceutical Sciences. 2012; 74(1): 69-72.

28.    Gupta VRM, Patil SS et al. Development and in-vitro evaluation of chronomodulated delivery systems of Terbutaline sulphate. International Journal of Research and Development in Pharmacy and Life Sciences. 2016; 5(4): 2280-2290.

29.    Hadi MA, Saleem MD, Rao AS, Rao VU. Surface response methodology for development and optimization of Aceclofenac pulsatile release drug delivery system. Asian Journal of Pharmacy and Technology. 2014; 4(2): 74-82.

30.    Patil V, Nagesh C, Praveen K, Rekha S, Chandrasekhara S et al. Pulsatile drug delivery system of Terbutaline sulphate; using ph sensitive polymer. American Journal of Advanced Drug Delivery. 2013; 1(4): 635-650.

31.    Patil SS, Patil SV, Lade PD, Janugade BU et al. Formulation and evaluation of press-coated Montelukast sodium tablets for pulsatile drug delivery system. International. Journal of chem tech research. 2009; 1(3): 690-691.

32.    Patel J, Patel D, Vachhani S, Prajapati ST, and Patel CN. Current status of technologies and devices for chronotherapeutic drug delivery systems. Research Journal of Pharmacy and Technology. 2010; 3(2): 344-352.

33.    Nawaj SS, Khan M, Khan Dr. GJ, Sohel A. Design, development and evaluation of press coated floating pulsatile tablet of antihypertensive agent. Research Journal of Pharmacy and Technology. 2018; 11(3): 921-929.

34.    Archana A, Manikanta AK, Shetty KSM. Formulation development and evaluation of Sumatriptan pulsatile drug delivery using pulsincap technology. Research Journal of Pharmacy and Technology. 2013; 6(12): 1375-1379.

35.    Kalyani V, Basanthi K, and Murthy TEGK. Formulation and evaluation of modified pulsincap drug delivery system for chronotherapeutic delivery of Montelukast sodium. Research Journal of Pharmaceutical Dosage Forms and Technology. 2014; 6(4): 225-229.

36.    Rao NGR, Hadi MA, Panchal H. Formulation and evaluation of biphasic drug delivery system of Montelukast sodium for chronotherapy. International Journal of Pharmaceutical and Chemical Sciences. 2012; 1(3): 1256-1265.

37.    Patel VD, Yegnoor AK. Development and evaluation of Celecoxib core in cup tablets for pulsatile drug delivery. Research Journal of Pharmacy and Technology. 2017; 10(3): 755-764.

38.    Chowdary KPR, Shobarani RH, Narasu L, Bhat A et al. Formulation and evaluation of chronopharmaceutical drug delivery of Theophylline for nocturnal asthma. International Journal of Pharmacy and Pharmaceutical Sciences. 2011; 3(2): 204-208.

39.    Costa P, Lobo J.M.S. Modeling and comparison of dissolution profiles. European Journal of Pharmaceutical Sciences. 2001; 13: 123-133.

40.    Dighe PA, Kharat AR, Patil SV, Ramteke KH et al. Mathematical models of drug dissolution: a review. Scholars Academic Journal of Pharmacy. 2014; 3(5): 388-396.

41.    Rama B, Sandhiya V, Rathnam G, Ubaidulla U, Roy PS, Swetha M et al. Chronopharmacotherapeutic release of HMG-COA reductase inhibitor: using novel coating technique. World Journal of Pharmaceutical Research. 2016; 5(5): 784-797.

42.    Harshitha R, Potturi PK, Ramesh R, Rajkumar N, Nagaraja G and Murthy PNVN et al. Development of time programmed pulsincap system for chronotherapeutic delivery of Diclofenac sodium. Research Journal of Pharmacy and Technology. 2010; 3(1): 234-238.

43.    Peppas NA, Ritger PL. A simple equation for description of solute release ii. Fickian and anomalous release from swellable devices. Journal of Controlled Release, 1987; 5: 37-42.

44.    Siepmann J, Siepmann F. Mathematical modeling of drug delivery. International Journal of Pharmaceutics. 2008; 364: 328-343.

 

 

 

 

 

Received on 31.03.2020            Modified on 10.06.2020

Accepted on 08.07.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(4):1867-1874.

DOI: 10.52711/0974-360X.2021.00330