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RESEARCH ARTICLE
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.
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Research J. Pharm. and Tech. 14(4): April 2021
numerous pathologies. The possibility of utilizing and absorbed only 33-50% of the total administered an
delayed-release to implement chronotherapy is quite oral dose and apart from which 60% is metabolized by
interesting for some diseases. The symptoms of which the liver under the first-pass metabolism24. Not only this,
returned mostly at night-time or in the early morning, for but the drug also undergoes metabolism by the gut
example, bronchial asthma, angina pectoris, and wall25. For these reasons, 15% of the oral bioavailability
rheumatoid arthritis7. The postponement in the onset of of the drug is found from the total administered dose26.
action has reached through hydrophilic or hydrophobic And also, the drug is having a small half-life 3-4 h needs
layers, osmotic mechanisms, covering a drug-loaded repeated administration27. Thus, evaluation and
core and swell-able or erodible masses coating a drug improvement of ChrDSS of terbutaline sulfate have been
comprising an insoluble capsule body8,9,10,11. The drug undertaken, but also the benefits of this system also
release pattern of the conventional drug delivery system consist of the improved utilization of drugs having small
fluctuates or in a sustaining release case, a constant half-life with expansive first-pass metabolism thereby
release rate observed, but it is not always ideal12,13. Due producing a better therapeutic result for nocturnal
to this reason, the latest release pattern of drug delivery asthma28.
developed, and that fulfilled by a pulsatile drug delivery
system (PDDS). From the maximum DSS, the controlled MATERIALS:
release DSS, and the conventional oral DSS, the drug The pure drug terbutaline sulfate bigheartedly provided
releases in a constant pattern or fluctuating pattern14. In a by Matrix Laboratory Limited, Hyderabad, India.
pulsatile release the drug release rate characterized by a Crospovidone and ethyl cellulose obtained as a gift
(lag time) time of very slow release rates, afterward, a sample from S.D. Fine Chemicals, Mumbai, India.
rapid and complete drug release wherein the method Mannitol and HPMC K100M purchased from Rankem
controls the lag time independent of body environmental Lab, Hyderabad, India. Karaya gum and magnesium
influences like GI motility, pH, enzymes15,16. The system stearate were generously supplied by Otto Chemicals,
designed and demand for a time-programmed therapeutic Pvt Ltd, Mumbai and NR chemicals, Chennai, India. The
arrangement, releasing the correct quantity of the drug at obtained analytical grade other reagents and chemicals
the correct time. The requirement of this pattern of were from S.D. Fine Chemicals, Mumbai25,28,29.
release achieved by a PDDS, which described by a lag
time that is an interval of a smaller amount of drug METHODS:
release afterward the drug releases speedily15,17. The Formulation of the core tablet:
PDDS is necessary for a verity of diseases similar to The terbutaline sulfate core tablets mass-produced
asthma, cancer, diabetes, duodenal ulcer, neurological through direct compression procedure. The powdered
disorders, hypercholesterolemia, arthritis, colonic ingredients like drug terbutaline sulfate and
transport, and diseases like cardiovascular18. One of the crospovidone were dry mixed for 20 min afterward,
diseases is asthma, where the PDDS can be suitable and magnesium stearate added, and the formula shown in
circadian fluctuations, observed in common lung Table I. The powder blends then additionally blended for
function, airway resistance rises in asthmatic patients 10 min and from the subsequent powder blend 50 mg
gradually at night18,19,20. A potent β-adrenoreceptor manually compressed by 16 station rotary tablet punch
agonist terbutaline sulfate is usually used in the instrument comprising 6 mm circular die and punch for
treatment of asthma21,22,23. The drug terbutaline sulfate the core tablet formulation16,18,30.
absorption from the gastrointestinal tract is inconstant
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
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Research J. Pharm. and Tech. 14(4): April 2021
Weight variation test: tablet (particles completely pass from the tube into the
This is a quality control and in-process quality control beaker through no 10 mesh) was noted18,30,36.
test to confirm that the manufacturers control each
compressed tablet comprises the proper amount of drug, Uniformity of content:
different pharmacopeias stated these weight variation The test uniformity of content is used to confirm that
tests. First, randomly selected 20 tablets average weight each tablet comprises the quantity of drug substance
calculated then the same 20 tablets individual weight design with little deviation among tablets within a batch.
calculated with the help of the analytical balance. The content uniformity test has added to the monographs
Afterward, the ±% limit of average weight compared to due to the need for better-quality awareness of the
an individual tablet. The ±% average weight limits of physiological availability of entire dosage forms coated
uncoated compressed tablets provided by the USP16,30,36. and uncoated tablets plus capsules proposed for the
administration of oral dosage form.
Hardness:
The hardness of a tablet influenced by its particle- Method:
particle bonding and tablet resistance power to capping, In this test, randomly selected 30 tablets from the batch,
breakage during transportation, and handling. Hardness, from that 10 tablets randomly selected and according to
which called crushing strength and it can be regulated by the official assay method, 10 of them assayed
pressure modification of tablet machine. A too-hard individually. Nine of the 10 tablets must have the
tablet may not disintegrate in the appropriate time, so strength within ±15% of the labeled drug content. Only
onset time will be more and too soft tablet not be able to one tablet may be within the limit of ±25%. If two
withstand the stress like transportation, handling, coating tablets within the limit of ±25%, then the remaining 20
and packaging, and easily break. It is the measurement tablets drug content must be estimated individually and
of strength needed to break the tablet when the force none may fall outside ±15% of the labeled content16,30,36.
applied by diametrical direction to the tablet. The in
terms of kg/cm2 average hardness was calculated30,36,37. Drug excipients compatibility:
In all pharmaceutical dosage forms, the excipients
Friability:
behave as a dynamic element. To formulate an effective
Friability test carried out by using 20 tablets. Randomly
and stable solid dosage form, it is highly necessary to
from each tablet formulation 20 tablets collected and
select appropriate excipients that should have no
weighed by using an analytical balance. The same tablets
interaction property between them. Which has helped
kept in a rotary drum and rotated at 25 rpm for 4 min
with easy administration, facilitate prolong release as
means a total of 100 revolutions. After 100 revolutions,
well as maintain the bioavailability in the body and to
the tablets removed from the rotary drum and weighed.
protect from decline? One of the most exact analytical
The percentage of weight loss calculated using the
techniques to detect functional groups of a drug is FTIR
following equation. During transportation, the tablet got
(FT/IR 4100, Jasco, MD, USA) spectroscopy thus the
stress like friction and shock and for this reason, the
pure drug and their formulations subjected to FTIR
tablets may chip, break. To appraise the capacity of the
studies taken in the range of 4000-500 cm-1. In the
tablet to withstand abrasion during packaging, handling,
ongoing study, the conducted technique was a potassium
and transportation, the friability test led. A weight loss,
bromide disc (pellet) technique21,22,25.
an extreme percentage of 20 tablets must not be over 1%
and measured by the apparatus Roche friabilator16,18,22,37.
In-vitro dissolution of the press-coated tablet:
Initial weight-Final weight The pulsatile delivery press-coated tablets of the
% Friability = (––––––––––––––––––––––––––) × 100 terbutaline sulfate drug release study performed in the
Initial weight USP Type-II (paddle) dissolution apparatus. The
(Eq. 6) dissolution medium of pulsatile tablets contains 900 ml
of pH 1.2 for the initial 2 hrs afterward pH 7.4 phosphate
Disintegration test: buffer at 37±0.5 °C at 50 rpm rotating speed of the
As described in Indian Pharmacopoeia the disintegration paddle, the dissolution studies performed. During the
apparatus was used to determine the disintegration time study, 5 ml of the filtrate drug solution withdrawn from
of the compact mass (tablet). In it, 2 basket assembly the dissolution basket at a specified time interval and
located, and each basket contains 6 glass tubes having 3 replaced with the same volume of fresh buffer solution.
inches long is present in a beaker having 1000 ml The collected dissolution samples absorbance checked at
capacity. The tubular upper part is open and the lower 276 nm in the UV-Visible spectrophotometer. Each
part fixed with 10 no mesh. Into each tube, one tablet formulation lag time and percentage release determined,
kept and pH 7.4 phosphate buffer solvent system used at and the graph was plotted18,31,38.
temp 37±0.5°C. The time required to disintegrate the
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Research J. Pharm. and Tech. 14(4): April 2021
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
Figure 1: 3D Plot shows the compressibility index 0.398±0.19 to 0.711±0.21 respectively. The obtained
outcomes found to be fit within the approved range
Post-compression parameters: (<1%) in all the manufactured formulations. The
In the tablet's production, the important parameters friability test of all the batches passed.
according to official specifications for thickness,
hardness, friability, weight variation, drug content, and Disintegration test:
in-vitro disintegration time measured and reported in Core tablets in-vitro disintegration time from F1 to F6
Table V and VI18,29,30. 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,
Thickness: and F6 tabulated in Table V.
The average thickness of the core and press-coated
tablets (n=3) of batches F1to F6 varied from 1.38±0.13 Uniformity of content:
mm to 1.55±0.15mm and 4.20±0.6mm to 4.51±0.2mm. The core tablets exhibited drug content in the range from
The standard deviation values indicated that all the 97.11±0.76 to 100.1±0.85, and similarly press coat
formulations were within the range. 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%).
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Research J. Pharm. and Tech. 14(4): April 2021
DISCUSSION:
Drug excipients compatibility:
The solid pure drug terbutaline sulfate and drug-
excipients mixture compatibility study performed in
Figure 2: FTIR graph of terbutaline sulfate pure drug (a) and FTIR and spectra represented in (Fig. 2). FTIR spectrum
optimized formulation (b) 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.
selected based on the drug release pattern because of, the effect as a result of the existence of ethyl cellulose in the
drug release delayed for 5 h and then the drug released external layer. This theory advises that in the external
rapidly within 2 h in F3 and 3 h in F6 respectively and layer ethyl cellulose might behave as a pore-forming
both formulations follow the zero-order kinetic drug agent instead of as a gelling agent, therefore enhancing
release pattern. It observed that the burst release may be the penetration of water before rupturing the surrounding
in F3 due to the use of a 1:3 ratio of HPMC K100M: external layer5,28,42.
ethyl cellulose mixture used as the external layer as well
as ethyl cellulose is a hydrophobic polymer porous In-vitro release kinetic studies:
creation in the external layer and the effect of the super In Table VII the release exponent values are shown,
disintegrant. In F6, burst release arises because of 1:3 representing that the dominant mechanism of drug
ratio of ethyl cellulose: karaya gum mixtures in which, release through F3 and F6 types of tablets was due to
as soon as karaya gum dissolves within 5 h, the drug swelling and erosion which continually associated with a
releases very quickly detailed in (Fig. 3). In F3 ethyl diffusion mechanism. The first-order release kinetics
cellulose mixed with HPMC K100M and in F6 ethyl followed by formulation F1, whereas residual F2 to F6
cellulose mixed with karaya gum to modulate the lag followed a zero-order release mechanism. From the
time and hence control the disintegration. HPMC slope, the release exponent ‘n’ value calculated, and it
K100M and karaya gum forms a firm gel, but does not describes the mechanism of drug release. The ‘n’ value
hydrate quickly while ethyl cellulose is a hydrophobic obtained for formulations F1, F2, F3, and F6 tablet was
polymer and shows erosion type of mechanism. in between (> 0.45 and < 0.89) and recommended that
Therefore, the drug instantly released from the core the drug release monitored non-Fickian anomalous
tablet as soon as a breakdown of the surrounding diffusion because of the hydrophilic polymers have a
external layer. In the pulsatile tablet, the burst release greater attraction to water. But the ‘n’ value of
carried out as a result of pressure escalation within a formulation F4 and F5 is greater than > 0.89 so, the
system. This escalation of pressure might be imputed to release following the super case II transport
the inflow of the dissolution medium by the erosion mechanism43,44.