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New modified release tablets of bisoprolol fumarate for the treatment of hypertension: characterization and in vitro evaluation
Accepted Manuscript Study of the design and characterization of new bisoprolol fumarate tablet formulations Alina Diana Panainte, Eliza Gratiela Popa, Carmen Gafitanu, Iulian Stoleriu, Liliana Mititelu Tar�ău, Maria-Cristina Popescu, Gabriela Lisa PII:
S1773-2247(18)31114-6
DOI:
https://doi.org/10.1016/j.jddst.2018.11.011
Reference:
JDDST 833
To appear in:
Journal of Drug Delivery Science and Technology
Received Date: 28 September 2018 Revised Date:
5 November 2018
Accepted Date: 11 November 2018
Please cite this article as: A.D. Panainte, E.G. Popa, C. Gafitanu, I. Stoleriu, L.M. Tar�ău, M.C. Popescu, G. Lisa, Study of the design and characterization of new bisoprolol fumarate tablet formulations, Journal of Drug Delivery Science and Technology (2019), doi: https://doi.org/10.1016/ j.jddst.2018.11.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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STUDY OF THE DESIGN AND CHARACTERIZATION OF NEW BISOPROLOL
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FUMARATE TABLET FORMULATIONS
Alina Diana Panaintea, Eliza Gratiela Popab*, Carmen Gafitanub, Iulian Stoleriuc, Liliana Mititelu
a
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Tarțăud, Maria-Cristina Popescue, Gabriela Lisaf, X
University of Medicine and Pharmacy ‘Grigore T. Popa’ Iasi, Faculty of Pharmacy, Department
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of Analytical Chemistry, 16, Universitatii St. no. 16, code 700115, Iasi, Romania b
University of Medicine and Pharmacy ‘Grigore T. Popa’ Iasi, Faculty of Pharmacy, Department
of Pharmaceutical Technology, Universitatii St. no. 16, code 700115, Iasi, Romania c
University ‘Al. I. Cuza’, Faculty of Mathematics, Carol I Bld, code 700506, Iasi, Romania
d
University of Medicine and Pharmacy ‘Grigore T. Popa’ Iasi, Faculty of Medicine, Department
e’
f
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of Pharmacology-Algesiology, Universitatii St. no. 16, code 700115, Iasi, Romania Petru Poni’ Institute of Macromolecular Chemistry of the Romanian Academy, Iasi, Romania
Department of Chemical Engineering, Faculty of Chemical Engineering and Environmental
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Protection, ‘Gheorghe Asachi’ Technical University of Iasi, Romania
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Abstract: Objectives: the purpose of the study was to develop sustained release tablets containing
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bisoprolol fumarate and an innovative combination of Precirol ATO5 and hydroxypropyl methylcellulose, in order to conclude upon: properties of pharmaceutical tablet formulations, drug-excipients interactions, evaluate their in vitro release behavior.
Methods: The tablet formulations with rate controlling polymers were prepared by melt
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granulation technique. The physical-chemical characterization of new tablet formulation was
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performed by FT-IR spectroscopy, differential scanning calorimetry, thermogravimetric analysis and X-ray diffraction. The formulations were also evaluated for in vitro dissolution test to select the optimized formulation.
Results: Structural evaluation indicated the presence of interactions between tablet components which did not affect drug release. The tablets displayed good mechanical properties,
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with friability values close to zero and drug content was found to be uniform in all formulas. Release profile showed a tendency to follow Korsmeyer-Peppas and Higuchi kinetics. Conclusions: In the present study we investigated the effect of concentration of matrix
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former compounds (hydroxypropyl methylcellulose and glyceril palmitostearate) on the release
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rate of bisoprolol fumarate. The study evidenced the assembling through physical bonds between the excipients and the drug, which do not affect the release of the bioactive compound. Keywords: bisoprolol fumarate, hydroxypropyl methylcellulose, glyceril palmitostearate,
oral drug delivery, formulation development, structural properties.
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1. Introduction Nowadays hypertension is one of the most significant risk factors for cardiovascular disease,
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affecting especially the adult population. One of the main classes of antihypertensive drugs for the oral route are the beta blockers [1]. In this specific therapeutic class, bisoprolol fumarate (BSP), chemically known as 1-[4-[[2-(1-Methylethoxy) ethoxy]-methyl]-3-[(1-methylethyl) amino]-2-propanol [2] salt, is a cardioselective β1-adrenergic blocking agent used for secondary
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prevention of myocardial infarction, heart failure, angina pectoris and mild to moderate
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hypertension [3-5]. The daily dose of bisoprolol is 5 to 10 mg, which can be increased, if necessary, to up to 20 mg/day. After oral administration bisoprolol is rapidly absorbed in gastrointestinal tract, the absolute bioavailability after a 10 mg oral dose of BSP being about 80% [6, 7]. The maintenance of a constant plasma level of a cardiovascular drug is important for the desired therapeutic response. Because the half-life of the bisoprolol is about 3-4 h, multiple
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doses need to be administered in order to maintain a constant plasma concentration. The immediate release tablets with bisoprolol (2.5, 5 or 10 mg/tablet) have been found to have many associated drawbacks such as diarrhea, weakness, fatigue, anxiety, headache, dry mouth, nausea,
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vomiting, stomach pain, etc. Therefore, to reduce frequency of administration and improve
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patient compliance, maintain a uniform drug therapeutic level and reduce side-effects, a sustained release dosage formulation of bisoprolol is desirable. Drug release from the dosage form is controlled by the type and proportion of modified-release polymer used in the preparations. The preparation of matrix tablets with rate controlling polymers is the simplest and most widely used method for achieving desired extended release rate for drugs. Several studies have investigated different matrix tablets (hydroxypropyl methylcellulose (HPMC) in association with sodium bicarbonate, Carbopol 974, glycerin, propylene glycol,
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polyethylene glycol and ethyl cellulose, with the purpose of controlling the release of bisoprolol [8-13]. Precirol ATO5 (PREC), a mixture of mono-, di-, and triglyceryl esters of palmitic and stearic
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acids, with a HLB value of 2, is a multipurpose pharmaceutical ingredient recommended to be used in topical and oral pharmaceutical formulations as a taste masking agent, lubricant and modified-release excipient [14]. Several research studies have been conducted to investigate the
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proportions of Precirol ATO5 for lipophilic matrix tablets and capsule formulations [15, 16]. For modified release purposes the recommended proportions vary between 10 and 50%, more likely
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10-25%. Innovative formulations have been investigated also for orally disintegrating tablets containing PREC as binder for taste masking purpose in proportions of 4.5-5%, which do not prolong the disintegration times [17, 18]. Given its highly fatty nature, PREC can be combined in modified release tablets with hydrophilic polymers such as hydroxypropyl methylcellulose
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(HPMC).
HPMC is a semisynthetic, inert, viscoelastic polymer widely used in solid oral dosage forms as a binder, a film coating, and a controlled-release matrix [19]. HPMC of various viscosity
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grades has been used as a polymer for hydrophilic matrix tablets, due to its swelling capacity in water. For achieving an optimal kinetics of tablets it is necessary a fast hydration of the outer
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layer of the HPMC matrix to form a gel barrier, which provides subsequent slow release of the drug [20]. In this context the drug release takes place mainly by diffusion through, and/or subsequent erosion of the gel layer; while the drug from the outer surface of the matrix is released firsty by a burst effect. Nevertheless, it has been demonstrated that modified drug release from HPMC matrix tablets depends also on the drug solubility [20, 21]. The water-
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soluble drugs are released mainly through diffusion mechanism, whereas insoluble and lowsoluble drugs are released through erosion [23]. Bisoprolol fumarate is a BCS class 1 drug, with high solubility and low permeability. For
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highly water soluble drugs [24], literature data suggest an inflexibility of release kinetics, which may lead to sub-optimal in vivo release profiles [23]. This characteristic has recommended modulation of release kinetics of HPMC matrix tablets by combining it with other excipients
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(PVP, carbopol, glyceryl esters, fatty acids) or by designing multi-layered tablets. The processing of the tablets in solid-state can lead to reactions between the drugs and formulations, possibly
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initiating alterations in their stability, solubility, dissolution rates and bioavailability. Therefore, structural evaluation of the matrix and compatibility studies are needed to ensure that potential physical and chemical interactions between a drug and excipient do not compromise the stability of the drug [25, 26].
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The purpose of the present study was to obtain modified release matrix tablets with bisoprolol fumarate using an innovative combination of Precirol ATO5 (PREC) and hydroxypropyl methylcellulose, in order to investigate the optimal ratio between these
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ingredients as matrix formers and to analyze the pharmaceutical properties and the kinetics release profile of bisoprolol modified release tablets, with a view to maximize duration and
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bioavailability of this drug and to improve efficacy and better patient compliance.
2. Materials and methods 2.1. Materials
The substances used for the pharmaceutical formulations were: Bisoprolol fumarate 20 mg/tablet weight (BSP, provided by Unichem Laboratories LTD, India), Precirol ATO5
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(glyceryl distearate - PREC, kindly offered by Gatefossé) and hydroxypropyl methylcellulose (HPMC K4M, 4000 cps, Premium, Colorcon). 2.2. Preparation of the pharmaceutical formulations
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The preparation of tablets was done by melt granulation process [27], using the property of PREC excipient to melt at low temperatures and consequently to bind the mixture particles. The powder (containing BSP, PREC and HPMC) was mixed and heated to 65°C in an oven. The
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resulted agglomerated mass was passed through a 600 µm aperture pharmaceutical sieve (Fisherbrand, 8̎’-FH-SS-SS-US-30). The obtained granules were further compressed on a Korsch
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EK0 tablet press (9 mm flat punches, 5 kN tabletting pressure). Since PREC is recommended as a good tablet lubricant, the addition of an extra lubricant in the granulation mixture was not considered [14]. Eight formulations of tablets containing BSP were prepared with various
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excipients ratios according to Table 1.
Table 1. The formulations of tablets containing BSP and their tested pharmaco-technical properties.
HPMC (%)
F2
F3
F4
F5
F6
F7
F8
Composition
10
15
20
25
30
35
40
45
76,66
71,66
66,66
61,66
56,66
51,66
46,66
41,66
150
150
150
150
150
150
150
150
0.22
0.00
0.00
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PREC (%)
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Formula
Total tablet
weight (mg) Pharmaco-technical properties Friability (%)
0.00
0.22
0.23
0.21
0.00
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n=20
Hardness (N) 34.3
36.66
40.2
43.9
45.8
46.7
49.7
52.3
2.16
2.12
2.06
2.06
2.00
2.08
2.07
2.10
9.02
9.01
9.01
8.99
8.99
8.99
9.01
8.99
n=10
n=10
Diameter (mm)
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n=10
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Thickness (mm)
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In order to be pharmacodinamically effective, the dose strength of 20 mg bisoprolol was selected for modified release as a sum of 2-8 therapeutic doses.
2.3. Methods of pharmaceutical formulation characterization 2.3.1. Pharmaco-technical properties
The pharmaco-technical properties of the tablets were tested: hardness, thickness and
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diameter, by using a Pharma Test Dr. Schleuniger hardness tester (N), and the friability with an Electrolab EFII friabilator (100 rpm, 4 minutes, according to the method recommended by the European Pharmacopoeia [28, 29].
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2.3.2. Fourier Transform Infrared Spectra (FTIR) The measurement of IR absorption spectra was made with an ALPHA spectrophotometer
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(Bruker, Germany) for the pure drug and the excipients separately, and then combined. Processing of the spectra was performed using the Grams 9.1 program (Thermo Fisher Scientific).
2.3.3. Wide Angle X Ray Diffraction – WAXD WAXD analysis was performed on a Diffractometer D8 ADVANCE (Bruker AXS, Germany), using the CuKα radiation (λ=0.1541 nm). The working conditions were 40 kV and 30
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mA, 2s/step, and 0.02 degree/step. All diffractograms were recorded in the range 10-90 2θ degrees, at room temperature. 2.3.4. Thermal analyses
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2.3.4.1. Thermogravimetric analyses
Thermogravimetric analysis (TGA) was carried out under constant nitrogen flow (200 ml/min) at a heating rate of 10 oC/min using a Mettler Toledo TGA/SDTA 851 balance. The
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heating scans were performed on 3-5 mg of sample in the temperature range 25–600oC. 2.3.4.2. Differential scanning calorimetry
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The DSC curves were recorded using a Mettler Toledo DSC1 device with a 10°C /min heating rate, in a nitrogen flow of 150 ml/min. The sampless weighing between 2.2 and 4.8 mg were taken in pin-holed aluminum pans and underwent two heating cycles and a cooling cycle within the 25-150, 200 or 240oC temperature range. The temperature accuracy was ±0.02 °C, and
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the heat flow resolution was 0.04 µW. The device was calibrated using indium and the In Check method stored in the STARe software, according to the instruction manual. 2.3.5. In vitro drug release tests
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BSP release from the tablets was investigated through dissolution test on a SR8 Plus Dissolution test station equipped with a Disoette II carousel for automatic sampling and a V530
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spectrophotometer (Hanson Research, U.S.A.). The test was performed over a period of 9 hours, according to the following protocol: Apparatus 2 (paddle); rotation: 50 rpm. The volume of the dissolution media for each vessel was 900 ml, as follows: for the first 2 hours 0.1 M HCl solution was used and for the remaining 7 hours the medium was replaced with pH 6.8 phosphate buffer solution, in order to mimic the physiological conditions. Samples were collected automatically every hour and the BSP concentration was determined by spectrophotometric method (wavelength = 222 nm). The same volume of fresh dissolution medium at the same temperature
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was added to replace the amount withdrawn after each sampling. The drug amount of cumulative release from tablets was calculated with a standard curve prepared using bracketed concentration of BSP each dissolution medium in a range 10 to 110% of a theoretical concentration of 5
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µg/mL.
Different kinetic models were applied [30, 31] to the release data of test formulations in order to investigate the release mechanism of drug from the sustained release matrix tablets,
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using a Matlab 7.9 software.
The zero-order release model: = ∗ , (where is the released percentage at
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time t).The predicted release (forecast) at = is % = ∗ % . The predicted time until complete release is determined by the following formula: = /. The first-order release model: = ∗ – ∗ (where is the released percentage at time t).The predicted release (forecast) at = is:
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% = ∗ – ∗ %
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The predicted time until complete release is determined by the following formula:
≌ 4.6052/
The Korsmeyer-Peppas release model is defined by the equation:
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= ∗ , where is the released percentage at time t. The predicted release
(forecast) at = is:
% = ⤫ %
The predicted time until complete release is determined by the folowing formula: = / / The Higuchi release model is defined by the equation:
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= ∗ √ , where is the released percentage at time t. The predicted release (forecast) at = is:
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% = ⤫ √ % The predicted time until complete release is determined by the folowing formula: = / 3. Results and discussions
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3.1. Pharmaco-technical properties
Uniform, intact, smooth-surfaced tablets could be obtained: their characteristics are
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displayed in Table 1. The hardness of tablets did not record high values, nevertheless increasing tablet hardness could be correlated with the higher proportion of PREC in the formulation, with a maximum value for F8 (52.3 N). A very low friability was an important characteristics displayed by all tablets, 4 formulas recording a zero value; this is attributed to the plasticity of the melt
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granulation binder PREC. The values of tablet thickness and diameter indicated a good die fill during the compression process of granules. 3.2. Compatibility study
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3.2.1. FT-IR analysis
FTIR spectroscopy is a sensitive technique for evaluating the intramolecular interaction
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and conformational arrangement which influence the spatial distribution in the structure of materials. Figure 1 shows the IR spectra in transmittance mode of the pure components and two formulations (F6 and F8) in the 3700-2400 cm-1 and 1800-800 cm-1 spectral region. In order to evaluate
the
intermolecular
interactions
between
the
formulation
components
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calculated/theoretic spectra were performed by using the additivity low [32]. The first spectral region contains the specific bands corresponding to stretching vibration of free and bonded OH and/or NH groups and to aliphatic and aromatic CH groups. As can be seen from Figure 1a, there
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are no differences between the experimental and calculated spectra of F6 and F8 formulations in the spectral region between 3000-2700 cm-1 (assigned to the stretching vibration of aliphatic and
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aromatic CH groups).
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Figure 1. FT-IR spectra of the studies samples in the 3700-2400 cm-1 (a) and 1800-800 cm-1 (b) spectral regions
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In the region assigned to the stretching vibration of free and OH and/or NH groups a small variation in intensity of the bands is observed. It is well-known that hydrogen bonds play an important role for the interaction of OH and NH groups with carbonyl or ether functionalities. In order to evaluate the content of OH and NH groups the deconvolution of this region in component bands was made (Fig. 2). For both calculated and experimental spectra the best fit was obtained with 5 bands, located at about 3580, 3505, 3435, 3324 and 3247 cm-1. The first 3 bands describe the free and hydrogen-bonded OH groups, while the last 2 describe the free and
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H-bonded NH groups. Depending on the strength of the interaction, the absorption bands of the
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involved functionalities undergo more or less extensive band shifts and intensity changes.
Figure 2. The deconvolution of experimental IR spectrum of the F6 formulation in the 37003000 cm-1 spectral region
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Further, after the deconvolution, was possible to evaluate the energy of the hydrogen bonds using the following formulae [29]
1 (ν 0 − ν ) k ν0
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EH =
where ν0 is the standard frequency of the OH (3650 cm-1) and NH (3474 cm-1) monomers
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observed in the gas phase, while ν is the stretching frequency of OH and NH groups observed in the infrared spectrum of the sample, and 1/k is a constant equal to 2.625*102 kJ. The energy values are about 5, 10.5, 15.4, 11.3 and 17.1 kJ for the experimental spectra
for both samples and with a slight shifted to higher values, in case of calculated spectra. Comparing the values corresponding to the integral area of the deconvoluted bands of the calculated and experimental spectra, it can be observed that the integral area of the bands corresponding to free OH and NH groups decrease from about 14.2, 12.2 % and 1.3% in the case
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of calculated F6 and F8 spectra to about 10.9 and 9.2 % and 0.2 and 0.4 % in the experimental spectra, respectively. The integral areas of H-bonded OH groups increase in experimental spectra from 66.3% to 73.4 % in case of the sample F6, and from 70.6 to 73.1 % in the case of the
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sample F8. The observation is similar for H-bonded NH groups, thus the integral areas of the experimental spectra increase from 13.3 to 15.9 % for sample F6 and from 13.3 to 14.1 % for the
new H-bonds between the system components.
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other sample. This confirm the involvement of the free OH and NH groups in the formation of
In the fingerprint spectral region, between 1800-800 cm-1, all components present a large
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number of bands. Thus, the IR spectrum of PREC indicate the main spectral bands: at 1735 cm-1 assigned to stretching vibration of C=O groups, at 1472 cm-1 assigned to scissoring vibration of CH2 groups, 1393 cm-1 assigned to rocking vibration CH2 groups, 1425 and 943 cm-1 assigned to bending vibration of OH groups, 1291, 1103 and 1062 cm-1 assigned to stretching vibration of C-
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O groups and at 719 cm-1 assigned to rocking vibration of methyl long-chain. The IR spectrum of HPMC present specific bands at 1647 cm-1 assigned to stretching vibration of cyclic C-O groups, 1459 cm-1 assigned to asymmetric stretching vibration of CH3 groups,
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1377 cm-1 assigned to asymmetric bending of cyclic C-O-C groups, 1118 and 1063 cm-1 assigned to stretching vibration of C-O-C groups and 848 cm-1 assigned to rocking vibration of CH2
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groups. In case of BSP characteristic bands appear at 1613, 1515 and 1466 cm-1 assigned to stretching vibration of aromatic C-C groups, 1092 and 1048 cm-1 assigned to bending vibration of C-H groups, 1364, 1314 cm-1 assigned to symmetric bending of CH3 and CH2 groups, 1236 cm-1 assigned to stretching vibration of C-O groups and 1178 cm-1 assigned to stretching vibration of -N-CH2 group. In the spectra of formulations all component bands were identified, but the position of some of them is shifted to different wavenumber. Thus, the band of BSP from
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1466 cm-1 is shifted to 1472 cm-1, from 1613 cm-1 to 1618 cm-1 and from 1236 cm-1 to 1239 cm-1. Comparing the experimental and calculated IR spectra of the studied formulations, significant differences appear for the bands situated at 1381 cm-1 in experimental spectrum which appears at
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about 1372 cm-1 in the case of calculated spectra, 1240 cm-1 is shifted at 1235 cm-1 and the band at 1102 cm-1 is shifted at 1094 cm-1. These bands are assigned to bending vibration of CH3 groups and to stretching vibration of C-O groups. These shifts indicate changes in
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conformational arrangement of the molecular chains and/or specific interactions between them. Principal component analysis (PCA). It is known that principal component analysis (PCA) is
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used to visualize interrelationships among the independent variables and is useful in identifying data outliers, therefore is useful to investigate the difference between spectra and derive
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parameters characterizing the interaction between the different components [33].
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Figure 3. Three dimensional PCA score plots of the studied samples
The principal component factor 1 (PC1) describes 83.2%, principal component factor 2
(PC2) describe 11.7% and principal component factor 3 (PC3) describe 4.8 % of data the variance, so 99.7% of the existed variances in all the studied spectra can be captured using these
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three dimensions instead of the initial data. The three-dimensional coordinate system of these PC scores is plotted in Fig. 3. According to this figure, the PC scores for the calculated and experimental spectra
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established some distinct patterns which clearly expressed their differences. It can be observed that the calculated spectra appear in the same plane (PC1-PC2 plane) like the components, the position depending on the components composition. This plane can be defined as the non-
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interaction reference plane. In this case the variation on PC3 direction is about zero. The concentration dependence related to these two factors is expressed by an arrangement of the
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spectra in a triangle shape like, having in the corners the pure components. In case of experimental samples a significant variation on PC3 score direction can be evidenced. Thus, the plane PC2-PC3 can be defined as the interaction plane. The distance between the experimental spectra of the formulations and the calculated spectra are evidenced for sample F6, therefore
3.2.2. X-ray diffraction
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indicating the presence of stronger interactions in this system.
X-ray diffraction is a structural characterization technique which gives information about
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formation of intermediate compounds and the mean grain sizes of the two phases. Figure 4 shows the X-ray diffractograms of pure components and F6 and F8 formulations. In the PREC
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diffractogram five signals were observed at 19.1, 19.5, 22.9, 23.6 and 24.0o with a corresponding d spacing of 4.654, 4.564, 3.871, 3.766 and 3.703 Å. On the other hand, the pure HPMC shows two broad bands at 2θ=9.26 and 19.48° (d spacing=9.545 and 4.554 Å) corresponding to its polymeric semicrystalline nature. BSP is a low molecular crystalline substance. The corresponding diffractogram contain a large number of distinct and sharp bands (see Figure 4 and Table 2).
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Figure 4. X-ray diffractograms of the studied samples
Table 2. The values of 2q o and interplanar distance d for BSP, F6 and F8 BSP
F6
No. d, Å
2q o
d, Å
2q o
d, Å
1
6.8
13.05
6.9
12.80
2
8.1
10.88
8.2
10.77
8.1
10.91
3
9.2
9.58
9.2
9.54
9.2
9.54
4
10.7
8.23
-
-
10.7
8.21
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2q o
F7
11.2
7.88
11.0
8.01
11.2
7.91
6
12.0
7.35
12.0
7.33
11.9
7.42
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5
7
13.0
6.79
13.0
6.77
13.0
6.79
8
13.6
6.49
13.6
6.48
13.4
6.59
9
14.0
6.30
14.1
6.26
14.1
6.29
10
14.9
5.93
15.0
5.89
14.9
5.93
11
15.3
5.77
15.4
5.73
15.9
5.55
12
16.2
5.47
16.1
5.49
16.4
5.40
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18.4
4.81
18.5
4.78
18.4
4.82
14
19.2
4.61
19.2
4.61
19.2
4.62
19.5
4.54
19.5
4.54
15 19.9
4.44
17
20.5
4.32
20.6
4.31
20.5
18
21.0
4.22
21.1
4.21
21.0
19
22.3
3.98
20
22.8
3.89 23.0
3.85
22 23.9
3.71
24
24.6
3.61
25
25.6
3.48
26
26.4
3.38
27
27.2
3.28
4.22
3.85
23.5
3.78
23.5
3.78
23.9
3.71
23.9
3.72
25.7
3.46
25.7
3.46
26.4
3.37
26.4
3.37
27.3
3.26
27.4
3.25
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23
23.0
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21
4.32
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16
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13
27.8
3.20
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In the case of the formulations, a part of the bands arising from BSP which are very small due especially to the low content of this component in the mixture and/or to the loss of
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crystalline structure on the preparation process, appear the intense and clear bands from PREC. Lately, the bands corresponding to HPMC appear like an amorphous background. As can be seen from table 1, the values for 2q in the formulations are slightly shifted for both PREC and BSP, indicating deformation of the crystalline network of these compounds due to the physical interaction between the system components.
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3.2.3. TG/DTG analysis In order to evaluate the thermal stability of the drug in the obtained formulation and to establish the interaction between used excipients and BSP, the TGA curves were recorded
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(Figure 5a). The first-order derivatives of TGA curves (DTG) (Figure 5b) reveal the temperatures corresponding to the maximum decomposition rate. The curves show that the studied samples exhibit one or two distinct and well-separated weight-loss processes (see the
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DTG curves – Fig 5b).
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Figure 5. TG (a) and DTG (b) curves of the studied samples
Tabel 3. TG/DTG results for the studied samples F6
T Ti1, ºC
PREC
-
HPMC
35
F8
BSP
32
exp
calc
exp
calc
34
34
33
33
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-
57
59
62
57
67
57
Tf1, ºC
-
103
105
101
101
111
111
Dw1, wt%
-
6.1
0.5
2.0
3.0
1.1
2.3
Ti2, ºC
201
241
113
136
136
141
141
Tm2, ºC
391
358
327
364
360
Tf2, ºC
469
431
485
467
467
Dw2, wt%
93.3
76.5
78.0
85.6
83.2
Dwresidue, wt%
3.4
13.15
15.0
8.3
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Tm1, ºC
363
478
478
86.1
85.2
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364
7.9
9.1
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10.0
Excepting PREC, in all studied samples, the first process occurs in the temperature interval between 32-35ºC and 101-111ºC, with a maximum between 57 and 67ºC and a corresponding mass loss of 1-6 wt% (Table 3). This process is related to the removal of the physical adsorbed water.
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The second thermogravimetric process for the pure components takes place between 201469ºC and 241-431ºC, with a maximum situated at about 358 in case of PREC and at 391ºC for HPMC. The mass loss in this stage is about 93.3 % for PREC and 76.5 % in case of HPMC. In
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this stage the fission of molecules to a variety of low molecular weight products, including
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carbon dioxide, carbon monoxide, water, hydrocarbons (acetaldehyde, glyoxal and acrolein) and hydrogen takes place. For the BSP, the second decomposition process takes place in the temperature interval between 113-485ºC and present three overlapped stages with a maximum at 327ºC and two shoulders at about 221ºC and 274ºC. In the case of the mixture of the excipients with the drug, the process is starting at 136ºC and finishes at 467ºC, in case of F6 sample and is shifted to higher temperature (141ºC and 478ºC) in the case of the sample with higher PREC
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content (F8). The temperature corresponding to the maximum rate of the decomposition process is the same for both studied samples, at 364ºC. Comparing the DTG curves for experimental and calculated data for F6 and F8 samples,
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it can be observed that the temperature corresponding to the maximum decomposition rate is shifted to higher values in the case of the experimental data, indicating a small increase in the thermal stability of the compounds. As mentioned before, this behavior can be determined by the
3.2.4. Differential scanning calorimetry (DSC)
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physical interactions taking pace between the system components in the mixing process.
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For thermal behavior evaluation the studied samples were heated to 200°C, cooled to 30°C and subsequently re-heated to 200°C. The DSC scans of pure drug and individual
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excipients and the drug excipient mixture are shown in Fig 6.
Figure 6. DSC curves for the studied samples
A sharp and asymmetric endothermic process is observed in the first heating scans of
PREC at 68.7ºC with the enthalpy of transition (DHf) of 189.64 J*g-1 and at 57.9ºC with a shoulder at 52.6ºC and with the heat of transition (DHf) of 116.46 J*g-1 in the second heating process. At cooling an exothermic process is observed at 52.9ºC with the enthalpy of transition of 116.71 J*g-1. This can be due to the melting process of PREC. The DSC curves of HPMC
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showed 2 endothermic processes in the first heating scan. The first one, is a broad process with a maximum at 67.1ºC and a enthalpy value of 168.74 J g-1, due to the evaporation of absorbed moisture and the second one, a small process with a maximum at 179.3ºC with a enthalpy value
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of about 0.81 J g-1. These processes are not observed in the cooling and second heating scans. BSP present two endothermic processes with maxima at 80.9 and 102.3ºC, respectively. These processes are not observed in the cooling scan. Further, in the second heating scan an exothermic
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process is evidenced at 35ºC and an endothermic process at about 100ºC. In the case of the drug formulation, the values of the temperatures and shape of the curves are slightly changed. The
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shapes of the curves are similar with those corresponding to BSP, but the temperatures are shifted to lower values. Thus for the first heating scan, the value corresponding to the maximum temperature of the endothermic process is 65.4ºC for F6, and 64.6 for F8. Both samples present shoulders at 59.9 and 57.3ºC, respectively, which is not observed in PREC in this process. In the
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cooling scan the maxima are shifted to 49.5 and 50.6ºC and the values corresponding to the shoulder to 41.4 and 43.2ºC, respectively. In the second heating scan, these temperatures appear at 56.7 and 56.3ºC for the maxima and 44.9 and 45.2ºC for the shoulders.
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The processes assigned to BSP are not observed in the DSC curves of the drug formulations. The variation in shape and temperature of PREC can be due to the purity of each
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component. The disappearance of the processes assigned to BSP can be due the low amount of drug in the formulation, to the solubilization of the drug inside the formulation matrix being in an amorphous form, and/or to the interactions between drug and excipients.
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3.3. In vitro drug release
The in vitro drug release from all formulations is presented in Figure 7. So, as seen in the graphs, all F1-F8 formulation containing BSP showed sustained drug release over 9
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80 70
F1
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60 50 40 30 20 10 0 0
1
pH=1.2
2
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Cumulative release of BSP (%)
hours.
3
4
5
pH=6.8
6
7
8
F2 F3 F4 F5 F6 F7 F8
9
time (hours)
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Figure 7. The release of BSP from matrix tablets.
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The cumulative drug release from the prepared tablets after 9 hours of dissolution (Rh9, %) was within the range 54.62-71.08% (Table 4). The formulations with the highest
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HPMC content displayed the slowest drug release (F1 and F2). Increasing the proportion of PREC lead to a more uniform drug release (F7 and F8). All formulations displayed faster release in the first 4 hours, followed by a much slower release in the next hours. Studies performed on tablets by Gohal et al. [34] claimed that HPMC can act as a channeling agent and can increase the release rate of drugs. This may be the cause of higher release rate of BSP from the F3.
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Table 4. Release model parameters fitted on the release kinetics of the investigated tablets
Formula/ F1
F2
F3
F4
F5
Kp
18.570
21.055
28.609
27.502
23.724
n
0.520
0.500
0.440
0.420
0.450
R2
0.989
0.982
0.989
0.988
0.991
F10
61.502
66.582
78.796
73.176
T
25.467
22.557
17.187
20.851
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Korsmeyer-Peppas model
F6
F7
F8
31.385
26.0590
31.267
0.350
0.430
0.350
0.9825
0.995
0.979
66.864
70.2629
70.138
69.998
24.459
27.4110
22.816
27.707
F4
F5
F6
F7
F8
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Parameter
Higuchi model Formula/ F2
F3
KH
19.2389
21.0551
25.7581
24.1153
21.7351
24.1863
23.0589
24.0883
R2
0.989
0.982
0.984
0.976
0.986
0.948
0.999
0.941
F10
60.838
66.582
81.454
76.259
68.732
76.483
72.918
76.173
T
27.017
22.557
15.072
17.195
21.167
17.094
18.807
17.234
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F1 Parameter
First order release model
Formula/
F1
F2
F3
F4
F5
F6
F7
F8
K1
0.103
0.118
0.162
0.144
0.123
0.142
0.135
0.140
R2
0.922
0.920
0.921
0.867
0.883
0.798
0.888
0.784
F10
64.611
69.395
80.386
76.303
70.861
75.882
74.108
75.572
Parameter
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T
44.342
38.902
28.276
31.990
37.353
32.386
34.088
32.680
F6
F7
F8
Zero order release model
F1
F2
F3
F4
F5
K0
7.498
8.194
9.966
9.301
8.422
R2
0.778
0.753
0.667
0.606
0.686
F10
74.983
81.946
99.664
93.015
84.222
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Formula/
T
13.336
12.203
10.033
10.750
11.873
9.273
8.925
9.227
0.481
0.669
0.460
92.736
89.257
92.272
10.783
11.203
10.837
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Parameter
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Kp=Korsmeyer-Peppas constant; n=release exponent; R2= determination coefficient; F10 (%) = prediction at t=10 h; T=predicted time (h) until complete release. KH= Higuchi constant; K1= First order release constant; K0= Zero order release constant.
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The correlation coefficient R2 values indicated that both the Higuchi and Peppas models suitably describe the release of BSP from the prepared matrix tablets. The value of release exponent n of Korsmeyer-Peppas model was found between 0.35-0.44 (for F8-F3), indicating the
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Fickian diffusion mechanism of BSP release. Formulas F1 and F2 released BSP by a non-fickian diffusion (n = 0.5, and 0.52). It is considered that, when n value ranges from 0.45 to 0.89, the
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drug is released by a combination of diffusion and erosion mechanisms [35]. F7 (PREC 40% and HPMC 46.66%) shows the best fitting on the Korsmeyer-Peppas model (R2 = 0.9959; Kp= 26.0590, n =0.43).
For the Higuchi model the release data obtained according to the determination coefficient (R2) had high linearity for F1, F2, F3, F5 and F7. That means for this formulations the
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drug and excipients dissolve at rates proportional to their solubility and diffusion coefficients in the dissolution medium. It is mainly the case of solid disperse systems [36, 37].
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4. Conclusions This study presents the design and the characterization of extended release tablets of bisoprolol by using the melt granulation technique, as a new pharmaceutical formulation with
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higher compliance for the elderly hypertensive patients.
The differences found in physico-chemical properties of the matrices were not consistent,
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but were significant enough to be able to modulate the amount of drug delivered. The FTIR spectral studies confirm the involvement of the free OH and NH groups in the formation of new H-bonds between the system components, which do not affect the release of the bioactive compound. The DTG curves indicating a small increase in the thermal stability of the
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compounds determined by the physical interactions taking pace between the system components in the mixing process. This was also demonstrated by X-ray diffraction. The present research shows that glyceryl palmitostearate (Precirol ATO5) at suitable
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concentrations combined with HPMC polymer can be used effectively to modify the release rates of bisoprolol in matrix tablets.
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The results showed that a matrix tablet prepared with HPMC and PREC is a better system
for sustained release of a highly water-soluble drug like bisoprolol. Among the various developed formulations of BSP, the formulations F7 appear
suitable for further
pharmacodynamic and pharmacokinetic evaluation in a suitable animal model. These developed optimized matrix tablets showed prolonged sustained release of bisoprolol fumarate lasting for hours, which might be beneficial over the conventional tablet formulations, in order to reduce dosing frequency, and improve patient compliance.
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bisoprolol fumarate buccal patches by using selected polymers. IJPCBS. 2013;3(3):854-860. 14. Precirol ATO5 Technical data sheet. https://www.gattefosse.com/precirol-ato-5 15. Çabasi, P, ÖzsoyY, Tunçel T. Investigations on the lipophilic matrix tablets of verapamil
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Declaration of interest
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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options,
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expert testimony, grants or patents received or pending, or royalties.
S1773-2247(18)31114-6
DOI:
https://doi.org/10.1016/j.jddst.2018.11.011
Reference:
JDDST 833
To appear in:
Journal of Drug Delivery Science and Technology
Received Date: 28 September 2018 Revised Date:
5 November 2018
Accepted Date: 11 November 2018
Please cite this article as: A.D. Panainte, E.G. Popa, C. Gafitanu, I. Stoleriu, L.M. Tar�ău, M.C. Popescu, G. Lisa, Study of the design and characterization of new bisoprolol fumarate tablet formulations, Journal of Drug Delivery Science and Technology (2019), doi: https://doi.org/10.1016/ j.jddst.2018.11.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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STUDY OF THE DESIGN AND CHARACTERIZATION OF NEW BISOPROLOL
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FUMARATE TABLET FORMULATIONS
Alina Diana Panaintea, Eliza Gratiela Popab*, Carmen Gafitanub, Iulian Stoleriuc, Liliana Mititelu
a
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Tarțăud, Maria-Cristina Popescue, Gabriela Lisaf, X
University of Medicine and Pharmacy ‘Grigore T. Popa’ Iasi, Faculty of Pharmacy, Department
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of Analytical Chemistry, 16, Universitatii St. no. 16, code 700115, Iasi, Romania b
University of Medicine and Pharmacy ‘Grigore T. Popa’ Iasi, Faculty of Pharmacy, Department
of Pharmaceutical Technology, Universitatii St. no. 16, code 700115, Iasi, Romania c
University ‘Al. I. Cuza’, Faculty of Mathematics, Carol I Bld, code 700506, Iasi, Romania
d
University of Medicine and Pharmacy ‘Grigore T. Popa’ Iasi, Faculty of Medicine, Department
e’
f
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of Pharmacology-Algesiology, Universitatii St. no. 16, code 700115, Iasi, Romania Petru Poni’ Institute of Macromolecular Chemistry of the Romanian Academy, Iasi, Romania
Department of Chemical Engineering, Faculty of Chemical Engineering and Environmental
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Protection, ‘Gheorghe Asachi’ Technical University of Iasi, Romania
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Abstract: Objectives: the purpose of the study was to develop sustained release tablets containing
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bisoprolol fumarate and an innovative combination of Precirol ATO5 and hydroxypropyl methylcellulose, in order to conclude upon: properties of pharmaceutical tablet formulations, drug-excipients interactions, evaluate their in vitro release behavior.
Methods: The tablet formulations with rate controlling polymers were prepared by melt
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granulation technique. The physical-chemical characterization of new tablet formulation was
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performed by FT-IR spectroscopy, differential scanning calorimetry, thermogravimetric analysis and X-ray diffraction. The formulations were also evaluated for in vitro dissolution test to select the optimized formulation.
Results: Structural evaluation indicated the presence of interactions between tablet components which did not affect drug release. The tablets displayed good mechanical properties,
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with friability values close to zero and drug content was found to be uniform in all formulas. Release profile showed a tendency to follow Korsmeyer-Peppas and Higuchi kinetics. Conclusions: In the present study we investigated the effect of concentration of matrix
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former compounds (hydroxypropyl methylcellulose and glyceril palmitostearate) on the release
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rate of bisoprolol fumarate. The study evidenced the assembling through physical bonds between the excipients and the drug, which do not affect the release of the bioactive compound. Keywords: bisoprolol fumarate, hydroxypropyl methylcellulose, glyceril palmitostearate,
oral drug delivery, formulation development, structural properties.
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1. Introduction Nowadays hypertension is one of the most significant risk factors for cardiovascular disease,
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affecting especially the adult population. One of the main classes of antihypertensive drugs for the oral route are the beta blockers [1]. In this specific therapeutic class, bisoprolol fumarate (BSP), chemically known as 1-[4-[[2-(1-Methylethoxy) ethoxy]-methyl]-3-[(1-methylethyl) amino]-2-propanol [2] salt, is a cardioselective β1-adrenergic blocking agent used for secondary
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prevention of myocardial infarction, heart failure, angina pectoris and mild to moderate
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hypertension [3-5]. The daily dose of bisoprolol is 5 to 10 mg, which can be increased, if necessary, to up to 20 mg/day. After oral administration bisoprolol is rapidly absorbed in gastrointestinal tract, the absolute bioavailability after a 10 mg oral dose of BSP being about 80% [6, 7]. The maintenance of a constant plasma level of a cardiovascular drug is important for the desired therapeutic response. Because the half-life of the bisoprolol is about 3-4 h, multiple
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doses need to be administered in order to maintain a constant plasma concentration. The immediate release tablets with bisoprolol (2.5, 5 or 10 mg/tablet) have been found to have many associated drawbacks such as diarrhea, weakness, fatigue, anxiety, headache, dry mouth, nausea,
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vomiting, stomach pain, etc. Therefore, to reduce frequency of administration and improve
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patient compliance, maintain a uniform drug therapeutic level and reduce side-effects, a sustained release dosage formulation of bisoprolol is desirable. Drug release from the dosage form is controlled by the type and proportion of modified-release polymer used in the preparations. The preparation of matrix tablets with rate controlling polymers is the simplest and most widely used method for achieving desired extended release rate for drugs. Several studies have investigated different matrix tablets (hydroxypropyl methylcellulose (HPMC) in association with sodium bicarbonate, Carbopol 974, glycerin, propylene glycol,
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polyethylene glycol and ethyl cellulose, with the purpose of controlling the release of bisoprolol [8-13]. Precirol ATO5 (PREC), a mixture of mono-, di-, and triglyceryl esters of palmitic and stearic
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acids, with a HLB value of 2, is a multipurpose pharmaceutical ingredient recommended to be used in topical and oral pharmaceutical formulations as a taste masking agent, lubricant and modified-release excipient [14]. Several research studies have been conducted to investigate the
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proportions of Precirol ATO5 for lipophilic matrix tablets and capsule formulations [15, 16]. For modified release purposes the recommended proportions vary between 10 and 50%, more likely
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10-25%. Innovative formulations have been investigated also for orally disintegrating tablets containing PREC as binder for taste masking purpose in proportions of 4.5-5%, which do not prolong the disintegration times [17, 18]. Given its highly fatty nature, PREC can be combined in modified release tablets with hydrophilic polymers such as hydroxypropyl methylcellulose
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(HPMC).
HPMC is a semisynthetic, inert, viscoelastic polymer widely used in solid oral dosage forms as a binder, a film coating, and a controlled-release matrix [19]. HPMC of various viscosity
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grades has been used as a polymer for hydrophilic matrix tablets, due to its swelling capacity in water. For achieving an optimal kinetics of tablets it is necessary a fast hydration of the outer
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layer of the HPMC matrix to form a gel barrier, which provides subsequent slow release of the drug [20]. In this context the drug release takes place mainly by diffusion through, and/or subsequent erosion of the gel layer; while the drug from the outer surface of the matrix is released firsty by a burst effect. Nevertheless, it has been demonstrated that modified drug release from HPMC matrix tablets depends also on the drug solubility [20, 21]. The water-
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soluble drugs are released mainly through diffusion mechanism, whereas insoluble and lowsoluble drugs are released through erosion [23]. Bisoprolol fumarate is a BCS class 1 drug, with high solubility and low permeability. For
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highly water soluble drugs [24], literature data suggest an inflexibility of release kinetics, which may lead to sub-optimal in vivo release profiles [23]. This characteristic has recommended modulation of release kinetics of HPMC matrix tablets by combining it with other excipients
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(PVP, carbopol, glyceryl esters, fatty acids) or by designing multi-layered tablets. The processing of the tablets in solid-state can lead to reactions between the drugs and formulations, possibly
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initiating alterations in their stability, solubility, dissolution rates and bioavailability. Therefore, structural evaluation of the matrix and compatibility studies are needed to ensure that potential physical and chemical interactions between a drug and excipient do not compromise the stability of the drug [25, 26].
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The purpose of the present study was to obtain modified release matrix tablets with bisoprolol fumarate using an innovative combination of Precirol ATO5 (PREC) and hydroxypropyl methylcellulose, in order to investigate the optimal ratio between these
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ingredients as matrix formers and to analyze the pharmaceutical properties and the kinetics release profile of bisoprolol modified release tablets, with a view to maximize duration and
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bioavailability of this drug and to improve efficacy and better patient compliance.
2. Materials and methods 2.1. Materials
The substances used for the pharmaceutical formulations were: Bisoprolol fumarate 20 mg/tablet weight (BSP, provided by Unichem Laboratories LTD, India), Precirol ATO5
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(glyceryl distearate - PREC, kindly offered by Gatefossé) and hydroxypropyl methylcellulose (HPMC K4M, 4000 cps, Premium, Colorcon). 2.2. Preparation of the pharmaceutical formulations
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The preparation of tablets was done by melt granulation process [27], using the property of PREC excipient to melt at low temperatures and consequently to bind the mixture particles. The powder (containing BSP, PREC and HPMC) was mixed and heated to 65°C in an oven. The
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resulted agglomerated mass was passed through a 600 µm aperture pharmaceutical sieve (Fisherbrand, 8̎’-FH-SS-SS-US-30). The obtained granules were further compressed on a Korsch
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EK0 tablet press (9 mm flat punches, 5 kN tabletting pressure). Since PREC is recommended as a good tablet lubricant, the addition of an extra lubricant in the granulation mixture was not considered [14]. Eight formulations of tablets containing BSP were prepared with various
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excipients ratios according to Table 1.
Table 1. The formulations of tablets containing BSP and their tested pharmaco-technical properties.
HPMC (%)
F2
F3
F4
F5
F6
F7
F8
Composition
10
15
20
25
30
35
40
45
76,66
71,66
66,66
61,66
56,66
51,66
46,66
41,66
150
150
150
150
150
150
150
150
0.22
0.00
0.00
AC C
PREC (%)
F1
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Formula
Total tablet
weight (mg) Pharmaco-technical properties Friability (%)
0.00
0.22
0.23
0.21
0.00
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n=20
Hardness (N) 34.3
36.66
40.2
43.9
45.8
46.7
49.7
52.3
2.16
2.12
2.06
2.06
2.00
2.08
2.07
2.10
9.02
9.01
9.01
8.99
8.99
8.99
9.01
8.99
n=10
n=10
Diameter (mm)
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n=10
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Thickness (mm)
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In order to be pharmacodinamically effective, the dose strength of 20 mg bisoprolol was selected for modified release as a sum of 2-8 therapeutic doses.
2.3. Methods of pharmaceutical formulation characterization 2.3.1. Pharmaco-technical properties
The pharmaco-technical properties of the tablets were tested: hardness, thickness and
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diameter, by using a Pharma Test Dr. Schleuniger hardness tester (N), and the friability with an Electrolab EFII friabilator (100 rpm, 4 minutes, according to the method recommended by the European Pharmacopoeia [28, 29].
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2.3.2. Fourier Transform Infrared Spectra (FTIR) The measurement of IR absorption spectra was made with an ALPHA spectrophotometer
AC C
(Bruker, Germany) for the pure drug and the excipients separately, and then combined. Processing of the spectra was performed using the Grams 9.1 program (Thermo Fisher Scientific).
2.3.3. Wide Angle X Ray Diffraction – WAXD WAXD analysis was performed on a Diffractometer D8 ADVANCE (Bruker AXS, Germany), using the CuKα radiation (λ=0.1541 nm). The working conditions were 40 kV and 30
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mA, 2s/step, and 0.02 degree/step. All diffractograms were recorded in the range 10-90 2θ degrees, at room temperature. 2.3.4. Thermal analyses
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2.3.4.1. Thermogravimetric analyses
Thermogravimetric analysis (TGA) was carried out under constant nitrogen flow (200 ml/min) at a heating rate of 10 oC/min using a Mettler Toledo TGA/SDTA 851 balance. The
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heating scans were performed on 3-5 mg of sample in the temperature range 25–600oC. 2.3.4.2. Differential scanning calorimetry
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The DSC curves were recorded using a Mettler Toledo DSC1 device with a 10°C /min heating rate, in a nitrogen flow of 150 ml/min. The sampless weighing between 2.2 and 4.8 mg were taken in pin-holed aluminum pans and underwent two heating cycles and a cooling cycle within the 25-150, 200 or 240oC temperature range. The temperature accuracy was ±0.02 °C, and
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the heat flow resolution was 0.04 µW. The device was calibrated using indium and the In Check method stored in the STARe software, according to the instruction manual. 2.3.5. In vitro drug release tests
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BSP release from the tablets was investigated through dissolution test on a SR8 Plus Dissolution test station equipped with a Disoette II carousel for automatic sampling and a V530
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spectrophotometer (Hanson Research, U.S.A.). The test was performed over a period of 9 hours, according to the following protocol: Apparatus 2 (paddle); rotation: 50 rpm. The volume of the dissolution media for each vessel was 900 ml, as follows: for the first 2 hours 0.1 M HCl solution was used and for the remaining 7 hours the medium was replaced with pH 6.8 phosphate buffer solution, in order to mimic the physiological conditions. Samples were collected automatically every hour and the BSP concentration was determined by spectrophotometric method (wavelength = 222 nm). The same volume of fresh dissolution medium at the same temperature
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was added to replace the amount withdrawn after each sampling. The drug amount of cumulative release from tablets was calculated with a standard curve prepared using bracketed concentration of BSP each dissolution medium in a range 10 to 110% of a theoretical concentration of 5
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µg/mL.
Different kinetic models were applied [30, 31] to the release data of test formulations in order to investigate the release mechanism of drug from the sustained release matrix tablets,
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using a Matlab 7.9 software.
The zero-order release model: = ∗ , (where is the released percentage at
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time t).The predicted release (forecast) at = is % = ∗ % . The predicted time until complete release is determined by the following formula: = /. The first-order release model: = ∗ – ∗ (where is the released percentage at time t).The predicted release (forecast) at = is:
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% = ∗ – ∗ %
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The predicted time until complete release is determined by the following formula:
≌ 4.6052/
The Korsmeyer-Peppas release model is defined by the equation:
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= ∗ , where is the released percentage at time t. The predicted release
(forecast) at = is:
% = ⤫ %
The predicted time until complete release is determined by the folowing formula: = / / The Higuchi release model is defined by the equation:
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= ∗ √ , where is the released percentage at time t. The predicted release (forecast) at = is:
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% = ⤫ √ % The predicted time until complete release is determined by the folowing formula: = / 3. Results and discussions
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3.1. Pharmaco-technical properties
Uniform, intact, smooth-surfaced tablets could be obtained: their characteristics are
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displayed in Table 1. The hardness of tablets did not record high values, nevertheless increasing tablet hardness could be correlated with the higher proportion of PREC in the formulation, with a maximum value for F8 (52.3 N). A very low friability was an important characteristics displayed by all tablets, 4 formulas recording a zero value; this is attributed to the plasticity of the melt
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granulation binder PREC. The values of tablet thickness and diameter indicated a good die fill during the compression process of granules. 3.2. Compatibility study
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3.2.1. FT-IR analysis
FTIR spectroscopy is a sensitive technique for evaluating the intramolecular interaction
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and conformational arrangement which influence the spatial distribution in the structure of materials. Figure 1 shows the IR spectra in transmittance mode of the pure components and two formulations (F6 and F8) in the 3700-2400 cm-1 and 1800-800 cm-1 spectral region. In order to evaluate
the
intermolecular
interactions
between
the
formulation
components
the
calculated/theoretic spectra were performed by using the additivity low [32]. The first spectral region contains the specific bands corresponding to stretching vibration of free and bonded OH and/or NH groups and to aliphatic and aromatic CH groups. As can be seen from Figure 1a, there
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are no differences between the experimental and calculated spectra of F6 and F8 formulations in the spectral region between 3000-2700 cm-1 (assigned to the stretching vibration of aliphatic and
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aromatic CH groups).
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Figure 1. FT-IR spectra of the studies samples in the 3700-2400 cm-1 (a) and 1800-800 cm-1 (b) spectral regions
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In the region assigned to the stretching vibration of free and OH and/or NH groups a small variation in intensity of the bands is observed. It is well-known that hydrogen bonds play an important role for the interaction of OH and NH groups with carbonyl or ether functionalities. In order to evaluate the content of OH and NH groups the deconvolution of this region in component bands was made (Fig. 2). For both calculated and experimental spectra the best fit was obtained with 5 bands, located at about 3580, 3505, 3435, 3324 and 3247 cm-1. The first 3 bands describe the free and hydrogen-bonded OH groups, while the last 2 describe the free and
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H-bonded NH groups. Depending on the strength of the interaction, the absorption bands of the
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involved functionalities undergo more or less extensive band shifts and intensity changes.
Figure 2. The deconvolution of experimental IR spectrum of the F6 formulation in the 37003000 cm-1 spectral region
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Further, after the deconvolution, was possible to evaluate the energy of the hydrogen bonds using the following formulae [29]
1 (ν 0 − ν ) k ν0
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EH =
where ν0 is the standard frequency of the OH (3650 cm-1) and NH (3474 cm-1) monomers
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observed in the gas phase, while ν is the stretching frequency of OH and NH groups observed in the infrared spectrum of the sample, and 1/k is a constant equal to 2.625*102 kJ. The energy values are about 5, 10.5, 15.4, 11.3 and 17.1 kJ for the experimental spectra
for both samples and with a slight shifted to higher values, in case of calculated spectra. Comparing the values corresponding to the integral area of the deconvoluted bands of the calculated and experimental spectra, it can be observed that the integral area of the bands corresponding to free OH and NH groups decrease from about 14.2, 12.2 % and 1.3% in the case
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of calculated F6 and F8 spectra to about 10.9 and 9.2 % and 0.2 and 0.4 % in the experimental spectra, respectively. The integral areas of H-bonded OH groups increase in experimental spectra from 66.3% to 73.4 % in case of the sample F6, and from 70.6 to 73.1 % in the case of the
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sample F8. The observation is similar for H-bonded NH groups, thus the integral areas of the experimental spectra increase from 13.3 to 15.9 % for sample F6 and from 13.3 to 14.1 % for the
new H-bonds between the system components.
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other sample. This confirm the involvement of the free OH and NH groups in the formation of
In the fingerprint spectral region, between 1800-800 cm-1, all components present a large
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number of bands. Thus, the IR spectrum of PREC indicate the main spectral bands: at 1735 cm-1 assigned to stretching vibration of C=O groups, at 1472 cm-1 assigned to scissoring vibration of CH2 groups, 1393 cm-1 assigned to rocking vibration CH2 groups, 1425 and 943 cm-1 assigned to bending vibration of OH groups, 1291, 1103 and 1062 cm-1 assigned to stretching vibration of C-
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O groups and at 719 cm-1 assigned to rocking vibration of methyl long-chain. The IR spectrum of HPMC present specific bands at 1647 cm-1 assigned to stretching vibration of cyclic C-O groups, 1459 cm-1 assigned to asymmetric stretching vibration of CH3 groups,
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1377 cm-1 assigned to asymmetric bending of cyclic C-O-C groups, 1118 and 1063 cm-1 assigned to stretching vibration of C-O-C groups and 848 cm-1 assigned to rocking vibration of CH2
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groups. In case of BSP characteristic bands appear at 1613, 1515 and 1466 cm-1 assigned to stretching vibration of aromatic C-C groups, 1092 and 1048 cm-1 assigned to bending vibration of C-H groups, 1364, 1314 cm-1 assigned to symmetric bending of CH3 and CH2 groups, 1236 cm-1 assigned to stretching vibration of C-O groups and 1178 cm-1 assigned to stretching vibration of -N-CH2 group. In the spectra of formulations all component bands were identified, but the position of some of them is shifted to different wavenumber. Thus, the band of BSP from
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1466 cm-1 is shifted to 1472 cm-1, from 1613 cm-1 to 1618 cm-1 and from 1236 cm-1 to 1239 cm-1. Comparing the experimental and calculated IR spectra of the studied formulations, significant differences appear for the bands situated at 1381 cm-1 in experimental spectrum which appears at
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about 1372 cm-1 in the case of calculated spectra, 1240 cm-1 is shifted at 1235 cm-1 and the band at 1102 cm-1 is shifted at 1094 cm-1. These bands are assigned to bending vibration of CH3 groups and to stretching vibration of C-O groups. These shifts indicate changes in
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conformational arrangement of the molecular chains and/or specific interactions between them. Principal component analysis (PCA). It is known that principal component analysis (PCA) is
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used to visualize interrelationships among the independent variables and is useful in identifying data outliers, therefore is useful to investigate the difference between spectra and derive
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parameters characterizing the interaction between the different components [33].
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Figure 3. Three dimensional PCA score plots of the studied samples
The principal component factor 1 (PC1) describes 83.2%, principal component factor 2
(PC2) describe 11.7% and principal component factor 3 (PC3) describe 4.8 % of data the variance, so 99.7% of the existed variances in all the studied spectra can be captured using these
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three dimensions instead of the initial data. The three-dimensional coordinate system of these PC scores is plotted in Fig. 3. According to this figure, the PC scores for the calculated and experimental spectra
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established some distinct patterns which clearly expressed their differences. It can be observed that the calculated spectra appear in the same plane (PC1-PC2 plane) like the components, the position depending on the components composition. This plane can be defined as the non-
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interaction reference plane. In this case the variation on PC3 direction is about zero. The concentration dependence related to these two factors is expressed by an arrangement of the
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spectra in a triangle shape like, having in the corners the pure components. In case of experimental samples a significant variation on PC3 score direction can be evidenced. Thus, the plane PC2-PC3 can be defined as the interaction plane. The distance between the experimental spectra of the formulations and the calculated spectra are evidenced for sample F6, therefore
3.2.2. X-ray diffraction
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indicating the presence of stronger interactions in this system.
X-ray diffraction is a structural characterization technique which gives information about
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formation of intermediate compounds and the mean grain sizes of the two phases. Figure 4 shows the X-ray diffractograms of pure components and F6 and F8 formulations. In the PREC
AC C
diffractogram five signals were observed at 19.1, 19.5, 22.9, 23.6 and 24.0o with a corresponding d spacing of 4.654, 4.564, 3.871, 3.766 and 3.703 Å. On the other hand, the pure HPMC shows two broad bands at 2θ=9.26 and 19.48° (d spacing=9.545 and 4.554 Å) corresponding to its polymeric semicrystalline nature. BSP is a low molecular crystalline substance. The corresponding diffractogram contain a large number of distinct and sharp bands (see Figure 4 and Table 2).
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Figure 4. X-ray diffractograms of the studied samples
Table 2. The values of 2q o and interplanar distance d for BSP, F6 and F8 BSP
F6
No. d, Å
2q o
d, Å
2q o
d, Å
1
6.8
13.05
6.9
12.80
2
8.1
10.88
8.2
10.77
8.1
10.91
3
9.2
9.58
9.2
9.54
9.2
9.54
4
10.7
8.23
-
-
10.7
8.21
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2q o
F7
11.2
7.88
11.0
8.01
11.2
7.91
6
12.0
7.35
12.0
7.33
11.9
7.42
AC C
5
7
13.0
6.79
13.0
6.77
13.0
6.79
8
13.6
6.49
13.6
6.48
13.4
6.59
9
14.0
6.30
14.1
6.26
14.1
6.29
10
14.9
5.93
15.0
5.89
14.9
5.93
11
15.3
5.77
15.4
5.73
15.9
5.55
12
16.2
5.47
16.1
5.49
16.4
5.40
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18.4
4.81
18.5
4.78
18.4
4.82
14
19.2
4.61
19.2
4.61
19.2
4.62
19.5
4.54
19.5
4.54
15 19.9
4.44
17
20.5
4.32
20.6
4.31
20.5
18
21.0
4.22
21.1
4.21
21.0
19
22.3
3.98
20
22.8
3.89 23.0
3.85
22 23.9
3.71
24
24.6
3.61
25
25.6
3.48
26
26.4
3.38
27
27.2
3.28
4.22
3.85
23.5
3.78
23.5
3.78
23.9
3.71
23.9
3.72
25.7
3.46
25.7
3.46
26.4
3.37
26.4
3.37
27.3
3.26
27.4
3.25
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23
23.0
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21
4.32
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16
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13
27.8
3.20
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In the case of the formulations, a part of the bands arising from BSP which are very small due especially to the low content of this component in the mixture and/or to the loss of
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crystalline structure on the preparation process, appear the intense and clear bands from PREC. Lately, the bands corresponding to HPMC appear like an amorphous background. As can be seen from table 1, the values for 2q in the formulations are slightly shifted for both PREC and BSP, indicating deformation of the crystalline network of these compounds due to the physical interaction between the system components.
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3.2.3. TG/DTG analysis In order to evaluate the thermal stability of the drug in the obtained formulation and to establish the interaction between used excipients and BSP, the TGA curves were recorded
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(Figure 5a). The first-order derivatives of TGA curves (DTG) (Figure 5b) reveal the temperatures corresponding to the maximum decomposition rate. The curves show that the studied samples exhibit one or two distinct and well-separated weight-loss processes (see the
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DTG curves – Fig 5b).
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Figure 5. TG (a) and DTG (b) curves of the studied samples
Tabel 3. TG/DTG results for the studied samples F6
T Ti1, ºC
PREC
-
HPMC
35
F8
BSP
32
exp
calc
exp
calc
34
34
33
33
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-
57
59
62
57
67
57
Tf1, ºC
-
103
105
101
101
111
111
Dw1, wt%
-
6.1
0.5
2.0
3.0
1.1
2.3
Ti2, ºC
201
241
113
136
136
141
141
Tm2, ºC
391
358
327
364
360
Tf2, ºC
469
431
485
467
467
Dw2, wt%
93.3
76.5
78.0
85.6
83.2
Dwresidue, wt%
3.4
13.15
15.0
8.3
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Tm1, ºC
363
478
478
86.1
85.2
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364
7.9
9.1
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10.0
Excepting PREC, in all studied samples, the first process occurs in the temperature interval between 32-35ºC and 101-111ºC, with a maximum between 57 and 67ºC and a corresponding mass loss of 1-6 wt% (Table 3). This process is related to the removal of the physical adsorbed water.
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The second thermogravimetric process for the pure components takes place between 201469ºC and 241-431ºC, with a maximum situated at about 358 in case of PREC and at 391ºC for HPMC. The mass loss in this stage is about 93.3 % for PREC and 76.5 % in case of HPMC. In
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this stage the fission of molecules to a variety of low molecular weight products, including
AC C
carbon dioxide, carbon monoxide, water, hydrocarbons (acetaldehyde, glyoxal and acrolein) and hydrogen takes place. For the BSP, the second decomposition process takes place in the temperature interval between 113-485ºC and present three overlapped stages with a maximum at 327ºC and two shoulders at about 221ºC and 274ºC. In the case of the mixture of the excipients with the drug, the process is starting at 136ºC and finishes at 467ºC, in case of F6 sample and is shifted to higher temperature (141ºC and 478ºC) in the case of the sample with higher PREC
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content (F8). The temperature corresponding to the maximum rate of the decomposition process is the same for both studied samples, at 364ºC. Comparing the DTG curves for experimental and calculated data for F6 and F8 samples,
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it can be observed that the temperature corresponding to the maximum decomposition rate is shifted to higher values in the case of the experimental data, indicating a small increase in the thermal stability of the compounds. As mentioned before, this behavior can be determined by the
3.2.4. Differential scanning calorimetry (DSC)
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physical interactions taking pace between the system components in the mixing process.
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For thermal behavior evaluation the studied samples were heated to 200°C, cooled to 30°C and subsequently re-heated to 200°C. The DSC scans of pure drug and individual
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excipients and the drug excipient mixture are shown in Fig 6.
Figure 6. DSC curves for the studied samples
A sharp and asymmetric endothermic process is observed in the first heating scans of
PREC at 68.7ºC with the enthalpy of transition (DHf) of 189.64 J*g-1 and at 57.9ºC with a shoulder at 52.6ºC and with the heat of transition (DHf) of 116.46 J*g-1 in the second heating process. At cooling an exothermic process is observed at 52.9ºC with the enthalpy of transition of 116.71 J*g-1. This can be due to the melting process of PREC. The DSC curves of HPMC
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showed 2 endothermic processes in the first heating scan. The first one, is a broad process with a maximum at 67.1ºC and a enthalpy value of 168.74 J g-1, due to the evaporation of absorbed moisture and the second one, a small process with a maximum at 179.3ºC with a enthalpy value
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of about 0.81 J g-1. These processes are not observed in the cooling and second heating scans. BSP present two endothermic processes with maxima at 80.9 and 102.3ºC, respectively. These processes are not observed in the cooling scan. Further, in the second heating scan an exothermic
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process is evidenced at 35ºC and an endothermic process at about 100ºC. In the case of the drug formulation, the values of the temperatures and shape of the curves are slightly changed. The
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shapes of the curves are similar with those corresponding to BSP, but the temperatures are shifted to lower values. Thus for the first heating scan, the value corresponding to the maximum temperature of the endothermic process is 65.4ºC for F6, and 64.6 for F8. Both samples present shoulders at 59.9 and 57.3ºC, respectively, which is not observed in PREC in this process. In the
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cooling scan the maxima are shifted to 49.5 and 50.6ºC and the values corresponding to the shoulder to 41.4 and 43.2ºC, respectively. In the second heating scan, these temperatures appear at 56.7 and 56.3ºC for the maxima and 44.9 and 45.2ºC for the shoulders.
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The processes assigned to BSP are not observed in the DSC curves of the drug formulations. The variation in shape and temperature of PREC can be due to the purity of each
AC C
component. The disappearance of the processes assigned to BSP can be due the low amount of drug in the formulation, to the solubilization of the drug inside the formulation matrix being in an amorphous form, and/or to the interactions between drug and excipients.
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3.3. In vitro drug release
The in vitro drug release from all formulations is presented in Figure 7. So, as seen in the graphs, all F1-F8 formulation containing BSP showed sustained drug release over 9
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80 70
F1
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60 50 40 30 20 10 0 0
1
pH=1.2
2
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Cumulative release of BSP (%)
hours.
3
4
5
pH=6.8
6
7
8
F2 F3 F4 F5 F6 F7 F8
9
time (hours)
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Figure 7. The release of BSP from matrix tablets.
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The cumulative drug release from the prepared tablets after 9 hours of dissolution (Rh9, %) was within the range 54.62-71.08% (Table 4). The formulations with the highest
AC C
HPMC content displayed the slowest drug release (F1 and F2). Increasing the proportion of PREC lead to a more uniform drug release (F7 and F8). All formulations displayed faster release in the first 4 hours, followed by a much slower release in the next hours. Studies performed on tablets by Gohal et al. [34] claimed that HPMC can act as a channeling agent and can increase the release rate of drugs. This may be the cause of higher release rate of BSP from the F3.
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Table 4. Release model parameters fitted on the release kinetics of the investigated tablets
Formula/ F1
F2
F3
F4
F5
Kp
18.570
21.055
28.609
27.502
23.724
n
0.520
0.500
0.440
0.420
0.450
R2
0.989
0.982
0.989
0.988
0.991
F10
61.502
66.582
78.796
73.176
T
25.467
22.557
17.187
20.851
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Korsmeyer-Peppas model
F6
F7
F8
31.385
26.0590
31.267
0.350
0.430
0.350
0.9825
0.995
0.979
66.864
70.2629
70.138
69.998
24.459
27.4110
22.816
27.707
F4
F5
F6
F7
F8
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Parameter
Higuchi model Formula/ F2
F3
KH
19.2389
21.0551
25.7581
24.1153
21.7351
24.1863
23.0589
24.0883
R2
0.989
0.982
0.984
0.976
0.986
0.948
0.999
0.941
F10
60.838
66.582
81.454
76.259
68.732
76.483
72.918
76.173
T
27.017
22.557
15.072
17.195
21.167
17.094
18.807
17.234
AC C
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F1 Parameter
First order release model
Formula/
F1
F2
F3
F4
F5
F6
F7
F8
K1
0.103
0.118
0.162
0.144
0.123
0.142
0.135
0.140
R2
0.922
0.920
0.921
0.867
0.883
0.798
0.888
0.784
F10
64.611
69.395
80.386
76.303
70.861
75.882
74.108
75.572
Parameter
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T
44.342
38.902
28.276
31.990
37.353
32.386
34.088
32.680
F6
F7
F8
Zero order release model
F1
F2
F3
F4
F5
K0
7.498
8.194
9.966
9.301
8.422
R2
0.778
0.753
0.667
0.606
0.686
F10
74.983
81.946
99.664
93.015
84.222
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Formula/
T
13.336
12.203
10.033
10.750
11.873
9.273
8.925
9.227
0.481
0.669
0.460
92.736
89.257
92.272
10.783
11.203
10.837
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Parameter
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Kp=Korsmeyer-Peppas constant; n=release exponent; R2= determination coefficient; F10 (%) = prediction at t=10 h; T=predicted time (h) until complete release. KH= Higuchi constant; K1= First order release constant; K0= Zero order release constant.
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The correlation coefficient R2 values indicated that both the Higuchi and Peppas models suitably describe the release of BSP from the prepared matrix tablets. The value of release exponent n of Korsmeyer-Peppas model was found between 0.35-0.44 (for F8-F3), indicating the
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Fickian diffusion mechanism of BSP release. Formulas F1 and F2 released BSP by a non-fickian diffusion (n = 0.5, and 0.52). It is considered that, when n value ranges from 0.45 to 0.89, the
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drug is released by a combination of diffusion and erosion mechanisms [35]. F7 (PREC 40% and HPMC 46.66%) shows the best fitting on the Korsmeyer-Peppas model (R2 = 0.9959; Kp= 26.0590, n =0.43).
For the Higuchi model the release data obtained according to the determination coefficient (R2) had high linearity for F1, F2, F3, F5 and F7. That means for this formulations the
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drug and excipients dissolve at rates proportional to their solubility and diffusion coefficients in the dissolution medium. It is mainly the case of solid disperse systems [36, 37].
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4. Conclusions This study presents the design and the characterization of extended release tablets of bisoprolol by using the melt granulation technique, as a new pharmaceutical formulation with
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higher compliance for the elderly hypertensive patients.
The differences found in physico-chemical properties of the matrices were not consistent,
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but were significant enough to be able to modulate the amount of drug delivered. The FTIR spectral studies confirm the involvement of the free OH and NH groups in the formation of new H-bonds between the system components, which do not affect the release of the bioactive compound. The DTG curves indicating a small increase in the thermal stability of the
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compounds determined by the physical interactions taking pace between the system components in the mixing process. This was also demonstrated by X-ray diffraction. The present research shows that glyceryl palmitostearate (Precirol ATO5) at suitable
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concentrations combined with HPMC polymer can be used effectively to modify the release rates of bisoprolol in matrix tablets.
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The results showed that a matrix tablet prepared with HPMC and PREC is a better system
for sustained release of a highly water-soluble drug like bisoprolol. Among the various developed formulations of BSP, the formulations F7 appear
suitable for further
pharmacodynamic and pharmacokinetic evaluation in a suitable animal model. These developed optimized matrix tablets showed prolonged sustained release of bisoprolol fumarate lasting for hours, which might be beneficial over the conventional tablet formulations, in order to reduce dosing frequency, and improve patient compliance.
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Declaration of interest
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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options,
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expert testimony, grants or patents received or pending, or royalties.