Starch/Stärke 2014, 66, 409–417
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DOI 10.1002/star.201300136
RESEARCH ARTICLE
Synthesis and characterisation of starch tartrate and its application as novel disintegrant in telmisartan tablets Fathi H. Assaleh 1, Prakash Katakam 1, Ramesh Botcha 2, Babu Rao Chandu 1 and Shanta Kumari Adiki 2 1 2
Faculty of Pharmacy, University of Zawia, Al-Zawia, Libya Nirmala College of Pharmacy, Guntur, Andhra Pradesh, India
The aim of the present study was to synthesize potato starch (PS) derivatives of tartaric acid (TA) under semi-dry conditions and to evaluate the physicochemical properties as per official compendia requirements. Starch tartrate (ST) was synthesized by reacting PS (St–OH) and TA in semi-dry condition using sodium hypophosphite (SHP) as a catalyst. Further we have applied its use as disintegrant in directly compressed telmisartan tablets. The microscopic, spectroscopic (FTIR), thermal (DSC) and crystallographic (XRD) studies confirmed the formation of ST. No gelling was observed at 100°C but it was converted to a clear solution with a swelling index of 1.666 times. ST was found to have suitable compression properties required for directly compressible tablets. The tablets formulated employing ST (5–15% w/w) as disintegrant gave rapid disintegration and dissolution rates compared to those prepared using commercial superdisintegrants (sodium starch glycolate and crosscarmellose sodium). The optimized formulation showed disintegration time of 31 3 s which is found superior to that of others. It is concluded that the synthesized ST could be employed as a promising disintegrant in dispersible tablet formulations.
Received: May 30, 2013 Revised: July 12, 2013 Accepted: July 17, 2013
Keywords: Characterization / Disintegrant / Starch tartrate / Telmisartan supporting information may be found in the online version of this article : Additional at the publisher’s web-site.
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Introduction
Starch and its derivatives enjoy a myriad of applications in the pharmaceutical industry due to their biodegradability and biocompatibility [1]. Starch is a versatile excipient used primarily in pharmaceutical formulations as thickening agent, emulsifier, binder, diluent, disintegrant, film former and bioadhesive [2–4]. Starch is used as a tablet disintegrant in the concentrations of 3–25% and other site-specific delivery systems [5–7]. Modified starches have achieved a wide range of functions from binding or disintegrating and
Correspondence: Dr. Prakash Katakam, Faculty of Pharmacy, University of Zawia, Al-Zawia, Libya E-mail:
[email protected] Fax: þ218-237-631-775 Abbreviations: CCS, crosscarmellose sodium; MCC, microcrystalline cellulose; PS, potato starch; SHP, sodium hypophosphite; SLS, sodium lauryl sulphate; SSG, sodium starch glycolate; ST, starch tartrate; TA, tartaric acid
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
imbibing or inhibiting moisture in tablet formulations [8, 9]. The modified starches generally show better paste clarity, better stability, increased resistance to retrogradation and increased freeze-thaw stability [10]. Chemical modifications of starch are carried out for improvement of specific properties. Different techniques are employed such as substitution reactions, cross linking reactions, degrading reactions and starch fractionation. Cross linking of starch could be attained with bifunctional and polyfunctional compounds. A low degree of substitution could result in key changes of the starch functionality. The investigations on modification of starch by reacting with various acids were carried out in the last decade [11]. Starch citrate was prepared from icacina starch and its properties were evaluated [12]. Carboxymethyl starch, sulfonic starch and starch succinate half ester were synthesized in recent years [13, 14]. Alkenyl succinate of starch was synthesized and used in nonalcoholic beverages for the stabilisation of flavours [15]. Calcium starch, a controlled release polymer, was prepared by reacting potato starch (PS) with calcium
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chloride [16]. Starch phosphates are used in foods as emulsion stabilizers for vegetable oil in water and thickening agents with good freeze-thaw stability [15]. PS is available as unimodal and lenticular granules in size 5–100 mm [2]. Telmisartan, 2-[4-[[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propyl-benzimidazol-1-yl]methyl]phenyl]benzoic acid, is an angiotensin II receptor antagonist, which is used in the management of hypertension. It belongs to class 2 of biopharmaceutical classification system of drugs having low solubility and high permeability in the biological systems. It is highly lipophilic with an aqueous solubility of 0.078 mg/ mL and poor bioavailability of 42–58% after oral administration [17–19]. Increasing aqueous solubility and dissolution of telmisartan is a challenge for pharmaceutical scientists. The simplest way to achieve quick disintegration is to use a superdisintegrant in concert with suitable diluents. Superdisintegrants such as croscarmellose sodium, crospovidone and sodium starch glycolate (SSG) are frequently used in tablet formulations to improve the rate of dissolution and thereby increasing in bioavailability of the drugs [20]. In the present investigation starch tartrate (ST) was synthesized by a new method. The physicochemical properties as a pharmaceutical excipient were characterized and its potential as a novel disintegrant in telmisartan tablets was investigated.
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Materials and methods
2.1 Materials PS (Code: 06120), reagent grade sodium hypophosphite (SHP) monohydrate (Code: 0590500500, CAS No. 10039-56-2), L-(þ)-tartaric acid (TA, Code: 0619500500, extra pure 99.5%, MW 150.09, CAS No. 87-69-4C), acetic acid (Code: 2915.2100, CAS No. 64-19-7), SSG (Code: 06007, extra pure, CAS No. 9063-38-1) and microcrystalline cellulose (MCC, Code: 02630, CAS No. 9004-34-6) utilised in the study were procured from Loba Chemie Pvt. Ltd., Mumbai, India. The starch contained approximately 23% AM and 77% AP. Telmisartan (CAS No. 144701-48-4) and croscarmellose sodium (CCS, CAS No. 74811-65-7) were gratis samples from Natco Pharma Ltd., Hyderabad, India. Sodium lauryl sulphate (SLS, CAS No. 8012-56-4) from Merck Specialities Pvt. Ltd., Mumbai; D-mannitol (CAS No. 69–65–8) from Finar Chemicals Pvt. Ltd., Mumbai; menthol (CAS No. 89-78-1) from Indian Research Products Ltd., Chennai; magnesium stearate from Oxford Laboratory, Mumbai and talc from Kemphasol Laboratory, Mumbai were purchased in India. Whatman filter paper (qualitative No. 4, 110 mm diameter) from Jay Scientific Co., Mumbai, India and deionised water was used throughout. All other chemicals used were of reagent or analytical grade appropriately. Commercial telmisartan 20 mg tablets (Micardis®, 20 mg) were from Boehringer Ingelheim Pvt. Ltd., Mumbai, India. ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
2.2 Synthesis of starch tartrate TA (10 g) and SHP (2 g) were dissolved in a minimal amount of water (10 mL) in a beaker. PS (10 g air-dried) was combined with the TA solution in a 100 mL glass beaker and mixed vigorously with a glass rod. The mixture was placed in a forced air oven to dehydrate at 100°C for 30 min. At this point, all surface moisture was removed, and the starch particles were coated with TA. The oven temperature was increased to 120°C, and the material was allowed to react for 5 h. The temperature and time for reaction were determined from several previous trials by varying these conditions [21]. The products of ST reaction were added to 100 mL of water, mixed with mechanical paddle stirrer (Remi Elektrotechnik Ltd., India) at 150 rpm for 30 min. The slurry was filtered using Whatman filter paper and washed with successive 60, 80 and 100 mL of water for 30 min. The ST was dried in an oven at 60° C for 1 h, the yield was determined and passed through ASTM mesh no. 85 [22]. 2.3 Physicochemical characterization of ST The synthesized ST was evaluated for its organoleptic properties, melting range, moisture content and loss on drying. The pH of 1% w/v ST in water was measured by digital pH meter (LI 120, Elico Ltd., Hyderabad, India). The identification tests for carbohydrates (Molish test), carbonyl groups (Tollen’s and Benedict’s tests) and esters (phenopthalein and hydroxamic acid test) were performed [23]. The solubility of 1% w/v of ST was tested in water, aqueous buffers (pH 1.2, 6.8, 7.4 and 7.5) and organic solvents (methyl alcohol, chloroform, acetone and ether) at 30 0.2°C. The relative viscosity of 1% w/v ST dispersion in water was measured using 10 cm3 U-tube Ostwald at 30 0.2°C [24]. The gelling property of ST was evaluated by heating 10% w/v dispersion in water at 60, 70, 80, 90 and 100°C for 15 min with occasional stirring [25]. Swelling index was tested using a modified pharmacopoeial method [26]. 200 mg were taken in a 25 mL ground glass stopper cylinder graduated in 0.5 mL divisions. About 10 mL of water or light liquid paraffin were added and shaken vigorously at every 10 min for 1 h and then allowed to stand for 12 h. The final volume of sediment was recorded and swelling index was calculated. 2.4 Microscopic studies Morphological characteristics of ST powder were studied by SEM analysis and optical microscopy. The SEM analysis was performed using a scanning electron microscope (Exacta Optech, Model B3, Optech Optical Technology, Germany). Prior to examination, samples were mounted on an aluminium stub using a double sided adhesive tape and making it electrically conductive by coating with a thin layer of gold (200 A) in vacuum. The scanning electron microscope
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was operated at an acceleration voltage of 0.5 kV and resolution of 4000. The mean projected diameter of ST was determined by an optical microscope (Leitz, laborlux II, Germany) on 625 particles.
16-station tablet punching machine (Cadmach Machinery Co. Pvt. Ltd., Ahmedabad, India) to a hardness of 3 kg/cm2 using 7.5 mm flat face punches. 2.10 Evaluation of tablets
2.5 Crystallographic studies Powder XRD was conducted using an automatic diffractometer (MXP3; MAC Science Ltd., Yokohama, Japan) with a voltage of 40 kV and a current of 20 mA. The sweep measurements of 2u angle were carried out at a scanning rate of 2°/min over a range of 5–60°. The results were interpreted using the XPRESS computer program (Bruker AXS K.K., Yokohama, Japan). The highest peak of diffraction was measured for crystallinity of the sample. 2.6 Thermal analysis The heat characteristics of PS, TA and ST were analysed using a Shimadzu DSC-50 (Shimadzu, Kyoto, Japan). The behaviour under heat was studied by heating the samples (2 mg) in an aluminium pan from 25 to 400°C at a heating rate of 10°C/ min under a flow of nitrogen at 10 cm3/min using an empty pan as a point of reference. 2.7 FTIR studies The FTIR spectra (400–000 cm1 and resolution of 4 cm1) of the PS and ST were measured by preparing dispersion in dry KBr using Shimadzu FTIR 8400S (Shimadzu Analytical India Pvt. Ltd., Mumbai, India). The transmission minima (absorption maxima) in the spectra obtained with these two polymers were compared. The presence of additional peaks corresponding to the functional groups was noted. 2.8 Micromeritic studies The synthesised ST was evaluated for particle size distribution by sieving method using ASTM standard sieves [27]. The ST and all the powder blends of telmisartan formulations were tested for bulk density, tapped density, angle of repose, compressibility index and Hausner’s ratio [28–31]. 2.9 Preparation of telmisartan dispersible tablets Dispersible tablets (200 mg) of telmisartan (20 mg) were prepared by direct compression method employing MCC (50% w/w) as binder, mannitol (q.s.) as diluent, SLS (1% w/w) as wetting agent, menthol (1% w/w) as a flavouring agent and talc and magnesium stearate (2.5% w/w) as lubricants. Three series of tablets were made by employing ST (F1–F3), CCS (F4–F6) and SSG (F7–F9) as disintegrants at concentrations of 5, 10 and 15% w/w separately. All the ingredients were weighed accurately, blended and compressed into tablets on ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Dispersible tablets were evaluated for weight variation, hardness, thickness, friability, tensile strength, disintegration time, wetting time and drug content uniformity [31, 32]. Disintegration time was determined using USP tablet disintegration test apparatus (Labindia Analytical Instruments Pvt. Ltd., Thane, India) and distilled water (900 mL) as medium at 37 2°C. The Roche friabilator (Labindia Analytical Instruments Pvt. Ltd., Thane, India) was used to measure tablet friability. The tensile strength of the tablets was determined at room temperature by diametral compression using a hardness tester (Optics Technology, Delhi, India) [32]. Drug content in pH 7.5 phosphate buffer was determined using a UV/Vis spectrophotometer (Aquamate Plus; Thermo Scientifics, Mumbai, India) at 296 nm. 2.11 In vitro dissolution study In vitro dissolution test was performed using United States Pharmacopoeia (USP) dissolution Apparatus II (Disso 2000; Labindia Analytical Instruments Pvt. Ltd., Thane, India) in pH 7.5 phosphate buffer (900 mL, 37 0.5°C) at 50 rpm [33]. Five mL sample was withdrawn at 2 min intervals up to 10 min and at 5 min intervals up to 40 min. The sample was replaced with the buffer solution to maintain constant volume throughout. The drug dissolved was determined using a calibration curve at 296 nm. To investigate the mechanism of drug release from the tablets, the data were analysed using zero-order, first-order, Highuchi and Koresmeyer Peppas kinetic models [34–36]. The in vitro dissolution of optimised formulation of STwas compared to marketed telmisartan tablets. The dissolution profiles of ST formulations were compared to those of all others using similarity factor (f2) at 0.25 and 0.5 h dissolution time points [37]. 2.12 Stability study The optimised formulations were filled in high density polyethylene (HDPE) containers and stored at 40 2°C/ 75 5% relative humidity for 90 days as per International Conference on Harmonization (ICH) guidelines. The samples were characterized for change in the physical parameters, disintegration time and drug content [38].
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Results
The reaction scheme of the formation of ST is shown in Fig. 1. An equal amount of PS and TA was optimum for the
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Table 1. Physicochemical characterization of ST
Parameter State Odour Taste Colour Projected diameter (optical microscopy) Particle size distribution
Figure 1. Scheme of synthesis of ST.
synthesis of ST. The product was a white amorphous, nonhygroscopic powder, with no characteristic odour or taste and with a yield of 79.4%. The ST did not melt during heating but charred at 270 0.5°C. Carbohydrates, carbonyl groups and esters were found in the synthesised ST. It was insoluble in water, aqueous buffers (pH 1.2, 6.8, 7.4 and 7.5) and some organic solvents (methanol, chloroform, ether and acetone). No gelling was observed even at 100°C but converted to a clear solution having a swelling index of 1.666. Other properties were summarised in Table 1. The scanning electron micrographs for ST were shown in Fig. 2. The particles were ovoid and spherical aggregates with irregular sizes. The XRD studies revealed that there was no characteristic peak for ST powder (Fig. 3). The DSC thermograms demonstrated a sharp melting point transition of PS, TA and STat 288.65, 172.73 and 278.32°C, respectively. The onset of transition started at 285.58, 169.80 and 279.91°C and the endothermic peaks were found at 295.49, 177.13 and 279.97° (Fig. 4, Figs. S1–S3). The FTIR spectra of PS and ST were shown in the Fig. 5, Figs. S4 and S5. The IR spectrum of ST showed characteristic peaks at 1717.40 cm1 due to the C –– O carbonyl structure present in acid group and 1783.76 cm1 due to C –– O stretching present in ester group but absent in that of PS. The precompression parameters of the powder blends of nine telmisartan formulations prepared using ST, CCS and SSG as disintegrants were summarised in Table 2. The bulk density was in the range 0.515 0.03–0.527 0.01 g/cm3. The tapped density was between 0.610 0.06 and 0.618 0.01 g/cm3. The flow properties were calculated using bulk and tapped density data. The angle of repose was in the range of 28.72 0.36–33.28 0.74°. The compressibility index was found between 14.56 0.70 and 16.53 0.69%, while the Hausner’s ratio was in the range of 1.170 0.02–1.198 0.04. Drug polymer interaction was studied by comparing FTIR spectra of the pure drug to those of the mixture of the drug ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Carbohydrates (Molish’s test) Carbonyl group (Tollen’s test) Esters (phenolpthalein test) Moisture content (IR balance method) Loss on drying Solubility pH (1% w/v aqueous dispersion) Melting point (°C) Relative viscosity (cps) Swelling index (%) Gelling property Bulk density (g/cm3) Tapped density (g/cm3) Angle of repose Compressibility index Carr’s index Hausner’s ratio
Result Amorphous powder No characteristic odour Tasteless White 52.8 16.2 mm 2.5 0.28% retained on #200 (73.7 mm) mesh and 8 0.73% retained on #325 (44.5 mm) mesh Positive Positive Positive 15.0 1.3% 17.6 2.9% Insoluble in aqueous and organic solvents 3.85 0.08 Did not melt but charred at 270 0.5 1.22 0.08 66.6 2.4 No gelling at 100°C but formed a clear solution 0.625 0.012 0.714 0.014 23.8 1.3° 13.54 12.46 1.14
Data expressed as mean SD, n ¼ 6.
with other ingredients. Telmisartan gave a peak at 1130.32 cm1 due to the presence of the secondary amine group. A peak at 1697.41 cm1 was also observed due to the presence of carboxylic group. The peaks of telmisartan in the
Figure 2. Scanning electron micrograph of ST.
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Figure 3. XRD graph of ST.
drug-excipients physical mixture were obtained intact 1450.25, 2952.76 and 1257.27 cm1(Figs. S6 and S7). The frequencies of functional groups of pure drug remained unaffected in the physical mixture containing different polymers and other ingredients. Dispersible tablets of telmisartan were prepared using direct compression method. The physical parameters of prepared tablets are shown in Table 3. Tablet weight variation was less than 4.1 0.2%. The %CV of thickness and hardness among the tablets were 0.551 and 2.54, respectively. The friability was less than 0.68 0.03% w/w. The tensile strength of prepared tablets was in the range of 7.35 0.06– 7.51 0.09 kg/cm2. The drug content uniformity in pH 7.5 phosphate buffer was between 98.1 1.55 and 102.4 0.34% w/w. The disintegration and wetting times of prepared tablets were less than 69 6 and 84 2 s, respectively. Over 57.67 3.85% of the drug was released from all the prepared formulations. Formulation F3 disintegrated more rapidly than other formulations and the drug was released within 15 min. Formulations containing ST released over 95% of the drug within 25 min, while those prepared using CCS and SSG released the drug up to 40 min (Table 4). All the formulations followed zero order release kinetics and the rate constants (k0) obtained were in the range of 2.390–6.404 mg/h. The correlation coefficient (r) was greater than 0.9431. During the stability studies, the formulations did not show any significant change in physical properties. The drug content did not change by more than 2.41 0.58% (Table 5).
4
Discussion
ST was successfully synthesised using PS and TA employing SHP as catalyst in semi-dry condition. SHP has been earlier reported as a promising catalyst in semi-dry condition for cross the linking of xylan and starch with citric acid [22, 39]. The temperature, time and reactant concentrations were optimised. The formation of ST involved a two-step process wherein tartaric anhydride was formed initially and then ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 4. DSC thermograms of (A) PS, (B) TA and (C) ST.
esterification took place with the OH group of starch (Fig. 1). The product was observed as amorphous, lacking sharp melting point as is evident from thermal and DSC studies. Lack of characteristic peaks in the XRD graph further revealed that ST was amorphous. The chemical properties of ST showed the presence of carbohydrates, carbonyl groups and esters which indicate their formation was confirmed by the FTIR study. Although ST was insoluble in aqueous and organic solvents, it was soluble in water at 100°C to form a clear solution. It exhibited no gelling or pasting properties unlike PS when heated in water. Although the pH value of 3.85 0.08 for ST was slightly lower than that of native PS it still falls within the range of pH 3–9 for most starches used in food, cosmetic and pharmaceutical industries [40]. It lacks any characteristic taste or odour, its use can be augmented as an excipient of choice in various formulations. Higher bulk density is advantageous in tableting due to a reduction in the fill volume of the die. An angle of repose of www.starch-journal.com
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Figure 5. FTIR spectra of PS (A) and ST (B).
less than 30°, compressibility index of less than 10% and Hausner’s ratio of 1.00–1.11 usually are indicative of free flowing and densification of powders [31, 41]. The obtained results were within the stated values for ST alone and in the powder blends of telmisartan formulations revealed its suitability for tableting process. To develop a stable formulation, the drug-excipient interaction study is performed during the product development stage generally employing FTIR spectroscopy. Lack of new characteristic peaks in the FTIR spectra indicates the absence of drug-excipient interactions. The prepared formulations using ST as a disintegrating agent showed acceptable tableting properties indicating that
ST can be employed as a directly compressible excipient [42]. Since the material was free flowing, the tablets obtained were of uniform weight due to homogeneous die fill. An indirect measure of strength of a cylindrical tablet is its tensile strength. Higher tensile strength and lower friability were observed in this study which designate good strength of tablets prepared using ST. Although the swelling index of ST (1.66 times) was much below that of CCS (4–8 times) and SSG (300 times) the formulation F3 containing ST (15% w/w) has shown faster disintegration and dissolution of telmisartan [2]. Swelling, capillary action alone or their combination is the basic property of a disintegrant material. However gelling of
Table 2. Micromeritic properties of the powder blends of telmisartan formulations
Formulation
Bulk density (g/cm3)
Tapped density (g/cm3)
Angle of repose (°)
Compressibility index (%)
Hausner’s ratio
F1 F2 F3 F4 F5 F6 F7 F8 F9 RSR
0.515 0.03 0.523 0.01 0.518 0.03 0.517 0.02 0.525 0.04 0.522 0.02 0.520 0.03 0.527 0.01 0.519 0.05 a
0.610 0.06 0.615 0.04 0.612 0.02 0.613 0.08 0.617 0.05 0.611 0.02 0.623 0.07 0.618 0.01 0.616 0.04 a
30.48 0.45 31.24 0.32 30.86 0.16 33.28 0.74 32.19 0.83 31.10 0.22 29.23 0.64 29.74 0.78 28.72 0.36
