Comparative Direct Compression Property of a Novel Pregelatinized Starch in Paracetamol Tablets

Background Among all the pharmaceutical dosage forms, tablets are still the most preferred and the most commonly used option because of their advantages. The direct compression method of tablet preparation exempts several steps needed in the granulation method. Therefore, the pursuit of better direct compression tablet excipients is evident in contemporary research endeavors. Pregelatinized Taro Boloso-I starch has comparable flow properties and higher compressibility and compactibility than Starch 1500®. However, there is no evidence in the literature regarding the lubricant sensitivity and dilution potential of pregelatinized Taro Boloso-I starch. This study was aimed at performing the in vitro evaluation of paracetamol tablets prepared using pregelatinized Taro Boloso-I starch as a direct compression excipient using paracetamol as a model drug. Methods Taro Boloso-I starch was pregelatinized, and its properties including amylose to amylopectin ratio, densities, flow properties, swelling power, water solubility index, particle morphology, moisture content, and moisture sorption profile were evaluated. Furthermore, the lubricant sensitivity test, dilution potential study, and compatibility test with the paracetamol drug using ATR spectroscopy were performed. The properties of the directly compressed tablets prepared accordingly were evaluated. The majority of evaluations were performed in comparison with Starch 1500®. Results and Discussion. PGTBIS had a significantly lower amount of amylose than Starch 1500®. In the ATR-IR spectra of the mixture of the paracetamol and pregelatinized PGTBIS, all the major absorbance peaks of the drug were maintained indicating the absence of chemical modifications. PGTBIS showed better flow properties than Starch 1500®. The modified starch was shown to withstand magnesium stearate up to 0.5% concentration. Conclusion PGTBIS could accommodate higher drug cargo than Starch 1500® with acceptable tablet properties. Accordingly, PGTBIS starch could be taken as a potential direct compression excipient.


Introduction
While there are several types of pharmaceutical dosage forms, tablets are still the most preferred and the most commonly used option [1,2].Te direct compression method of tablet preparation is the most desirable method.Te wet granulation method has drawbacks in terms of achieving batch-to-batch reproducibility and higher productivity, especially in a low-particle size range.It is a resource-intensive process besides its stability concerns on heat and moisture-sensitive drugs.
Direct compression overcomes these problems.It is more economical as it requires fewer unit operations.It also reduces the chances of contamination and steps to be validated and documented.It avoids stability problems of especially moisture and heat-sensitive drugs, drugs whose dissolution profle is likely to change on storage, and drugs at risk of microbial growth.Furthermore, it favors faster dissolution as the tablet disintegrates directly into API particles than into granules.It reduces the wear and tear of punches due to the exemption of high compaction pressure involved in the production of tablets by slugging or roller compaction.
Flowability, low friction tendency, compressibility, and fast disintegration capacity are some of the features and criteria of directly compressible excipients [3][4][5][6][7].Terefore, the pursuit of better direct compression tablet excipients is prominent in the research endeavor.
While starch is one of the leading polymers for use as a pharmaceutical excipient of several advantages [7], native Taro Boloso-I starch is reported to have appreciable compressibility and also compatibility with paracetamol [8].However, it has poor fowability [9].
Pregelatinization enhances fow property of Taro Boloso-I starch.Tere is a report in the literature [10] that was compared with NTBIS and Starch 1500 ® in terms of the bulk density, tapped density, true density, Hausner ratio, and Carr's index, and as a result, it is considered a potential direct compression binder.In addition, compressibility/compactibility of PGTBIS is also pronounced with a Heckel yield pressure of 104.4 MPa and a tablet-breaking force of 138.0 N when 300 mg PGTBIS is compressed at 12 kN.Accordingly, it is recognized as an encouraging direct compression excipient.
Tere is no evidence in the literature regarding the compatibility of the PGTBIS with paracetamol, its lubricant sensitivity, and dilution potential by using specifc drugs.Tis study was aimed at performing the in vitro evaluation of paracetamol tablets prepared using pregelatinized Taro Boloso-I starch as a direct compression excipient.

Preparation and Characterization of the Pregelatinized
Starch.Taro Boloso-I starch (NTBIS) was extracted as per the methods described elsewhere in the literature [10].Ten, it was pregelatinized using a method optimized by Balla et al. [10,11].Accordingly, 15% (w/v) slurry of NTBIS was heated in a water bath at 66.22 °C with continuous heating and uniform stirring for 20 min.Te pregelatinized starches were then dried at 40 °C for 48 h and powdered in a laboratory grinder (Pulverisette 2, Fritsch, Germany) and passed through a 224 μm aperture sieve.Finally, the samples were stored separately in tightly sealed glass containers.Te amylose to amylopectin ratio was determined by the colorimetric assay method, and the morphological study was performed using scanning electron microscopy (SEM) [12].Swelling power, water solubility index, and moisture sorption pattern were determined by the methods by Balcha et al. and Paulos et al. [9,13].

Lubricant Sensitivity Study.
Te lubricant sensitivity study was performed using the method used elsewhere by Svačinová et al. [14].Tablets of PGTBIS were prepared with magnesium stearate at various concentrations including 0.00, 0.25, 0.50, 0.75, 1.00, 1.50, and 2.00% (w/w).Forty grams of each of the mixtures was mixed for 5 min in a Turbula mixer (Willy A. Bachofen AG, Turbula 2 TF, Basel, Switzerland) and compressed to produce 10 mm diameter fat-surfaced 300 mg tablets at 17 kN.Te compactibility was assessed by using the method used elsewhere [15,16].Te tablet properties including the lubricant sensitivity ratios were calculated 24 hrs after compression using the following equation: where LSR, TS0, and TBL stand for the lubricant sensitivity ratio, tensile strength of PGTBIS alone, and the tensile strength of PGTBIS mixed with lubricant, respectively.

Dilution Potential Study.
Tablets of 300 mg weight containing 20%, 30%, 40%, and 50% paracetamol were prepared using PGTBIS or Starch 1500 ® by the direct compression method (Table 1).In brief, paracetamol, Ac-Di-Sol ® , and starch were mixed for 10 min in the Turbula mixer, and after the addition of 0.5% magnesium stearate, mixing was continued for 5 min.Paracetamol tablets were then compressed using the instrumented single-punch tablet machine (Korsch AG XP1 K0010288, Germany) at a compression force of 17 kN [17].In all cases, the tablet properties were evaluated after 24 h of production.

Properties of Compressed Tablets.
To determine thicknesses, 10 tablets were taken and their thicknesses were measured using a sliding caliper scale (Nippon, Sokutei, Japan).Te tablet bulk density was determined from the weight, thickness, and diameter data according to the methods described elsewhere [18].To measure the tabletbreaking force (TBF), 10 tablets from each batch were taken and the average of force readings using a tablet hardness tester (CALEVA, G.B., Caleva Ltd., UK) was reported.Te tensile strength was calculated from the TBF, thickness, and diameter data according to the following equation [14,18]: where TS, TBF, D, and T stand for tensile strength, the breaking strength, diameter, and thickness of tablets, respectively.
In order to evaluate the friability of compressed tablets, 20 tablets of each batch were placed into the friability tester.Te friability tester was rotated for 4 min at 25 rpm, letting 2 Advances in Pharmacological and Pharmaceutical Sciences the tablets fall a distance of 6 inches.Ten, the tablets were taken out and dusted, and the percent weight loss was calculated.Te disintegration and dissolution tests were performed according to the methods described in USP-NF [19] on a disintegration tester (ERWEKA ZT504, Germany) and the type II apparatus (ERWEKA, DT600, Germany), respectively.Phosphate bufer (pH 5.8) of 900 ml medium at 37 ± 0.5 °C with a stirring rate of 50 rpm was used.Five ml of aliquots was removed with blank replacement at 5, 10, 15, 20, 30, 45, and 60 min and fltered using Whatman number 1 flter paper.One ml of the fltered samples was diluted to 25 ml, and absorbance readings were taken with a spectrofuorometer CM 2203 (Solar, Belarus, Russia) at 243 nm.Phosphate bufer (pH 5.8) was used as a blank.Te necessary corrections for dilution were made when calculating drug dissolution.

ATR-IR Spectroscopy.
Te attenuated total refectance (ATR)-IR spectra of pure paracetamol, PGTBIS, and paracetamol-PGTBIS physical mixture (1 : 1) were obtained with an infrared spectrophotometer (Tensor II FTIR Spectrometer, Bruker Optics, USA) in the ATR mode.For each run, 16 scans were performed in the range of a wave number of 4000-500 cm −1 at a resolution of 4 cm −1 .For data presentation, Origin version 7 (Origin LabTM Corporation, USA) was applied.

Statistical Analysis.
All the results of direct measurements were presented as the arithmetic mean ± standard deviation (π ± σ).Te target limit of the signifcance of statistical data was 95% CI.

Results
3.1.Amylose to Amylopectin Ratio.After the preparation of PGTBIS, its amylose and amylopectin contents were determined comparatively with that of NTBIS and Starch 1500 ® (Table 2).3.

ATR-IR Analysis.
To study the compatibility of the starch with paracetamol, functional groups that defne paracetamol were assessed using the attenuated total refectance (ATR) spectra of PGTBIS, 1 : 1 ratio mixture of paracetamol and PGTBIS, and pure paracetamol (Figure 4).

Lubricant Sensitivity.
Te TBF, friability, and radial tensile strength values of tablets of pure PGTBIS and lubricated at diferent concentrations of Mg stearate (0-2.00%w/w) were investigated (Table 3).

Dilution Potential.
Te dilution potential of PGTBIS was tested in paracetamol tablets compressed at a force of 17 kN with variable concentrations of the drug at 20, 30, 40, and 50% w/w.Te weight variation, TBF, TS, friability, and disintegration time were determined.Tablets of the same formulation and processes were repeated substituting PGTBIS with Starch 1500 ® as comparators (Table 4).
Similarly, the dissolution profles of the tablets were formulated as described in Figure 5.

Discussion
As the results show, PGTBIS had a signifcantly lower amount of amylose than Starch 1500 ® .Moreover, the process of pre/gelatinization did not have any signifcant efect on the amylose to amylopectin ratio of NTBIS.Te reason is that pregelatinization is a physical modifcation and that a physical modifcation does not change the amylose to amylopectin ratio as described in the literature [20].
Te swelling power of the three starches followed the order: PGTBIS > Starch 1500 ® > NTBIS at 20, 37, 50, and 65 °C (Figure 1(a)).A possible explanation for the increase in the swelling power of PGTBIS than NTBIS is that the thermal disruption of crystalline phases sets starch molecules free to absorb more water molecules than amorphous  Advances in Pharmacological and Pharmaceutical Sciences intercluster lamellae [21].However, beyond the cutof temperature of the onset of pregelatinization, i.e., after 68.40 °C [10], both PGTBIS and NTBIS had comparable swelling power.Te graph (Figure 1(b)) indicates that pregelatinization also increased the solubility index of the starch probably due to amylose leaching [22].Te similar fndings were reported elsewhere, for example, rice and corn starches [23].At 75 and 85 °C, NTBIS and PGTBIS were observed to have comparable swelling power and solubility index.In comparison with PGTBIS and NTBIS, the swelling power of Starch 1500 ® was, respectively, lower and higher at and below 65 °C.
As it is clear from the fgure, the pregelatinized starch particles had slightly smoother polygonal shapes than native granules.Te morphological change might be because of partial pregelatinization that had taken place which resulted in more aggregated granules, having less physical integrity compared to NTBIS.More spherical shape, aggregation, and loss of physical integrity make changes similar to that of heat moisture-treated low amylose rice starches reported elsewhere [24,25].
Te moisture sorption profle of PGTBIS was higher than the corresponding values of Starch 1500 ® at RH values of 65.4% and beyond (p < 0.05).At the RH values of 75.4% and higher, the moisture sorption of PGTBIS was higher than that of NTBIS.Te likely reason for the increased moisture sorption of PGTBIS compared to that of NTBIS was the decrement of crystal phases due to hydrothermal disruption accompanied by pregelatinization [20], and it is expected for pregelatinized starches [27].
Te ATR of pure PGTBIS, pure paracetamol, and PGTBIS with paracetamol in a 1 : 1 ratio (w/w) is presented in Figure 4. To ensure drug excipient compatibility, the absorbance peaks in the fngerprint region and other   Advances in Pharmacological and Pharmaceutical Sciences characteristic vibrations of paracetamol including -NH-, -OH-CO, -CH 3 , benzene ring, and phenyl-OH were considered.Te peaks in the fnger print region (2000-400 cm −1 ) of the mixture were coinciding with those of pure paracetamol.Te sharp absorption band at 3321.29 cm −1 and 1650.70 cm −1 were corresponding to the symmetric stretching and out-of-plane (OOP) bending bands of -NH-bonds, respectively.Similarly, the strong peaks at 3164.36 cm −1 and 3108.69 cm −1 represent CO-H stretching vibration bands.Te presence of a strong band in the range 3162-3035 belongs to the stretching vibration of CH 3 .Te presence of aromatic rings was evidenced because there are the doublets (1562.20 cm −1 and 1505.14 cm −1 ), possible weak overtone, and combination bands between 2000 cm −1 and 1700 cm −1 .Te broad background absorption around 3350.00-3108.69cm −1 (OH-stretches) with the consideration of the fnger print region the phenolic -OH group.Te presence of the acetyl group was supported as there were strong bands at 2930.38 cm −1 , 2887.58 cm −1 , and 1369.60 cm −1 of the methyl C-H bonds.It was reinforced considering the presence of the strong protruding band at 1650.66 cm −1 , suggesting CO stretching vibration.Te presence of the peaks at 1256.90 cm −1 and 1224.10 cm −1 is common to C-O/C-N stretching vibrations [28,29].Te presence of the vibrational absorbance bands which possibly qualify the structural groups of paracetamol implies that the chemical interaction of paracetamol with PGTBIS is unlikely [30].
Te weight variation of all the tablets was quite acceptable which is below 7.5% [31].Te TBF and friability in all cases decreased and increased with the increasing concentration of the lubricant, respectively (p < 0.05).Tis is likely due to increasing bond inhibition [17].Te TBF of PGTBIS tablets without magnesium stearate, with 0.25% magnesium stearate, and with 0.5% magnesium stearate was 136.3 ± 5.1 N, 92.4 ± 4.2 N, and 75.9 ± 5.2 N, respectively.Tis showed the corresponding harder tablets of PGTBIS than those of Starch 1500 ® for which the TBF was 86.1 ± 4.0, 63.0 ± 2.6, and 56.8 ± 2.6, respectively.Tensile strengths of the tablets of PGTBIS and Starch 1500 ® revealed the same implications.Te tensile strengths of all the tablets decreased with the addition of the magnesium stearate lubricant and increase in its concentration.Te literature suggests that the optimum tensile strengths for tablets range from 0.56 to 1.12 [32].Te tensile strengths of PGTBIS exceeded this limit at and below 0.5% of the magnesium stearate concentration.Tis was taken as a room for the excipient to perform better when mixed with drugs of poor tabletability.In other words, it suggests that PGTBIS can be taken as a direct compression binder [33].In all cases, whether with or without the lubricant, the tensile strengths of tablets of PGTBIS showed higher tensile strength values than those of Starch 1500 ® .LSR was also observed to increase with the increase in the lubricant concentration.However, for some unknown reason, the lubricant sensitivity ratio of PGTBIS was higher than that of Starch 1500 ® .Similarly, the percent friability values of the corresponding tablets of PGTBIS were 0.27 ± 0.01%, 0.39 ± 0.01%, and 0.56 ± 0.01%, whereas those of Starch 1500 ® were 0.52 ± 0.01%, 0.71 ± 0.01%, and 1.05 ± 0.01%, respectively, which again supported that the tablets of PGTBIS were more attrition resistant than those of Starch 1500 ® tablets prepared under the same conditions of the formulation and process factors.Te increase in the  6 Advances in Pharmacological and Pharmaceutical Sciences concentration of MgS was shown to continuously increase the DT in all cases.Tis is expected due to impaired wetting by hydrophobic flm formation around the particles [34].All the tablets of both of the starches disintegrated within an acceptable time for tablets [35].
Te weight variation of all the tablets was quite acceptable which was below 7.5% [31].Te TBF of the tablets prepared with PGTBIS was maintained in the acceptable range up to 30% of paracetamol, whereas the same tablets prepared with Starch 1500 ® were acceptable only up to 20% of the paracetamol concentration.Te tensile strength of paracetamol tablets prepared with PGTBIS was observed to be >1 MPa which is an ideal target according to the established evidence [36].According to another claim in the literature, the optimum range is within 0.56-1.12MPa [14,32,37], and this is met when 40% of paracetamol is incorporated into PGTBIS.Up to 30% (w/w) dilution of PGTBIS with paracetamol, the tablets retained the quality requirements, experiencing higher dilution potential than Starch 1500 ® , 20% (w/w).Beyond these respective con- centrations, the poor compressibility and elastic recovery of paracetamol exhibited dominance and resulted in higher friability values.Te disintegration time of the tablets of paracetamol was shown to increase with the increasing concentration of the drug in the cases of both the PGTBIS and Starch 1500 ® .
Te weight uniformity of PGTBIS-containing paracetamol tablets satisfes compendial requirements, i.e., within ±5% of the mean.Te TBF of paracetamol tablets was shown to reasonably increase with the increasing proportion of the starches.Te tablets of the PGTBIS paracetamol tablets were acceptably hard (TS � 1.19 MPa), up to 30% of the drug.In contrast, Starch 1500 ® equivalent was hard and attrition resistant enough up to only 20% (w/w).At all the paracetamol levels, the tablets of PGTBIS had higher mechanical strength (TS) than those of Starch 1500 ® .Te paracetamol tablets of both PGTBIS and Starch 1500 ® be- yond the respective paracetamol concentration of 30% and 20% (w/w) had low tensile strength, higher friability (>1%), or capping and lamination [38].Te DTs of paracetamol tablets in the study decreased with the increasing concentration of the drug.At all levels of the drug, PGTBIScontaining tablets disintegrated faster than that of Starch 1500 ® .Moreover, the tablets of PGTBIS fulflled the re- quirements of fast-dissolving tablets (<3 minutes).By any means, the tablets had acceptable DT (<15 min), at all levels of the drug cargo for both types of starches.
According to the compendial requirements, the dissolution profle of paracetamol tablets is tested at a pH of 5.8.
[19].In view of that, the dissolution profles of tablets prepared using paracetamol contents of 20, 30, and 40% (w/ w) of with PGTBIS and 20 and 30% (w/w) with starch 1500 ® were such that all the tablets released more than 90% within 30 min.For the frst 20 min, the dissolution was faster with increasing concentration of the drug for both of the starches.At and beyond 30 min, the dissolution rate was comparable for all the tablets of both of the starches, in all of the cases, perhaps because disintegration of the majority of the tablets and the subsequent dissolution that took place.

Conclusion
Te fndings of the present study showed that PGTBIS has comparable fow properties with standard Starch 1500 ® .As far as ATR spectroscopy is concerned, the pregelatinized starch did not chemically interact with paracetamol when mixed for tablet preparation.When mixed with equal respective amounts of the magnesium stearate lubricant and the paracetamol drug cargo, PGTBIS performs better than Starch 1500 ® .It was shown to accommodate higher drug cargo (30%) than Starch 1500 ® (20%) with better perfor- mance.In terms of both the lubricant sensitivity and the dilution potential, it shows higher tablet-breaking strengths and lower percent friability values.Accordingly, the PGTBIS starch could be taken as a potential direct compression excipient calling for further investigations towards its application including the brittle fracture index, Young's modulus, toughness, and stability studies both in paracetamol and other drugs.

Figure
Figure Te dissolution profles of the directly compressed paracetamol tablets prepared at diferent concentrations of PGTBIS and Starch 1500 ® with paracetamol.

Table 1 :
Tablet formulation for the dilution potential study.Te formulations in the table were used in triplicates corresponding to both of the binding starches PGTBIS and Starch 1500 ® . *

Table 2 :
Amylose and amylopectin contents of the starches.

Table 4 :
Properties of tablets compressed at 17 kN of various paracetamol concentrations.TS and DT stand for tensile strength and disintegration time, respectively. *