Psyllium (Plantago Ovata Forsk) Husk Powder as a Natural Superdisintegrant for Orodispersible Formulations: A Study on Meloxicam Tablets

(1) Background: In this work, we investigated the application of a natural superdisintegrant, psyllium (Plantago ovata Forsk) husk powder, for the manufacture of orodispersible meloxicam tablets. Meloxicam was chosen as a model compound for the study. (2) Methods: The tablets were prepared using different concentrations of psyllium husk by direct compression. Bulk density, tapped density, hardness, friability, in vitro disintegration, and dissolution time tests were used to assess the quality of the formulations. (3) Results: Psyllium husk powder significantly increased the dissolution rate of meloxicam. The formulation containing 16 mg of psyllium husk powder showed the lowest wetting time, the highest water absorption ratio, and the lowest disintegration time compared to the control and to the other formulations. These effects may be attributed to the rapid uptake of water due to the vigorous swelling ability of psyllium husk powder. (4) Conclusions: The powder could be recommended as an effective natural superdisintegrant for orodispersible formulations.


Introduction
Plantago ovata belongs to the family of Plantaginaceae [1]. The seeds and psyllium husk of this plant are valuable sources of fibers and mucilage. Psyllium husk is used in the pharmaceutical industry as a laxative [1], to lower the glycemic index [2,3], and for the development of controlled-release formulations [4,5]. Due to quick water absorption, the weight of psyllium husk increases up to 10 times [6]. Hydrocolloids make up 10-30% of psyllium husk; these are water soluble polysaccharides that form mucilage layers when exposed to water. During hydrolysis, mucilage splits and polysaccharides, including xylose, arabinose, galacturonic acid, rhamnose, and galactose, are obtained [7][8][9]. These compounds are responsible for the disintegrative properties of psyllium husk and could be applied as natural disintegrants in drug manufacturing [1,6,10].
Tablet disintegration rate has a big impact on the characteristics of release of the active substance from the drug formulation. This rate depends on the properties of the disintegrants present in the tablet which are responsible for disintegration enhancement. Disintegrants are the substances or substance mixtures that facilitate decomposition and disintegration of a tablet or other drug formulations into smaller particles [11,12]. Thus, disintegrants are used to ensure that tablets split into smaller fragments was capable of ensuring excellent flowability and compressibility [27,28]; it also demonstrated a pleasant taste, therefore, it was chosen as a diluent along with mannitol. Mannitol has a negative heat of solution, which is responsible for a pleasant cooling sensation in the mouth. It also provides multidimensional benefits, such as good aqueous solubility and good wetting properties [29,30], that facilitate tablet breakdown. Psyllium (Plantago ovata Forsk) husk powder (Figure 1) was added as a natural superdisintegrant.
Molecules 2019, 24, x FOR PEER REVIEW 3 of 12 3 Orodispersible meloxicam tablets were prepared by the direct compression method, which was the most simple and cost-effective technique [11,12]. Sorbitol, a highly compressible saccharide, was capable of ensuring excellent flowability and compressibility [27,28]; it also demonstrated a pleasant taste, therefore, it was chosen as a diluent along with mannitol. Mannitol has a negative heat of solution, which is responsible for a pleasant cooling sensation in the mouth. It also provides multidimensional benefits, such as good aqueous solubility and good wetting properties [29,30], that facilitate tablet breakdown. Psyllium (Plantago ovata Forsk) husk powder (Figure 1) was added as a natural superdisintegrant. In our study, four formulation batches (M1-M4) with different psyllium husk powder amounts and one control batch (M5) without superdisintegrant addition were prepared (Table 1).

Pre-Compression Parameters of the Prepared Formulations
Pre-compression parameters of all prepared formulation batches were evaluated in the next series of experiments (Figure 2a  In our study, four formulation batches (M1-M4) with different psyllium husk powder amounts and one control batch (M5) without superdisintegrant addition were prepared (Table 1).

Pre-Compression Parameters of the Prepared Formulations
Pre-compression parameters of all prepared formulation batches were evaluated in the next series of experiments (Figure 2a-e).
There was no significant difference in bulk density between the control and formulation batches (M1-M4) (Figure 2a), however, due to increasing particle size with higher amounts of psyllium husk in M3 and M4 batches, we noticed a slight, but statistically significant, decrease in tapped density ( Figure 2b Data are presented as the mean ± SD, n = 5. The results were analyzed with one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test. The batches were compared to the control and to each other. p < 0.05 showed a statistically significant difference: * compared to control (M5), ** compared to M1, # compared to M2, ## compared to M3, ^ compared to M4.
There was no significant difference in bulk density between the control and formulation batches (M1-M4) (Figure 2a), however, due to increasing particle size with higher amounts of psyllium husk in M3 and M4 batches, we noticed a slight, but statistically significant, decrease in tapped density  Hausner's ratio of the prepared powder blends. Data are presented as the mean ± SD, n = 5. The results were analyzed with one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test. The batches were compared to the control and to each other. p < 0.05 showed a statistically significant difference: * compared to control (M5), ** compared to M1, # compared to M2, ## compared to M3,ˆcompared to M4.

Post-Compression Parameters of the Prepared Formulations
After the powder blends were compressed into tablets, the post-compression parameters of all of the prepared formulations were evaluated (Figure 3a-g). Data are presented as the mean ± SD, n = 5. The results were analyzed with one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test. The batches were compared to the control and to each other. p < 0.05 showed a statistically significant difference: * compared to control (M5), ** compared to M1, # compared to M2, ## compared to M3, ^ compared to M4 batch. The results were analyzed with one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test. The batches were compared to the control and to each other. p < 0.05 showed a statistically significant difference: * compared to control (M5), ** compared to M1, # compared to M2, ## compared to M3,ˆcompared to M4 batch.
All tablets from each formulation passed a weight variation test (Figure 3a) as the percentage of weight variation was within the limits (± 7.5%) defined in the requirements of European Pharmacopoeia (Ph. Eur. 01/2016:20905). All tablets were of uniform appearance and the thickness varied from 3.8 to 3.84 mm. The drug content was found to be in the range of 97.7% to 99.5% (Figure 3b), which was within the acceptable limits (85-115%) described by European Pharmacopoeia (Ph. Eur. 01/2016:20906).
General problems encountered by rapidly disintegrating tablets are related to low physical resistance, low drug loading, and high friability [11,13,24]. A hardness test was used to determine the hardness of all tablet formulations. The hardness of the tablets was found to be in the range of 4.8-5.7 kg/cm2 (Figure 3c). A friability of less than 1% is required by European Pharmacopoeia (Ph. Eur. 01/2016:20907). In our study, the friability of all formulations was between 0.33-0.46% (Figure 3d), indicating that tablets had good mechanical resistance. Swamy et al. reported the hardness and friability of the optimized orodispersible meloxicam (7.5 mg) formulation with synthetic disintegrants (2% w/w sodium starch glycolate and 1.5% w/w croscarmellose sodium) to be 3.5 kg/cm 2 and 0.69% [33]; thus, the psyllium husk was responsible for the slightly better physical resistance of the tablets compared to synthetic disintegrants.
The water absorption ratio and wetting time are important criteria in the understanding of the capacity of the disintegrants to swell in the presence of a small amount of water. The wetting time for all formulations was within the range of 59.67-123.33 s (Figure 3e). The formulation containing 16 mg of psyllium husk powder showed the lowest wetting time (59.67 s, Figure 3e) and the highest water absorption ratio (97.33%, Figure 3g) compared to other formulations containing psyllium husk powder. In a study conducted by Swamy et al., the wetting time of the optimized orodispersible meloxicam (7.5 mg) formulation with synthetic disintegrants (2% w/w sodium starch glycolate and 1.5% w/w croscarmellose sodium) were 5 s and 76.4%, respectively [33]. This wetting time, which was 10 times lower compared to our results, could be related to the different composition of the orodispersible tablets, i.e., microcrystalline cellulose in the study by Swamy et al. and mannitol in our study. However, the water absorption ratio was much higher using psyllium husk as a superdisintegrant compared to the synthetic compounds. A wetting time of 12-50 s was also reported in the investigation conducted by Pawar and Varkhade [26], but this cannot be directly compared to our work as another model compound, valsartan, with different solubility characteristics than meloxicam, was used in their study.
The in vitro disintegration time for all formulations varied from 119 s to 185 s (Figure 3f). The M4 formulation, which contained 16 mg of psyllium husk powder, showed the lowest disintegration time (119 s). The disintegration time of commercially available orodispersible meloxicam, Mobic TM tablets (7.5 mg), which contain povidone as a disintegrant, was reported to be 210 ± 16.92 s [24]. Thus, psyllium husk could improve the disintegration time of orodispersible meloxicam formulations.

In Vitro Dissolution Studies
All formulations of the orodispersible meloxicam tablets were subjected to in vitro dissolution studies in phosphate buffer (pH 6.8) mimicking saliva pH to evaluate the superdisintegrating effect of the psyllium husk powder (Figure 4).
The release of meloxicam directly depended on the amount of psyllium husk powder in the prepared tablets (Figure 4). The highest meloxicam release (95.36% after 10 min) was obtained from the M4 batch tablets, which contained 16 mg of psyllium husk powder. Our results showed the lowest meloxicam release (76.68% after 10 min) from the M1 batch tablets, which contained 11.5 mg of psyllium husk powder. More than 75% of meloxicam was released after 10 min from all tablets containing psyllium husk powder (M1-M4), whereas only 58.5% of meloxicam was released from the control tablets (Figure 4). A faster dissolution rate in the presence of psyllium husk polysaccharide was also observed in the study of valsartan orodispersible formulations [26], and psyllium husk in the investigation of famotidine tablets [34]. However, the meloxicam release from Mobic TM tablets (7.5 mg) with povidone as a disintegrant was reported to be 65% after 10 min, which showed a dissolution efficiency of 79.1 ± 3.24% [24]. The release of meloxicam from the optimized orodispersible meloxicam (7.5 mg) formulation with synthetic disintegrants (2% w/w sodium starch glycolate and 1.5% w/w croscarmellose sodium) in the study by Swamy

In Vitro Dissolution Studies
All formulations of the orodispersible meloxicam tablets were subjected to in vitro dissolution studies in phosphate buffer (pH 6.8) mimicking saliva pH to evaluate the superdisintegrating effect of the psyllium husk powder (Figure 4). The release of meloxicam directly depended on the amount of psyllium husk powder in the prepared tablets ( Figure 4). The highest meloxicam release (95.36% after 10 min) was obtained from the M4 batch tablets, which contained 16 mg of psyllium husk powder. Our results showed the lowest meloxicam release (76.68% after 10 min) from the M1 batch tablets, which contained 11.5 mg of psyllium husk powder. More than 75% of meloxicam was released after 10 min from all tablets containing psyllium husk powder (M1-M4), whereas only 58.5% of meloxicam was released from the control tablets ( Figure 4). A faster dissolution rate in the presence of psyllium husk polysaccharide was also observed in the study of valsartan orodispersible formulations [26], and psyllium husk in the investigation of famotidine tablets [34]. However, the meloxicam release from Mobic TM tablets (7.5 mg) with povidone as a disintegrant was reported to be 65% after 10 min, which showed a dissolution efficiency of 79.1 ± 3.24% [24]. The release of meloxicam from the optimized orodispersible meloxicam (7.5 mg) formulation with synthetic disintegrants (2% w/w sodium starch glycolate and 1.5% w/w croscarmellose sodium) in the study by Swamy et al. was 34.17% [33]. Thus, our results suggest that the demonstrated faster dissolution effect could be due to the disintegration properties of psyllium husk powder.

Stability Studies
The optimized formulations (M3 and M4) were subjected to stability studies according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for six months. The tablets were stored as bulk material. Tablets were evaluated The results were analyzed with one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test. M1-M4 batches significantly differed (p < 0.05) compared to the control (M5) and between themselves.

Stability Studies
The optimized formulations (M3 and M4) were subjected to stability studies according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for six months. The tablets were stored as bulk material. Tablets were evaluated for physical appearance, friability, drug content (%), and disintegration time ( Table 2). The tablets did not show any significant change during storage. Furthermore, in vitro dissolution tests were repeated after storage and no significant difference was obtained compared to the results before storage. Thus, it was concluded that the optimized tablets had good stability during their shelf life.

Conclusions
The dissolution rate of meloxicam was significantly enhanced in the orodispersible tablets prepared with psyllium (Plantago ovata Forsk) husk powder as a superdisintegrant. The formulation containing 16 mg of psyllium husk powder showed the lowest wetting time, the highest water absorption ratio, and the lowest disintegration time compared to control and to the other formulations containing psyllium husk powder. These effects may be attributed to the rapid uptake of water due to the vigorous swelling ability of psyllium husk powder. The gradual increase in friability by 0.1% in the tablets with the most psyllium husk powder was noted, however, this was much lower than the threshold (<1%) required by European Pharmacopoeia (Ph. Eur. 01/2016:20907). Therefore, psyllium husk powder could be recommended as an effective natural superdisintegrant for orodispersible formulations.

Preparation of Psyllium (Plantago Ovata Forsk) Husk Powder
The dried Plantago ovata seed husk was powdered by Retsch™ ZM 200 Model Ultra-Centrifugal Mill (Fisher Scientific UK Ltd., Loughborough, UK) with the Retsch FV 2703 rotor for 5 min. The 0.5 mm sieve set was used to separate the powder. The sieved powder was collected and checked for absence of foreign particles. This was preserved in an air-tight, dry container for further use.

Pre-Compression Parameters of Powder Blend
The flow properties of the powder are vital for the performance of the tablet. Hence, the flow properties of the powder were analyzed before compression into tablet form.
Bulk and tapped volumes (V 0 and V tapped ) were measured by the method from European Pharmacopoeia (Ph. Eur., USP) using a density tester (SVM 102, Erweka, Germany). The determined values were then used for the calculation of Hausner's ratio and Carr's index: The angle of repose was determined using the funnel method. The blend was poured through a funnel (105 mm in diameter, 190 mm high, with a stem 105 mm long, and an internal diameter of 5 mm) that could be raised vertically until a maximum cone height (h) was obtained. The radius of the heap (r) was measured and the angle of repose (θ) was calculated:

Formulation of Orodispersible Tablets by Direct Compression Method
Orally disintegrating tablets were prepared using the direct compression method. All ingredients were passed through mesh No. 60 separately, then, the ingredients were weighed and mixed in geometrical order and compressed into tablets of 200 mg using 9 mm round flat punches on a manual hydraulic press (Specac Limited, Kent, UK). The mixing time was 10 min and the amplitude was 40 mm. A batch of 100 tablets was prepared for each of the designed formulations.

Post-Compression Parameters of Orally Disintegrating Tablets
All tablets were evaluated for different parameters, including appearance, weight variation, hardness, thickness, friability, wetting time, water absorption ratio, and disintegration time.
Weight variation tests were performed by weighing 20 tablets individually, calculating the average weight, and comparing the individual tablet weight to the average weight.
For drug content assay, 10 tablets were weighed and carefully grinded to receive a homogenous powder. The powder was dispersed in 10 mL of methanol solution in a volumetric flask and kept for 15 min in an ultrasound bath (Memmert WNB7 waterbath, Memmert GmbH & Co. KG, Schwabach, Germany). The solution was passed through a 0.22 µm membrane filter for UPLC analysis. Determination of the meloxicam content was carried out using the Waters Acquity UPLC chromatography system (Waters, Milford, MA, USA), which was equipped with a photodiode array detector (Waters 996 UPLC) at a wavelength of 350 nm.
The tablet friability test was performed using the SOTAX FT2 tablet friability tester (Sotax GmbH, Lörrach, Germany). A total of 20 tablets were weighed with an accuracy of 0.001 g and transferred to the tester. The internal diameter of the drum was 200 mm, the rotation speed was 25 ± 1 rpm, and the testing time was 5 min. At each turn of the drum, the tablets rolled or slid and fell onto the drum wall or onto each other. After the test, the tablets were removed and accurately weighed. Tablet friability (D) was calculated according to the formula: where D is friability (%), m 1 is the initial tablet weight (g), and m 2 is the tablet weight after the friability test (g). Tablet hardness was determined using the manual tablet hardness tester SOTAX HT1 (Sotax GmbH, Lörrach, Germany).
For a wetting time assay, a tablet was transferred onto a piece of tissue paper of 10 cm diameter, which was placed in a Petri dish with a 10 cm diameter containing 10 mL of water. The time required for water to reach the upper surface of the tablet was been noted as the wetting time.
The water absorption test was performed using the same procedure as that of the wetting time. A tablet was weighed and then transferred onto a piece of tissue paper of 10 cm diameter, which was placed in a Petri dish with a 10 cm diameter containing 10 mL of water. The tablet was weighed again after the water reached the upper surface of the tablet. The water absorption ratio (R) was calculated according to the formula: where V a is the tablet weight before water absorption and V b is the tablet weight after water absorption. To assess the tablet disintegration time, 6 tablets were placed in 900 mL of distilled water in the basket rack of the SOTAX DT-2 disintegration tester (Sotax GmbH, Lörrach, Germany). One tablet was placed in each of the six tubes of the basket and the assembly was raised and lowered at a rate of 30 cycles per minute in the water at 37 ± 0.5 • C.

In Vitro Release Studies
Dissolution profiles of meloxicam in designed formulations of orodispersible tablets were determined using the SOTAX AT7 smart model semi-automated paddle type dissolution tester (Sotax GmbH, Lörrach, Germany). The basket method was applied using phosphate buffer (50 rpm, 700 mL). The pH value was maintained at 6.8 (37 ± 0.5 • C). Aliquots (5 mL) were manually extracted from parallel dissolution vessels at 2, 4, 6, 8, and 10 min time points, filtered through a membrane filter (0.22 µm), and quantified via UPLC with a photodiode array detector (Waters 996 UPLC) at a wavelength of 350 nm. The dissolution media in each vessel was topped off with fresh phosphate buffer (5 mL) to restore the original volume. The mean value of six trial runs and the standard deviation were calculated.

Stability Studies
Accelerated stability testing studies were performed for 6 months according to ICH guidelines at a temperature of 40 ± 2 • C and a relative humidity of 75 ± 5% in a CLIMACELL stability chamber (MMM Medcenter Einrichtungen GmbH, Planegg/München, Germany). The tablets were stored as bulk material. The samples were withdrawn after 0, 3, and 6 months of storage. Physical appearance assessment, tablet friability, drug content (%), and disintegration time tests were performed to evaluate the influence of storage on the stability of the tablets.

Statistical Analysis
Data are presented as the mean ± SD. Statistical analysis was performed by one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test with the software package Prism v. 5.04 (GraphPad Software Inc., La Jolla, CA, USA). A value of p < 0.05 was used as the level of statistical significance.