Evaluation and Characterization of Sildenafil 50 mg Orodispersible Tablets Using Sublimation Technique

Objective: The aim of this work focused on formulation and evaluation of sildenafil 50 mg orodispersible tablets by sublimation technique. Methods: Active ingredient and excipients mixtures were evaluated for physicochemical changes of the drug utilizing FTIR spectroscopy and DSC thermal analysis. Nineteen proposed formulae N1-N19 were prepared by sublimation technique using menthol as a sublimating agent. Three different types of superdisintegrants (sodium starch glycolate, croscarmellose sodium and plasidone XL) were used in three different ratios (3, 6 and 9 % w/w), percentage of inter-granular and intragranular disintegrant. Hydrophilic filler such as mannitol and hydrophobic filler such as microcrystalline cellulose were used in the ratio (1:1, 2:1 and 4:1 w/w).Elimination of bitterness using sucralose as a potent sweetener. Granulation was achieved by alcoholic solution of PVP K25 as binder at Diosna® high shear mixer. Lubricant (hydrophobic magnesium stearate and hydrophilic sodium stearyl fumarate). Un-lubricated granules were characterized for bulk density, tapped density, true density, particle size distribution, Carr'sindex, Hausner ratio, flow rate and angle of repose. Tablets were firstly compressed on rotary machine then subjected to vacuum oven at 60 C for 6 hours. Post compression characterization for tablets after sublimation including content uniformity, average weight, hardness, thickness, In-vitro disintegration, friability, wetting time, assay and dissolution profile of the proposed formulae against the immediate release marketed tablet Viagra ® 50 mg tablet. Results: The formula (N 16) which granulated using 1% PVP k25 with 9% plasidone XL (60% of it is inter-granular while 30% intra-granular), menthol 1%, Microcrystalline cellulose: Mannitol 1:1 and magnesium stearate was the most effective formulation as it showed wetting time of 30.7 seconds, disintegration time of 25 seconds and cumulative % drug release of 92.8 and 95.8 % after 1 and 3 minute respectively. Conclusion: Sildenafil 50 mg ODT successfully was prepared by sublimation technique with better wetting time, disintegration time, assay dissolution profile, hardness and friability.


INTRODUCTION
The oral route of administration is the most preferred route due to its many advantages like ease of administration, accurate dosage, self-medication, pain avoidance, versatility and patient compliance 1 .US FDA defined fast dissolving or disintegrating tablets (FDT) as "A solid dosage form containing medicinal substances which disintegrates rapidly within a matter of seconds, when placed upon the tongue".Fast disintegrating tablets are also known as fast dissolving, mouth dissolving, rapid dissolving, quick dissolving, orally disintegrating, rapid melt, orodispersible, porous tablets 2 .The most evident drawback of the commonly used oral dosage forms like tablets and capsules is difficulty in swallowing, leading to patient's incompliance particularly in case of geriatric patients.Dysphagia is commonly found among all age groups.Due to this problem, approximately 50% of population suffers.The difficulty in swallowing may be due to the taste, size and surface of dosage form.During journey, sometimes water is not easily accessible so a patient feels difficulty in swallowing solid dosage form 3 .
The presence of a highly porous surface in the tablet matrix is the key factor for rapid disintegration ofODT 4 .Improving the porosity, volatile substances such as sublimating agents can be used in tableting process for improving porosity 5,6 .
The basic approach used in development of FDTs is the use of superdisintegrants and the elimination of bitterness.These techniques are based on the principles of increasing porosity and/or addition of superdisintegrants and water soluble excipients in the tablets.Superdisintegrants can help to facilitate drug dissolution and subsequently improve bioavailability.In sublimation method, the rapid disintegration of the tablets is achieved by creation of pores in the tablets up on sublimation of volatile components added in the tablets 7 .The saliva will enter these pores and cause the rapid disintegration of the tablets in the oral cavity.The porous structure is responsible for the faster water uptake; hence it facilitates wicking action in bringing about fasterdisintegration 8 .
Orally disintegrating tablets have better patient acceptance and compliance and may offer improved biopharmaceutical properties, efficacy and increased bioavailability compared with conventional oral dosage forms 9 .
Because of low porosity, compressed tablets containing highly water-soluble excipients as tablet matrix material often do not dissolve rapidly in water.Some inert volatile substances like urea, urethane, ammonium carbonate, naphthalene and camphor are added to other tablet excipients and the blend is compressed into tablet.Removal of volatile substances by sublimation generates a porous structure.Additionally, several solvents like cyclohexane and benzene can be used as pore forming agents 10 .Some researchers mentioned that the prepared tablets were subjected to vacuum at 80 ºC for 30 minutes to eliminate camphor and thus create pores in the tablet.Porous tablet exhibits good mechanical strength and dissolve quickly 10,11 .The low porosity of compressed tablets may reduce water penetration into the tablet matrix resulting in slow disintegration or dissolution because these processes only occur at the surface.However, when volatile solids are compressed into tablets using a conventional method, they can be removed by sublimation to produce highly porous structures 12 .
Various scientific techniques including freeze drying, molding, spray drying, sublimation, direct compression, cotton candy process, mass extrusion, melt granulation can be used in ODTs manufacture 13 .

Pre-formulation study by estimation of possible interaction between sildenafil citrate and some proposed excipients using spectroscopy DSC and by IR Differential Scanning Calorimetry (DSC)
DSC is the measurement of the energy change that occurs as a sample is heated at a constant rate [14][15] .The principal process involves the heating of two ovens to the same temperature at the same rate.One heater contains the sample in a sealed pan and the other containing an empty pan serving as the reference 14,16 .Approximately (3-7 mg) samples of pure drug sildenafil citrate and binary mixtures of sildenafil citrate and the proposed excipients such as (Mannitol, microcrystalline cellulose, PVP k25, Croscarmelose sodium, sodium starchglycolate, crospovidone, sucralose, pineapple powder, Aerosil 200,menthol,magnesium stearate and sodium stearyl fumarate).DSC thermograms of sildenafil citrate and each of the excipients were compared with their corresponding physical mixtures.The blending ratio was determined based on the common drug excipient ratio of (1:1 in case of filler, binder and subliming agent, 1:0.5 ratio in case of disintegrant and 4:1 ratio is used for drug /lubricant and glidant.The 1:1 w/w ratio was chosen because it maximizes the observation of any reaction.DSC thermograms were generated at temperatures between 30 and 400ºC using a Model (DSC 4000, PerkinElmer, Waltham, MA, USA) with equipment and PC control unit at a heating rate of 10ºC/min and a nitrogen atmosphere.Data analysis was undertaken using Pyris™ Manager Software 14 .

Fourier transform infrared (FTIR) spectroscopy
FTIR spectra were captured for binary blends in closed vials which kept under stress conditions (14 days at 50º C) and mixed with Potassium bromide.Data were used to confirm the results of DSC.The FTIR spectra were obtained on FTIR spectrometer (Nicolet iS10, Thermo Scientific, USA) over the range 400 -4000 cm-1 14 .

Preparation of ODT by sublimation Method
Tablets were prepared according to Table 1 by wet granulation technique using (PVP k25/Ethanol absolute).Dry blend sildenafil citrate, Avicel 101 (MCC), mannitol and specific ratio of inter granular disintegrant.Granulation process was preceded using high shear mixer (DIOSNA, Germany).The granulation process was standardized on basis of preliminary trials occurs on three steps:(a) Pre-blind (b) Binder addition (c) wet massing 9,17 .Granules were dried on tray oven with controllable temperature (Heraeus, Germany) at 60ᵒ C. Finally were sieved through 500 mm mesh.Addition of Sublimating agent (Menthol dissolved in acetone as solvent).Allow the granules to dry at room temperature to evaporate acetone only while maintain menthol inside the granules 18 .

Granules characterization (Pre-compression Evaluation) Densities
Bulk Density (Db) or Envelope Density (gm/ml): It is the ratio of total mass of powder (M) to the bulk volume (Vb).Apparent bulk density was determined by pouring pre-sieved drug excipient blend into a graduated cylinder and measuring the volume and weight it.Bulk density (expressed in gm/ml) was calculated according to formula: Db= M/ Vb Where, M = Mass of the Powder Vb= Bulk volume of the powder 19,20 Tapped Density (Dt) (gm/ml): It is the ratio of total mass of powder to the tapped volume of powder.It was determined by placing a graduated cylinder, containing a known mass of drug-excipient blend, on mechanical tapping apparatus.The cylinder was allowed to fall under its own weight onto a hard surface from the height of 10 cm at 2 seconds interval.The tapping was continued until no further change in volume was noted.Tapped density (expressed in gm/ml) was calculated according to formula: Dt= M/Vt Where, M = Mass of the Powder Vt= Tapped volume of the powder 19,21 .The helium pycnometer measures the true volume and density of solid powders.Density calculated was the mean of three measurements of each sample 22 .

Granules size and shape
Volume surface mean diameter "D (4, 3)" Granule size distribution was determined by laser diffraction method.A Malvern Mastersizer (Malvern 2000Worcestershire, UK) was used to measure granule size distribution.The diffractometer is equipped with a He-Ne laser with 18mm beam diameter collimated and spatially filtered to a single transverse mode.The active beam length was 10 mm, and a 1000mm lens was used for the measurements with a range of 4-500 _m.The samples were introduced using a dry powder feeder (Malvern Instruments, UK) at a feed rate of 3.0gm and a jet pressure of 2.4 Bar.All measurements were made in triplets to assure the reproducibility of the method.The mass or the volume moment mean diameter (or the Brouckere mean, D [4,3]) and the 10, 50 (median).and90% fractiles were also determined using the Mastersizer software version 2.18 (Malvern Instruments, UK).Particle diameter distribution was evaluated for D [4,3] and the 10, 50 (median).and90% fractiles for each sample 23 .

Flowability parameters Carr's Index (Consolidation Index or Compressibility index)
It is directly related to flow rate, cohesiveness and particle size.It indicates the powder flow properties.It is expressed in percentage and is given by formula: % compressibility (I) = [Tapped density -Bulk density/ Tapped density] x 100 [24][25] .

Hausner Ratio
It is an indirect index of ease of powder flow.It is calculated by the following formula: Hausner ratio = Tapped density/ Bulk density Lower Hausner ratio (<1.25) indicates better flow properties than higher ones (>1.25) [25][26] .
Carr's index and Hausner's ratio measure the propensity of powder to be compressed and the flowability of powder 25,26 .

Flow rate gm/sec
Granules flow rate was assessed using flowmeter (Automated powder flow analyzer, model PTG-S4, Pharma Test, Hainburg, Germany).A sample of 50 gm of the granules was poured into the funnel of the flowmeter which has the following dimension; 12 cm the diameter at the top and 0.9 cm the diameter of the efflux orifice.The results were obtained as an average of three measurements for each granulates 27 .

Angle of Repose (θ)
Granules flow rate was determined by indirect method using angle of repose.Powders with angles greater than 50º have unsatisfactory flow properties, whereas minimum angles close to 25º correspond to very good flow properties 27 .The frictional forces in case of loose powder are measured by the angle of repose.It is defined as the maximum angle possible between the surface of a pile of powder and the horizontal plane.It is determined by funnel method.Angle of Repose was calculated using the formula: Tan θ = 2h/d Tan θ = h/r θ = Tan-1(h/r) Where, θ = Angle of repose H = height of the pile (cm) r = radius of heap (plane surface occupied by the powder) 24,28 .
The Angle of repose and flow rate of granules was evaluated using the automatic powder flow tester (model PTG-S4, Pharma Test, Hainburg, Germany); the results were obtained as an average of three measurements for each granulates.

Compression of sildenafil Oral disintrgrating tablets
Add extra granular disintegrant, sucralose (sweetener),pineapple powder flavor while sieving and Aerosil 200 (glidant).addlubricant magnesium stearate or sodium stearyl fumarate after sieving through 355 micron followed by compression of the blend on a 10 station rotary compression machine (Korsch, Germany) using 9 mm round flat scored punches on 6.5 KN.The tablets were collected and vacuum dried at 60°C until a constant weight was obtained to ensure the complete removal of sublimating components to make the tablet porous 18 .
In this approach sublimation occur from the compressed tablet not from the granules.The tablet weight was adjusted to 300 mg ± 7.5%.The tablet press was run at low speed 20 rpm to guarantee accurate filling of the die.

Post-compression evaluation of FDTs (Evaluation of Tablets)
Tablets from all the formulation were subjected to following quality control test.

Visual inspection
Upper and lower punches were inspected by naked eye for presence of sticking or picking.The general appearance of a tablet, its visual identity and overall elegance is essential for consumer acceptance.It indicates tablet size, shape, color, presence or absence of an odour, surface texture, consistency and legibility of any identification markings 29 .

Drug Content Uniformity
Drug content for each formula was determined by dissolving 10 tablets from each formula.Accurately weighed portion of the ground tablets equivalent to about 50 mg sildenafil citrate was dispersed in 25 ml of methanol.The flasks were placed in a sonicator till complete dissolution; 1 ml of the solution was filtered through a Millipore filter of 0.45 µm pore size after those samples were filtered using syringe filter, assayed using HPLC 26 .

Tablet thickness
The thickness of the tablets was determined using a dial thickness gauge.Five tablets from each type of formulation were used and average values were calculated.It is expressed in mm.Thickness measurement were performed directly after compression process.

Uniformity of weight or Weight variation
Twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance.The average weight of one tablet was determined from the collective weight.The weight variation test would be a satisfactory method of determining the drug content uniformity 26,30,31 .

Hardness (Tablet tensile strength or crushing test)
The average breaking strength of tablets was determined by tablet hardness tester (DR.SCHLEUNIGER Pharmatron, USA).From each formula, 10 tablets were tested for their hardness; the mean hardness (±SD) in Newton (N) of each formula was determined. 27The tablet was held along its oblong axis in between the two jaws of the tester.At this point, reading should be zero kg/cm 2 .Then constant force was applied by rotating the knob until the tablet fractured 24,25,26,32 .

Friability test
Ten pre-weighed tablets from each formula were tested, accurately placed in the drum of the friabilator (PharmaTest, Germany) and rotated at 25 rpm for a period of 4 min, then reweighed.The percentage loss in weights was calculated and taken as a measure of friability 26,33,34 .% Friability = [(W1-W2)100]/W1 W1= Weight of tablet before test (Initial Weight) W2 = Weight of tablet after test (Final Weight).Thus, it is necessary that this parameter should be evaluated and the results are within bound limits not more than 1 % 34,35 .

In-vitro wetting time
Ten milliliters of water soluble dye Carmosine solution 0.1 % is added to petri dish containing five circular filter papers of 10 cm diameter.Tablets were carefully placed on the surface of the filter paper and the time required for water to reach upper surface of the tablet was noted as the wetting time.The test results were presented as mean value of six determinations (± SD) 9,36,37,38 .

In-vitro disintegration time
Disintegration times of ODTs were determined using six tablets in distilled water kept at 37 ± 0.5°C using a disintegration tester (ERWEKA,USA).The time when there were no particles of tablets or only a trace amount of soft residue remains on the screen was selected as the disintegration time.The test results presented are the average of three determinations (n=3) 2,14 .

In-vitro dissolution time
The test was performed using a dissolution tester (model VK7010, Varian Inc., USA) equipped with an auto-sampler (model VK8000).The dissolution profile ODTS compared with the immediate release plain drug and market product (Viagra®) were determined using the USP dissolution tester I (Varian dissolution tester, Germany).Dissolution media were 900 ml of the most suitable media0.01N HCl (PH=1.2) maintained at of 37 ± 0.5°C with a basket rotation speed at 100 r.p.m.The amount of drug used was 70 mg sildenafil citrate equivalent to 50 mg sildenafil base.At specified time intervals (1, 3, 5, 10 and 15 min.), 3 ml of dissolution media were withdrawn, and replaced with an equal volume of the fresh medium to maintain a constant total volume.Samples were filtered through 0.45um Millipore filter and assayed for drug content using HPLC 2,14, 39 .The dissolution profiles of all the ODT formulations for sildenafil citrate were compared with the marketed immediate release formulation by using a model independent approach of similarity factor, f2 is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) dissolution between the two curves of marketed and test formulations 40 .The equation for calculating similarity factor is: Where 'n' is the number of dissolution time intervals and Rt and Tt are the reference (theoretical) and test dissolution values at time 't'.Dissolution profile was considered satisfactory if f2 value is more than 50.Two dissolution profiles are considered similar when the f2 value is 50 to 100 18 .

Pre-formulation study by estimation of possible interaction between sildenafil citrate and some proposed excipients using spectroscopy DSC and by IR Differential Scanning Calorimetry (DSC)
The DSC thermogram of pure sildenafil citrate shows one main characteristic sharp melting endothermic peak at 200°C.The DSC thermograms of physical mixtures of drug and different excipients illustrated in Figure 2 reveal no significant change in the melting point of sildenafil citrate in the presence of excipients, indicating no interaction between the drug and excipient 14,41 .The 1:1 w/w ratio was chosen because it maximizes the observation of any reaction.The incompatibilities were detected by appearance, shift or disappearance of the corresponding peaks of each substance.It is clear from Figure 2    The peak for SC is not present or shifted from its position indicating that at high temperatures an interaction between SC and mannitol occurs.This interaction is more than likely due to a small amount of reducing sugar that may be present in mannitol, thereby precipitating a Maillard reaction 41 .DSC results showed that may there is an incompatibility between mannitol and SC.
Fourier transform infrared (FTIR) spectroscopy Figure 3 illustrate spectra of sildenafil citrate and binary mixtures with the used excipients mimic its concentration in formula.
Figure 4 shows possible main absorption peaks for sildenafil citrate and its near infrared spectrum including peaks at 1172.5 and 1357.84 cm -1 for symmetric and asymmetric SO2, respectively, at 1581.4 and 1700.79 cm -1 for symmetric and asymmetric COOH respectively, hydroxyl (OH) at 3616 cm -1 , NH symmetric and asymmetric stretching at 3298.4 cm -1 (major peak), CH bond aromatic on benzene (=CH) at 3027.85 cm -1 and aliphatic methyl and methylene (CH) at 2904.6-2949 cm -1 .
Figure 5 shows main absorption peaks for mannitol includes a number of characteristic peaks.The very broad peak at 3400.06 cm -1 represents OH band stretching.The three peaks at 2984.8 cm -1 , 2948.21cm -1 and 2910.88 cm -1 may be attributed to CH stretching while the peaks at 1281.97 cm -1 and 1260.27cm -1 corresponding to primary and secondary alcohol OH plane deformation.The peaks at 1080.49cm -1 and 1045cm -1 represent primary and secondary alcohol C=O stretching, respectively.
To ensure that no interaction between SC and mannitol occurred as show in an IR spectra of a 1:1 binary mixture of SC and mannitol was generated as shown in Figures 5, 6(a), 6(b) and revealed the presence of all characteristic peaks for SC and mannitol.It was thought that the Maillard reaction had occurred with reducing sugars found in mannitol, reacting with the secondary amine to form an imine.The spectrum highlights that no imine product was formed as a characteristic peak for imine would appear at a wave number of 1630cm -1 .The absence of this peak confirms the fact that at room temperatures a Maillard reaction is not likely to have taken place 41 .This result is in accordance to work done Abdel Halim, S. A., 2013.

Granules characterization (Pre-compression Evaluation) Evaluation for bulk density, tapped density, Carr's index, Hausnerratio, angle of reposes and flow rate
The powder mixtures of all batches (N1-N19) are evaluated for bulk density, tapped density, Carr's index, Hausner ratio and angle of repose and are shown in Table 4. Bulk density range from 0.344 to 0.449 g/ml, Tapped density range from 0.458 to 0.647 g/ml, True density range from 1.563 to 1.689 g/cc , Angle of repose range from 33.2 ᵒ to 40.1 ᵒ ,Hausner ratio from 1.27 to 1.54 and Carr's index ranged from 19.99 to 35.44 %.All these results indicating that the powder mixture have a good flow property and compressibility index.
These results were being in accordance with work done by Realpe A. et al who mentioned the initial particle size distribution has a strong effect upon granule growth rate and the mechanism by which wet granulation occur 42 .

Post-compression evaluation of ODTs (Evaluation of Tablets) Uniformity of SC content
Results revealed uniform sildenafil citrate content in ODTs from formulae N1:N19 ranged from (97 ± 0.55to 103±0.21).Results are presented in Table 4.

Uniformity of weight
Results are presented in Table 4 reveals the average weight for ODTs formulae N1:N19 ranged from (300±0.47 mg to 307 ±1.22 mg), therefore all the tablets fall within the acceptable weight variation range; according to the European pharmacopoeia (2017), not more than two tablets deviated from the average weight by more than 7.5% and not deviated by more than twice this percentage.

Friability test
Table 4 reveals the friability results for the prepared ODTs.According to compendial standards (European pharmacopeia 2017), the tablets comply with the friability test if the weight loss during the test was less than 1%, in addition, the tablets should not break or  show any capping or cracking during the test.Results showed that ODTs formulated with PVPK25 as a binder former showed percentage fines within the acceptable range for tablets (less than 1%).Some ODTs were more friable than the others, as they showed higher percentage of weight loss.N1,N2 and N12 showed higher percentage weight loss (1.05,1.1,1%respectively) while ODT formulae N9,N7,N5 and N3 showed percentage weight loss of (0.6 , 0.7, 0.8 and 0.9%) respectively while N15,N16,N14 and N13 formulae showed lower amount of friability (0.29,0.26,0.36 and 0.36%) respectively.

In-vitro disintegration time
Results are presented in Table 4 reveals the average disintegration time for ODTs formulae N1:N19 ranged from (25 ± 0.71 mg to 110 ± 0.89 mg).

Wetting time
Table 4 shows the average wetting times of the different formulae.These results correlate with result obtained from disintegration time testing.Wetting time was significant affected by disintegrant type and lubricant.The wetting time range from (23.83 -90.83 seconds).
N3 shows the shortest wetting time it contain 9 % CCS, higher % of mannitol and hydrophilic lubricant (sodium stearyl fumarate).The fact of croscarmellose sodium show shortest wetting time followed by sodium starch glycolate then plasidone XL ,the filament structure of croscarmellose sod aid in rapid uptake of water by tablet.Plasidone XL is insoluble disintegrant 46 .
In vitro release studies carried out for sildenafil formulae and compared with the marketed immediate release Viagra® 50 mg tablet shown in Figures 9-17.All formulae show acceptable dissolution rate were more than 90% in 5 minute.The result indicate that sublimation technique used to prepare the ODTs enhance the extent and the rate of dissolution.N16, N17, N18 and N19 show fast release after 1 min (92.8,81.8, 94.3 and 100 %) respectively, wetting time was (30, 70.3, 76.8, 79.67 ) respectively and disintegration time was (25, 29, 30 and 31 seconds).

CONCLUSION
Orally disintegrating tablets (ODT) of sildenafil citrate is successfully prepared by using sublimation method.From the study, it can be concluded that sublimation method showed better disintegration and drug release.The prepared tablets disintegrate within few seconds without need of water; thereby enhance the absorption leading to its increased bioavailability.This technique would be an effective alternative approach compared with the use of more expensive adjuvants in the formulation of mouth dissolving tablets.Formula N16 is considered to be a future promising formula for sildenafil citrate due to the presence of high percent of plasidone XL 9% as superdisintegrant while 60 % of this ratio was intergranular, 1% menthol was sufficient to produce porous structure, Mannitol /MCC ratio at 1:1, magnesium stearate as lubricant.This formula show better wetting time, disintegration time and in vitro drug release.

Figure 3 .Figure 2 .
Figure 3. FTIR spectra of sildenafil citrate and binary mixture with the used excipients mimic its concentration in formula.

Table 1 . Composition of Sildenafil citrate ODTs prepared by sublimation technique
N: code for each formula

Table 3 . Particle size distribution by diffractometerTable 4 . Evaluation of different sildenafil citrate oral disintegrating tablet
ISSN:

ISSN: 2357-0547 (Print) Research Article / JAPR ISSN: 2357-0539 (Online) Abbas et al., 2018, 2 (4), 292-311 http
that SC has a main sharp characteristic endothermic melting peak at 200 °C.The sharp endothermic peak signifies that SC was in a pure crystalline state.It notice that there was no shift in SC peak upon mixing with plasidone XL reveal endothermic melting peak at 203°C , Sodium starch glycolate at 202.48 °C , croscarmellose sodium at 202.76 °C, Sucralose at broad endothermic peak at 216 °C , pineapple at 204 °C, PVP K25 have two endothermic peak at 200 °C and other peak 193.84 specific for PVP k25, menthol at 193.84 and other specific peak for menthol 48.76 °C and , microcrystalline cellulose at 199 °C, sodium stearyl fumarate have two peak 197 °C for SC and 125 for sodium stearyl fumarate, magnesium stearate at 202 °C, Aerosil 200 at 203 °C, as shown in ://aprh.journals.ekb.eg/300