Influence of native and acid-modified sweet potato (Ipomoea batatas ...

This Journal is © IPEC-Americas June 2022 J. Excipients and Food Chem. 13 (2) 2022 33

*Corresponding address: Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, University of Ibadan, FW22+5MW, 200132 Ibadan, Nigeria, E-Mail: [email protected], [email protected]

ABSTRACT

Ambroxol hydrochloride is a mucolytic agent administered orally 2 to 3 times daily because of its short half-life. A formulation of a floating bilayer tablet of ambroxol hydrochloride with immediate and sustained release layers for once-daily administration will prolong drug retention time, increase absorption and increasee patient compliance. Thus, the aim of this study was to design floating bilayer tablets of ambroxol hydrochloride using sodium starch glycolate, SSG, as the immediate release polymer (4.0% w/w) and native and acid-modified sweet potato starches as sustained release polymers (5.0, 7.5 and 10.0 % w/w) comparing with HPMC K15M as standard. A 32 factorial design was employed to evaluate the influence of polymer type and polymer concentration on buoyancy, mechanical and release properties of the tablets. Native and modified starches were characterized using SEM, FTIR, swelling and flow properties. Buoyancy characteristics of the tablets were evaluated using floating lag time and total floating time. Mechanical properties were evaluated using crushing strength and friability, while the release properties were evaluated using disintegration and dissolution times. SEM showed an increase in starch particle size and distortion in shape on acid-modification while FTIR revealed distinct differences in the spectra. The bilayer tablets containing the acid modified sweet potato starch had the highest total floating time, crushing strength, disintegration and dissolution times compared with those containing native starch and HPMC. Polymer type had greater influence on total floating time, crushing strength (p=0.001), disintegration time and dissolution time (p = 0.003) while polymer concentration influenced floating lag time and friability (p>0.05). Optimized formulations exhibiting prolonged buoyancy, high mechanical strength and sustained drug release was obtained with acid-modified sweet potato starch at polymer concentration of 10% w/w. Acid-modified sweet potato starch may provide a suitable polymer for the formulation of floating bilayer tablets for prolonged buoyancy, sustained release, reduction in dose and dosing frequency.

Received: January 22, 2022; Accepted: April 30, 2022 Original Article

The influence of native and acid-modified sweet potato (Ipomoea batatas) starches on the buoyancy, mechanical and release properties of floating bilayer tablets of ambroxol hydrochloride

Adenike Okunlola*

Department of Pharmaceutics & Industrial Pharmacy, University of Ibadan, Ibadan, Nigeria

KEY WORDS: Ambroxol hydrochloride, acid-hydrolysis, factorial design, floating bilayer tablets, gastro-retentive delivery, sweet potato starch, excipients

INTRODUCTION

A bilayer tablet is a combination of two or more active pharmaceutical ingredients (API) in a single dosage form suitable for separating two physically or chemically incompatible substances, suitable for the consecutive release of two different drugs obtained

by combining them into one formulation, or for sustained release formulations in which one layer is an immediate release layer propagating fast action while the second layer is for sustained release to maintain a desired plasma concentration for a longer duration of time (1, 2).

Oral bioavailability in many drugs can be limited by the non-uniformity of absorption in well-defined


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parts of the gastrointestinal tract (GIT) referred to as the absorption window. For drugs that have a narrow absorption window, only a fraction of the drug released before the absorption window or close to its vicinity, is made available for therapeutic effect. Any drug released after this window is laid to waste and resulting in reduced bioavailability of the APIs (3). A gastro-retentive sustained release formulation would remain in the gastric region for long periods and hence significantly prolong the gastric residence time of the drug (4).

Prolonged gastric retention improves bioavailability, reduces dose and improves solubility for drugs that are less soluble in a high pH environment. In the formulation of gastro-retentive floating tablets, carbon dioxide gas is released and entrapped in the swollen hydrocolloid layer of the tablet, reducing its density to below that of the gastric content which consequently confers buoyancy of the dosage form. In spite of the advantages bilayer tablets offer, a major challenge of bilayer tablet formulation is that it is more difficult to predict the long-term mechanical properties of these delivery systems due to poor mechanical and compression characteristics of the constituent materials in the compacted adjacent layers. The use of suitable excipients such as modified starches that can impart mechanical strength to the formulation of bilayer tablets could overcome this challenge.

Sweet potato (Ipomoea batatas, Family Convulvulaceae) is the seventh most important food crop in the world in terms of production (5, 6). The crop is cultivated for both the leaves (as greens) and tubers (as a high source of carbohydrate and beta carotene) (5). Sweet potato is well suited to grow in the fertile tropical soils of Africa even without fertilizers or irrigation. The plant has relative tolerance to water stress, relatively short growing season and adapts to a wide range of environmental conditions (7). The starch content of the sweet potato variant cultivated in Nigeria is in the range from 17.58 to 22.0% (6).

The disintegrant property of pregelatinized and phosphate-modified sweet potato starches have been evaluated in paracetamol tablet formulations and found

to be comparable to corn starch BP (8). In another study, sweet potato starch was modified by acid hydrolysis at different steeping times and evaluation of the effect of acid modification on the compaction properties revealed improved physicochemical and compaction properties that yielded starches that could be suitable as directly compressible excipients (9). A search through literature shows that no one has worked on the native and acid-modified forms of the starch with a view to evaluate their potential as sustained release polymers in gastro-retentive floating bilayer tablets.

The drug of choice for this study was ambroxol hydrochloride (trans-4-[(2-amino-3, 5-dibromobenzyl) amino]-cyclohexanol hydrochloride), a semisynthetic derivative of vasicine obtained from the Indian shrub Justicia adhatoda. Ambroxol hydrochloride is a metabolic product of bromhexine, used as a mucolytic in a variety of respiratory disorders including chronic bronchitis and cough (10). It has a half-life of 4 hours and the usual oral dosage regimen is 75 – 120 mg, usually divided into 2 or 3 times daily, making the drug a good candidate for sustained release.

The aim of this study was to design floating bilayer tablets of ambroxol hydrochloride using native and acid-modified sweet potato starches as sustained release polymers comparing them to HPMC, while sodium starch glycolate, SSG, was used as the immediate release polymer. A 32 full factorial design was used to determine the effects of independent variables X1 (polymer type) and X2 (polymer concentration) on dependent variables buoyancy (floating lag time, total floating time), mechanical strength (crushing strength and friability) and release properties (disintegration and dissolution times).

MATERIALS AND METHODS

Materials

Ambroxol hydrochloride was purchased from Xi’an Sgonek Biological Technology Co., Ltd., Xi’an City, China. Magnesium stearate was obtained from Sigma-Aldrich, USA., Purified Talc BP., Ibuprofen, Sodium hydroxide, Monochloroacetic acid, Isopropyl


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alcohol and hydrochloric acid were purchased from BDH, England. Hydroxypropylmethylcellulose was obtained from Oxford Lab Chemicals, Maharashtra, India. Polyvinylpyrrolidone (PVP) was obtained from Zhengzhou Qiangjin Science and Technology Trading Co., Ltd. Henan, China while sodium bicarbonate was from Sigma- Aldrich, Germany. Sweet potato tubers were obtained from local farmers in Ibadan, Nigeria. Methods

Extraction of the sweet potato starch

The sweet potato tubers were thoroughly washed to remove remnants of soil and then washed with distilled water, peeled, washed again and then cut into small pieces. These small pieces were milled into a fine paste using a laboratory mill and the slurry was strained through a muslin cloth. The filtrate was left to settle while the supernatant was decanted at 12-hour intervals and the starch slurry re-suspended in distilled water. Sodium meta-bisulphite was added to prevent color change due to oxidation. The starch cake was collected after 72 hours and dried in a hot air oven at 50°C for 48 hours. The dried mass was pulverized using a laboratory blender and then screened through a mesh sieve of 250 micrometer size.

Modification of sweet potato starch by acid-hydrolysis

Three hundred grams of native sweet potato starch were hydrolyzed by incubating the starch in 600ml of a 6% HCl solution for 192 hours without stirring. The suspension was neutralized with 10% (w/v) NaOH solution, and the starch slurry was washed five times with distilled water and dried in a hot air oven at 40°C for 24 hours. The starch milled into powder using a laboratory mill and passed through a 125 micro meter mesh size sieve.

Characterization of native and modified starches

Morphology

The mean particle size of 300 starch granules was determined using an optical microscope (Olympus

XSZ-107BN, Shinjuku, Japan). The morphology of the starches was observed using a scanning electron microscope (Hitachi SU8030 FE-SEM Tokyo, Japan) at an accelerating potential of 10.0 kV.

FTIR Analysis

The starches were analyzed using a Fourier Transform Infrared (FTIR) spectroscopy (FT-IR Spectrum BX II by Pekin Elmer Waltham, MA, USA) in transmission mode. About 5 mg of starch was mixed with KBr (400mg) and then formed into a disc in a press. Transmission spectra were recorded using at least 20 scans with 4 cm-1 resolution in the spectral range 4000-400 cm-1.

Swelling

The swelling power of the native and modified starches was determined using the method described by Bowen and Vadino (11). The starch suspension (5% w/v) was prepared at room temperature whilst shaking for 5 minutes. The dispersion was allowed to stand for 24 hours before the sedimentation volume (V) was measured and the swelling capacity was calculated as the ratio of sedimentation volume (V) to initial volume (Vo) of the dried starch powder.

Measurement of densities

The liquid pycnometer method was used to determine the particle density of the starch powders using xylene as the displacement fluid (12). The bulk density of each starch at zero pressure (loose density) was determined by pouring 10 g of the powder at an angle of 45° through a funnel into a glass measuring cylinder with a diameter of 21 mm and a volume of 50 ml. The tapped density was determined by applying 100 taps to 10 g of each of the starch samples in a 100 ml graduated cylinder at a standardized rate of 30 taps per minute.

Flow properties

The flowability of the starches was determined using Hausner ratio (Equation 1) and Carr’s index. The Hausner ratio was determined as the ratio of the initial


Original Article

Hausner ratioTapped densityBulk density

= Eq. 1

Carr s indexTapped density Bulk density

Tapped densityx'

( )�

�100 Eq. 2

� � �Tan 1 h r Eq. 3

Eq. 4D DL x Ttt � �( . )/1 0 693 1 2

bulk volume to the tapped volume while the Carr’s index (percentage compressibility) was calculated using Equation 2:

An open-ended cylinder with a diameter 2.8 cm was placed on a base of similar diameter. 10 g of starch powder was allowed to flow through a funnel, under the force of gravity, to form a conical heap. The angle of repose was calculated using Equation 3:

where, h is the height of the powder and r is the radius at the base of the cone. The angle of repose was calculated from an average of three values.

Preparation of floating bilayer tablets

The fast release layer was prepared by mixing uniformly ambroxol hydrochloride (15.0% w/w) with sodium starch glycolate, SSG (4.0% w/w), colorant (carmine red) (0.1% w/w), magnesium stearate (1% w/w), talc (1% w/w) and lactose to 100% w/w in a planetary mixer ( Model A120, Hobert Manufacturing Co, UK). The magnesium stearate was added last.

The sustained release layer was prepared by direct compression. Ambroxol hydrochloride (15.6% w/w), native sweet potato starch, acid-hydrolyzed sweet potato starch or HPMC (5.0, 7.5 and 10.0% w/w), polyvinylpyrrolidone (2.5% w/w), sodium bicarbonate (10.0% w/w), talc (1% w/w) and lactose to 100% w/w, were passed through a 250 micro meter mesh size sieve and dry mixed for 5 min in a planetary mixer. Magnesium stearate (1% w/w) was then added and the powder was stored in an airtight container.

The total dose of ambroxol hydrochloride in the sustained layer per tablet was calculated using Equation 4:

where, Dt = total dose of drug; DL (Loading dose) =75mg; T= time; t1/2 = half-life of ambroxol hydrochloride

Dt = 30 x (1+ 0.693 X12/4) = 92. 37

Sustained release layer = 92.37 – 30 = 62.37 mg ~62.40 mg.

The composition of the nine batches of formulations is presented in Table 1.

Compression of floating bilayer tablets of ambroxol hydrochloride

400 mg of the sustained release layer was compressed using a predetermined load (0.5 Tons) on a Carver hydraulic press with a 10 mm die and flat-faced punch for 30 seconds. 200 mg of the fast release layer was placed over the previously compressed layer and final compression at 1.0 Ton was performed to form a 600 mg tablet.

Evaluation of floating bilayer tablets of ambroxol hydrochloride

Tablet weight and thickness

Twenty tablets were selected at random from each batch and average weight was determined. The thickness of twenty tablets was measured within ± 0.001 mm using a micrometer screw gauge.

Buoyancy

The floating lag time (FLT and the total floating time (TFT) were used to assess in vitro buoyancy. One tablet from each formulation batch was placed in a USP type II dissolution apparatus containing 900 ml 0.1 N HCl dissolution medium using the paddle at a rotational speed of 100 RPM. The temperature of the medium was maintained at 37° ± 2°C. The time taken for the tablets to emerge on the surface and float was taken as floating lag time (FLT). The duration of time


Original Article

TABLET LAYER INGREDIENT F1 F2 F3 F4 F5 F6 F7 F8 F9

Fast Release

Ambroxol hydrochloride 30 30 30 30 30 30 30 30 30

SSG 8 8 8 8 8 8 8 8 8

Carmine red 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2

Talc 2 2 2 2 2 2 2 2 2

Magnesium stearate 2 2 2 2 2 2 2 2 2

Lactose to 200 200 200 200 200 200 200 200 200

Sustained Release

Ambroxol hydrochloride 62.4 62.4 62.4 62.4 62.4 62.4 62.4 62.4 62.4

Acid-modified starch - 40 - - 20 30 - - -Native starch - 30 20 - - - - 40

HPMC K15 40 - - - - - 20 30 -

PVP 10 10 10 10 10 10 10 10 10

Sodium bicarbonate 40 40 40 40 40 40 40 40 40

Talc 4 4 4 4 4 4 4 4 4

Magnesium stearate 4 4 4 4 4 4 4 4 4

Lactose to 400 400 400 400 400 400 400 400 400

Table 1 Formulations of floating bilayer tablets of ambroxol hydrochloride

that the tablets constantly remained on the surface of the medium was determined as the total floating time (TFT).

Mechanical strength

The crushing strength of the tablets was determined at room temperature by diametrical compression using a tablet hardness tester (MHT- 100, Model P&M01, Pharma Alliance Group, Indonesia). The results were taken only from tablets which split cleanly into two halves without any sign of lamination. The percent friability of twenty tablets was determined using a friabilator (DBK Instruments, England) operated at 25 RPM for 4 minutes.

Disintegration and dissolution times

The disintegration time of the tablets was determined in distilled water at 37°C ±0.5°C using the disintegration tester (DBK disintegration testing apparatus 40TDA01, India). The dissolution rate test was carried out on tablets using the USPXX I basket method (DBK Instrument, Mumbai, India).

Dissolution of the tablet of each batch was carried out

on a USP type I apparatus using 900-ml of dissolution media (0.1N HCl) maintained at 37°C ± 2°C and the rotational speed 50 RPM. Samples of 10 ml were withdrawn at predetermined time interval for 12 hours and replaced with the same volume of fresh medium. The samples were analyzed for drug content against dissolution media as a blank at 244 nm using a UV/Visible Spectrophotometer (Spectrumlab 752S, China).All determinations were carried out in triplicate and results are presented as the mean ± standard deviation.

Experimental design

A 32 full factorial design was performed using two factors, each at three levels giving nine possible combinations The effects of independent variables X1 (polymer type) and X2 (polymer concentration) on dependent variables floating lag time, total floating time, crushing strength, friability, disintegration time and time taken for 50% dissolution, t50, were determined. The data were subjected to multiple regression analysis using statistical software (Minitab 16 Software USA.). The relationship between the dependent and independent variables was further elucidated using the 3-D response surface plots.


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Figure 1 Scanning Electron Micrograph images of (a) native and (b) acid-modified sweet potato starches (mg 2000x)

Table 2 Material and physicochemical properties of native and acid-modified sweet potato starches

STARCHPARTICLE

SIZE (µm)

PARTICLE SHAPE

SWELLING INDEX

PARTICLE DENSITY

(gcm-3)

BULKDENSITY

(gcm3)

TAPPED DENSITY

(gcm-3)

CARR’S INDEX

(%)

HAUSNER RATIO

ANGLE OF REPOSE °

NATIVE 6.20±0.63 Spherical 1.03±0.04 1.480±0.005 0.490±0.020 0.625±0.001 29.20±0.95 1.30±0.04 60.40±4.50

ACID-MODIFIED 15.55±1.40 Irregular 0.75±0.00 1.425±0.120 0.577±0.020 0.667±0.001 15.60±1.00 1.20±0.10 34.07±3.05

RESULTS AND DISCUSSION

Properties of native and acid-modified starches

Starch yield

The yield of the extracted sweet potato content was 13.71%, while the yield following the acid modification was 65.9%. The relatively low values of the starch extracted could be due to the time of harvest, sweet potato variety and extraction procedure (13).

Morphology of starches

The scanning electron micrographs (SEM) of the native and modified sweet potato starches are presented in Figure 1. The SEM images revealed that native starch granules were spherical in shape with smooth surfaces while the acid-modified starch granules had larger, irregular shape with pitted surfaces.

Fourier Transform Infrared (FTIR) spectroscopy

The FTIR spectra of the native and acid modified starches are presented in Figure 2 and the stretching OH (3396cm-1) and the stretching CH at 2920cm-1 indicate the hydrolysis of the glycosidic linkage in the native starch. Acid hydrolysis causes the cleavage of the glycosidic bonds, converting some of the starch polymer to monosaccharides thus decreasing molar mass, viscosity and syneresis but increasing crystallinity, content of free aldehyde groups and solubility (9).

Material and physicochemical properties of the starches

The results of the material and physicochemical properties of the native and modified starches are presented in Table 2.

Swelling index

The swelling index of the acid-modified starch reduced when compared to the native starch owing to the cleavage of the glycosidic bonds and erosion of the amorphous region of the starch (14).

Densities and flow properties of starches

The bulk density of a powder sample is determined as the ratio of the mass to the total volume occupied by that sample (including the interparticulate void spaces). The tapped density of a powder material indicates the rate and extent of packing to be experienced by that


Original Article

Figure 2 FTIR spectra of native and acid-modified sweet potato starches.

material during the various unit operations involved in the tableting process. It is the density of a sample after a specific compaction has occurred to reduce interparticulate voids, usually carried out by vibrating the container. The particle density of the acid-modified starch was lower than the native showing their capacity to readily form tablets at lower compression pressures since materials with low particle density values at a given pressure would yield more cohesive compacts than those with higher values. On the other hand, bulk and tapped densities of the native starch were higher than those of acid modified starch. The bulk and tapped densities were used in determining Carr’s index and Hausner ratio, both useful parameters for evaluating the flow properties of the starch powders.The results indicate that modification by acid hydrolysis enhanced the flow properties of the native starch powder and this was confirmed by the results of angle of repose.

Evaluation of floating bilayer tablets of ambroxol hydrochloride

The coded and real values of factors of the factorial design as well as the results of buoyancy, mechanical and release properties of the formulations of floating bilayer tablets of ambroxol hydrochloride are presented in Table 3.

Tablet weight and thickness

All the tablets were within ±7.5% of their weight. The average thickness of each batch was within the acceptable limits of ± 5% (15).

Buoyancy

In the formulation of the floating bilayer tablets, sodium bicarbonate (10% w/w) was used as a gas-


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Table 3 Coded values, real values of factors and responses for the formulations of floating bilayer tablets of ambroxol hydrochloride (mean ± sd, n = 3)

FORMULATION CODED VALUE

REALVALUE RESPONSES

Polymer type

Polymer concentration

(% w/w)

Floating lag time (s)

Total floating time (h)

Crushing strength

(N)

Friability

(%)

Disintegration time (min) t50

(h)Immediate Sustained

F1 +1 +1 HPMC K15 10.0 9.80±0.80 7.65±0.60 155.70±10.00 0.98±0.00 2.55±0.02 26.60±1.00 3.80±0.43

F2 -1 +1 Acid-modified 10.0 4.55±0.33 26.50±1.00 293.30±16.55 0.81±0.06 2.95±0.00 90.65±5.60 9.50±0.08

F3 0 0 Native 7.5 27.50±1.15 3.40±0.00 90.50±7.40 1.96±0.04 3.00±0.00 11.50±1.20 0.80±0.03

F4 0 -1 Native 5.0 20.55±1.60 2.90±0.10 82.80±7.25 1.90±0.02 3.45±0.01 10.00±0.90 0.75±0.06

F5 - 1 -1 Acid-modified 5.0 3.50±0.20 24.50±2.22 210.15±15.90 0.90±0.00 3.50±0.10 50.00±4.00 6.50±0.04

F6 - 1 0 Acid-modified 7.5 5.55±0.50 25.50±2.10 233.55±20.66 0.88±0.01 2.00±0.04 75.50±6.88 7.75±0.32

F7 +1 -1 HPMC K15 5.0 6.10±0.44 6.20±0.54 120.00±9.65 1.25±0.00 3.25±0.00 15.10±0.90 2.20±0.20

F8 +1 0 HPMC K15 7.5 7.25±0.56 6.70±0.62 133.30±10.33 1.15±0.01 3.10±0.03 20.60±3.01 3.00±0.22

F9 0 +1 Native 10.0 38.22±0.25 4.11±0.40 119.50±9.77 1.11±0.00 2.50±0.02 13.15±1.42 1.10±0.10

generating agent in the sustained release layer. Sodium bicarbonate induced carbon dioxide generation in the presence of dissolution medium (0.1N HCl). The gas generated was trapped and protected within the gel formed by hydration of polymer, thus decreasing the density of the tablet. As the density of the tablet decreased, the tablet became buoyant (16). The results of in vitro buoyancy studies revealed a fast onset of floating in the tablets, in a matter of seconds with ranking of acid-modified<HPMC<native. The sustained release layer disintegrated to release particles that floated upward and stayed buoyant in the vessel for hours, accompanied by release of gas. This shows the suitability of sodium bicarbonate as a gas-generating excipient in floating tablet formulations. Although all batches of the tablets had the same concentration of sodium bicarbonate, the tablets containing the acid modified starch remained buoyant for more than 24 hours while those containing HPMC were buoyant for 6.20 ±0.54 to 7.65 ±0.60 hours.

Mechanical strength

Assessing the mechanical strength and release

properties of tablets is essential as a tablet should possess the strength to withstand shock encountered in its production, shipping and dispensing while at the same time should be able to release the medicinal agent(s) into the body in a predictable and reproducible manner.

The results of the crushing strength for the nine batches revealed that floating bilayer tablets containing the acid modified sweet potato starch had higher crushing strength values compared to those containing HPMC and the native starch. With increasing concentrations of the starch, the crushing strength increased, suggesting that greater concentrations of the modified starches conferred mechanical stability to the tablets. Floating bilayer tablets containing the modified sweet potato starches had lower friability values which was <1% w/w. All the tablets containing native starch however failed the friability test (>1% w/w). The relatively high friability values of tablets containing the native starch could be due to insufficient adhesion between the two layers or the compression pressure used (17).


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Figure 3 Dissolution plots of batches of floating bilayer tablets of ambroxol hydrochloride.

Disintegration and dissolution times

The disintegration time of a tablet is the time taken for the mechanical breakup of the tablets into small, dissolvable granules under specified conditions (18). For the immediate release layer, all the tablets conformed to the British Pharmacopoeia standards for the disintegration for an uncoated tablet (≤15 minutes). For the sustained release layer, value of disintegration time was in the order of acid-modified > HPMC> native. This result revealed that the acid modified starch has significant sustained release potential in comparison to HPMC and the native form.

The dissolution plots of cumulative drug release vs time for the nine formulations are presented in Figure 3. The plots reveal an initial sharp rise due to the fast release of the drug from the immediate release layer. From the plots, the time taken for 50% drug release (t50) were determined and are presented in Table 3. The value of t50 was in the order acid-modified>HMC>native with tablets containing the acid-modified starch having the most prolonged drug release.

Experimental design

The 32 Full factorial design involves formulation of nine batches (F1-F9). The technique requires minimum experimentation and time, thus providing a far more effective and cost-effective approach than the conventional methods of formulating dosage forms (19). The polynomial regression equations generated can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (i.e., whether positive or negative). Positive values of the coefficient indicate that changing the variable (X1 or X2) from low to high resulted in increase in response while the negative coefficient implies that changing the variable from low to high resulted in decrease in response. The interaction terms (X1X2) show how the response changes when the two factors are simultaneously changed. Results of the two-way ANOVA for the dependent variables are presented in Table 4.

The following polynomial equation was derived from the multiple regression analysis of the data obtained for floating lag time (FLT) and is shown in Equation 5:


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Table 4 Results of the two-way ANOVA for the dependent variables

DEPENDENT VARIABLE SOURCE DEGREE OF

FREEDOMSUM OF

SQUARESMEAN

SQUARE F P

FLOATING LAG TIME

Regression 5 1126.85 225.37 8.26 0.06

X1 1 15.20 15.20 0.56 0.51

X2 1 83.78 83.78 3.07 0.18

X1X2 1 1.76 1.76 0.06 0.82

Residual 3 81.87 1.76

Total 8 1208.73

TOTAL FLOATING TIME

Regression 5 848.29 169.66 4833.16 0.00

X1 1 521.73 521.73 14863.03 0.00

X2 1 3.62 3.62 103.10 0.00

X1X2 1 0.076 0.076 2.15 0.24

Residual 3

Total 8 848.39

CRUSHING STRENGTH

Regression 5 40220.80 8044.20 103.02 0.00

X1 1 17930.70 17930.70 229.64 0.00

X2 1 4032.60 4032.60 51.65 0.01

X1X2 1 562.90 562.90 7.21 0.08

Residual 3 234.20 234.20 78.10

Total 8 40455.10

FRIABILITY

Regression 5 1.27 1.27 3.72 0.15

X1 1 0.10 0.10 1.53 0.30

X2 1 0.22 0.22 3.24 0.17

X1X2 1 0.01 0.01 0.12 0.75

Residual 3 0.20 0.07

Total 8 1.41

DISINTEGRATION TIME IMMEDIATE

LAYER

Regression 5 1.09 0.22 0.77 0.63

X1 1 0.03 0.03 0.12 0.75

X2 1 0.81 0.81 2.88 0.19

X1X2 1 0.01 0.01 0.02 0.90


Total 8 1.93

DISINTEGRATION TIME

SUSTAINED LAYER

Regression 5 7102.52 1420.50 22.68 0.01

X1 1 3944.97 3944.97 63.00 0.00

X2 1 509.68 509.68 8.14 0.07

X1X2 1 212.43 212.43 3.39 0.16

Residual 3 187.86 62.62

Total 8 7290.37

T80

Regression 5 82.73 16.55 38.53 0.01

X1 1 36.26 36.26 84.44 0.00

X2 1 4.08 4.08 9.51 0.05

X1X2 1 0.49 0.49 1.14 0.36


Total 8 84.01


Original Article

FLT� � � �

� �

28 55 1 59 3 74

0 66 22 65 0 341 2

1 2 12

22

. . .

. . .

X X

X X X XEq. 5

TFT� � � �

� �

3 40 9 33 0 78

0 14 12 71 0 111 2

1 2 12

22

. . .

. . .

X X

X X X XEq. 6

CS� � � �

� �

90 18 54 67 25 93

11 86 93 40 11 131 2

1 2 12

22

. . .

. . .

X X

X X X XEq. 7

FR � � � �

� �

1 77 0 13 0 19

0 05 0 66 0 171 2

1 2 12

22

. . .

. . .

X X

X X X XEq. 8

The effect of both variables X1and X2 are positive indicating that changing the polymer concentration from low to high and changing the polymer type from acid-modified sweet potato starch to the native form and HPMC, respectively, resulted in an increase in floating lag time. The coefficient of X2 is greater than X1, suggesting that polymer concentration had a greater influence on FLT than polymer type. The interaction of both independent variables (X1X2) is also positive, implying that polymer type and polymer concentrations interacted to prolong onset of floating. However, the p-values of X1, X2 and X1X2 showed that polymer type and polymer concentration, individually and when used simultaneously, did not significantly affect floating lag time (p > 0.05).

The polynomial regression equation for total floating time (TFT) is as follows Equation 6:

The co-efficient value for independent variable X1 on TFT is negative, implying that total floating time was highest with acid-modified starch and reduced when the polymer was changed from acid modified sweet potato to native starch and HPMC. On the other hand, the coefficient value of X2 is positive, implying that increase in polymer concentration produced significantly longer duration of floating (p = 0.00). The increase in total floating time obtained by increasing the proportion of the polymers is expected since these polymers are hydrogels that also contribute to the floating properties of the dosage form, in addition to the presence of gas-generating material (10% w/w in all the formulations) in the stomach (20). The magnitude of the coefficient for X1 was greater than X2 showing it had a significantly higher influence on total floating time ( p = 0.00). The interaction between independent variables (X1X2) was also positive but not significant (p = 0.24) in prolonging total floating time.

The following polynomial regression equation was

obtained for crushing strength (CS) is shown in Equation 7:

The negative coefficient value obtained for X1 indicates that crushing strength was greatest when the floating bilayer tablets contained acid-modified starch which reduced as the polymer type changed to the native form and HPMC. On the other hand, coefficient for X2 was positive showing that crushing strength increased significantly (p = 0.01) with polymer concentration. This could be attributed to the availability of more contact points between particles as the polymer concentration increased, resulting in the formation of solid bonds which resulted in higher CS (21). The magnitude of the coefficient for X1 was greater than X2 showing it had a significantly higher influence on crushing strength (p = 0.00). The interactive term X1X2 showed a negative effect indicating that crushing strength decreased when both factors were simultaneously used even though their effect was not significant (p = 0.08).

The regression equation characterizing the influence of the two independent variables on friability (FR) was obtained using Equation 8:

The positive coefficient value obtained for X1 indicates that friability was lowest when the floating bilayer tablets contained acid-modified starch which increased as the polymer type changed to native starch and HPMC. On the other hand, the coefficient for X2 was negative showing that friability decreased with increasing polymer concentration. The friability test is important as the tablets are likely to be subjected to various abrasive motions during production and subsequent use. Conventional compressed tablets that lose less than 1% of their weight during the friability test are generally considered acceptable (22). The magnitude of the coefficient for X2 was higher than X1 showing that polymer concentration had a higher influence on friability. The interactive term X1 X2 showed a negative


Original Article

DTI� � � �

� �

2 76 0 08 0 37

0 04 0 09 0 331 2

1 2 12

22

. . .

. . .

X X

X X X XEq. 9

DTS� � � �

� �

12 63 25 67 9 22

7 29 34 86 1 621 2

1 2 12

22

. . .

. . .

X X

X X X XEq. 10

t50 1 2

1 2 12

22

0 80 2 46 0 83

0 35 4 58 0 13

� � � �

� �

. . .

. . .

X X

X X X XEq. 11

effect indicating that friability decreased when both factors were used simultaneously. The individual and interactive effects of the two factors on friability were not significant.

The regression equation characterizing the influence of the independent variables on disintegration time of the immediate layer (DTI) and disintegration time for the sustained release layer (DTS) were obtained using Equations 9 and 10 respectively:

The negative coefficient value obtained for X1 indicates that disintegration time was highest with acid-modified starch which reduced as the polymer type changed to HPMC and the native form in both the immediate and sustained release layers. On the other hand, coefficient for X2 was positive showing that disintegration time increased with polymer concentration which could be attributed to the increase in crushing strength observed with polymer concentration. The magnitude of the coefficient for X1 was higher (p = 0.00) than X2 on disintegration time for the sustained release layer only. The interactive term X1 X2 showed a negative effect indicating that disintegration times in both layers of the tablets decreased when factors X1X2 were simultaneously used even though the effects were not significant (p > 0.05).

The polynomial regression was obtained for dissolution time t50 is shown in Equation 11:

The negative coefficient value obtained for X1 indicates that dissolution time, t50, was greatest with acid-modified starch which reduced as the polymer type changed to HPMC and the native form. On the other hand, coefficient for X2 was positive showing that t50 increased with polymer concentration. The magnitude

of the coefficient for X1 was significantly higher than X2 (p = 0.00). The interactive term X1 X2 showed a negative effect indicating that disintegration times in both layers of the tablets decreased when factors X1X2 were simultaneously used even though the effects were not significant (p > 0.05).

Response surface plots, the graphic representations of the influence of the factors on the properties of the microspheres, were generated for each response parameters to study effect of each factor and the interaction effects of the factors on the responses at a time (23). Figures 4 (a), (b) and (c) represent the effects of varying polymer type blend (X1) and polymer concentration (X2) on total floating time, crushing strength and t80, respectively. Figure 4(a) shows that a change of polymer type from acid-modified to native starch led to a decrease in total floating time which then increased as the polymer type was changed from native to HPMC. On the other hand, increase in polymer concentration resulted in increase in total floating time. The longest floating time was reported with acid-modified sweet potato starch at polymer concentration of 10% w/w. Figures 4(b) an (c) show a decline in crushing strength and t50, respectively, as polymer type was changed from acid-modified starch to the native form but increased when polymer type was HPMC. On the other hand, increase in polymer concentration resulted in increase in the response. The highest crushing strength and longest dissolution time was observed in tablets containing acid-modified sweet potato starch at polymer concentration of 10% w/w. Thus, the optimized formulation that exhibited prolonged buoyancy, high mechanical strength and sustained drug release was Batch F2 containing acid-modified sweet potato starch at a polymer concentration of 10% w/w.

CONCLUSION

Floating bilayer tablets of ambroxol hydrochloride were successfully formulated using native and acid-modified sweet potato starches and HPMC K15 as sustained-release polymers and SSG for immediate release drug. The optimization of polymer type and polymer concentration in the floating bilayer tablet


Original Article

Figure 4 Surface response plots of (a) total floating time, (b) crushing strength and (c) t50 versus X2, X1.

formulations was carried out using 32 full factorial designs. The floating bilayer tablets containing acid-modified starch at 10% w/w exhibited buoyancy, high mechanical strength and sustained drug release

that was significantly greater than the those exhibited by floating bilayer tablets containing HPMC at the same polymer concentration. Acid-modified sweet potato starch may provide a suitable polymer for


Original Article

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prolonged buoyancy, sustained release, reduction in dose, dosing frequency and dose related side effects in the formulation of floating bilayer tablets of ambroxol hydrochloride. The potential of this local starch as a suitable and more affordable substitute to imported polymers has been demonstrated with a view to reduce the cost of manufacturing of tablets in an economically-challenged environment as is obtained in Nigeria. However, this floating bilayer tablet formulation remains a model system for now. Further research into large scale manufacturing and refining sweet potato starch to meet pharmacopoeia standards, as well as scale-up of tablet production have to be carried out to permit commercialization of the dosage form in the future.

ACKNOWLEDGEMENTS The author wishes to acknowledge the assistance of Ms. Olufunmilayo M. Ojo in the characterization of the starches used in this study.

CONFLICT OF INTEREST

The author declares no conflict of interest.


Original Article

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