Formulation and evaluation of orodispersible tablet of taste masked doxylamine succinate using ion exchange resin

2.2.1.1 Scanning of doxylamine succinate in 0.1 N hydrochloric acid

The solution containing 20 μg/ml of doxylamine succinate in 0.1 N hydrochloric acid was prepared and scanned over range of 200–400 nm against 0.1 N hydrochloric acid as a blank using Thermo Alfa Helios double beam UV spectrophotometer. The λ_max was found to be 262.0 nm, which confirms to the reported value.

2.2.1.2 Preparation of dissolution medium for standard curves

In the present work, doxylamine succinate was estimated by UV spectrophotometry in distilled water, 0.01 N hydrochloric acid, 0.1 N hydrochloric acid and in simulated salivary fluid.

2.2.1.3 Preparation of standard calibration curve in distilled water

Various drug concentrations (5–50 μg/ml) in distilled water were prepared and the absorbance was measured at 262 nm.

For the standard curve, 100 mg of doxylamine succinate was accurately weighed and dissolved in 100 ml of distilled water, then 5 ml of the resulting solution was diluted to 100 ml with distilled water to make stock solution of concentration 50 μg/ml. Further serial dilutions were carried out with distilled water to get drug concentrations 5, 10, 15, 20, 25, 30, 35, 40, 45 and 50 μg/ml. The absorbance of dilutions was measured against distilled water as a blank at 262 nm using double beam UV/Visible spectrophotometer. The plot of absorbance Vs concentration was plotted and subjected to linear regression analysis. Drug was found to obey Beer Lambert's law in the concentration range of 5–50 μg/ml.

2.2.1.4 Preparation of standard calibration curve in simulated salivary fluid

Various drug concentrations (5–50 μg/ml) in simulated salivary fluid were prepared and the absorbance was measured at 262 nm (Clarke, 1986). For the standard curve, 100 mg doxylamine succinate was accurately weighed and dissolved in 100 ml of simulated salivary fluid, and then 5 ml of the resulting solution was diluted to 100 ml with simulated salivary fluid. Further serial dilutions were carried out with simulated salivary fluid to get drug concentrations 5, 10, 15, 20, 25, 30, 35, 40, 45 and 50 μg/ml. The absorbance of dilutions was measured against simulated salivary fluid as a blank at 262 nm using double beam UV/visible spectrophotometer. The plot of absorbance Vs concentration was plotted and subjected to linear regression analysis. Drug was found to obey Beer Lambert's law in the concentration range of 5–50 μg/ml.

2.2.2.1 Effect of drug: resin ratio

The Indion 234 which showed highest amount of drug loading for ratio 1:1 was optimized for various drug:resin ratios. In each case, 100 mg of doxylamine succinate was stirred with varying amount of resin in deionised water using magnetic stirrer at 500 rpm. The amount of drug loaded at different time intervals was determined indirectly by estimating the amount remaining to be loaded in solution spectrophotometrically at 262 nm. A plot of mean of three determinations for percentage drug loaded as a function of time is plotted in Fig. 1. Results are displayed in Table 1.

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Figure 1

Effect of drug–resin ratio.

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2.2.2.2 Effect of pH on drug loading

The study was carried out at five pH values 3, 4, 5, 6 and 7. The pH was adjusted to desired value using 2 N citric acid. Solution of 100 mg doxylamine succinate drug was stirred with 200 mg of resin using magnetic stirrer at 500 rpm. The amount of drug loaded at different time intervals was determined indirectly by estimating the amount remaining to be loaded in solution spectrophotometrically at 262 nm. A plot of mean of three determinations for percentage drug loaded as a function of time at different pH was obtained.

2.2.2.3 Effect of temperature on drug loading

The study was carried out at four temperature conditions 30 °C, 40 °C, 50 °C and 60 °C. In each case, 100 mg of doxylamine succinate was stirred with 200 mg of resin in deionised water using magnetic stirrer at 500 rpm. The amount of drug loaded at different time intervals was determined indirectly by estimating the amount remaining to be loaded in solution spectrophotometrically at 262 nm. A plot of mean of three determinations for percentage drug loaded as a function of time was obtained.

2.2.2.4 Effect of drug concentration on drug loading

The study was carried out at three different concentrations 2 mg/ml, 4 mg/ml and 6 mg/ml. In each case, solution equivalent to 100 mg drug was stirred with 200 mg resin in deionised water using magnetic stirrer at 500 rpm. The amount of drug loaded at different time intervals was determined indirectly by estimating the amount remaining to be loaded in solution spectrophotometrically at 262 nm. A plot of mean of three determinations for percentage drug loaded as a function of time was obtained.

2.2.2.5 Optimized conditions

Following are the optimum conditions for the preparation of drug–resin complex of doxylamine succinate and are best suited for optimum loading

• Drug:resin ratio: 1:2

• pH: pH 5

• Drug concentration: 4 mg/ml

• Time: 30 min

2.2.2.6 Preparation of drug–resin complex

In batch process, 200 mg of activated resin was placed in a beaker containing deionised water and allow to swell for 30 min. Accurately weighed doxylamine succinate 100 mg was added and stirred for one hour. The mixtures were filtered and residue was washed with deionised water. DRC was then washed with sufficient quantity of deionised water for three times to remove loosely adsorbed drug from resinate surface. DRC was allowed to dry at room temperature and was stored in tightly closed container and used in further studies.

2.2.3.1 Drug release from DRC

Drug release from DRC was determined using United States Pharmacopoeia (USP) type II dissolution apparatus. DRC equivalent to 30 mg of resinate was weighed accurately and added to 900 ml of 0.01 N hydrochloric acid and maintained at 37 °C. Drug release was performed at 50 rpm for 15 min. Aliquots of the medium were withdrawn at regular intervals, filtered and the absorbance determined on spectrophotometer. From absorbance values, percent drug dissolved at various time intervals was determined. A plot of mean of three determinations for percentage drug released as a function of time is plotted in Fig. 2 and results are displayed in Table 2.

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Figure 2

Drug release from DRC.

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2.2.3.2 Taste panel evaluation of different batches of resinate

In this the different batches of resinate were tested to determine most suitable ratio of complex for successful taste masking.

The results (Table 3) showed excellent correlation with the evaluation of the taste panel employed. From above observations, Formulation C was selected for further study.

2.2.3.3 Taste panel evaluation for ‘Batch C’ resinate

Bitterness was quantitated by consensus of trained taste panel. A time intensity method was used, in which a sample equivalent to a normal dose was held in the mouth for 10 s (Fu et al., 1991). Bitterness level were recorded immediately, then spat out (Table 4).

A numerical scale was used with the following values: 0-tasteless, 0.5-very slight, 1-slight, 1.5-slight to moderate, 2-moderate, 2.5-moderate to strong, 3-strong, 3⁺-very strong.

2.2.3.4 ‘In vivo’ evaluation of drug complex

The said resinate was given to panel of healthy human volunteers for taste masking evaluation using time intensity method which shows satisfactory masking of taste (Table 5).

2.2.3.5 ‘In vitro’ evaluation of drug content

Drug release from the DRC was also performed in 10 ml of pH 6.7 solution by adding drug complex equivalent to 10 mg of Doxylamine succinate to a test tube. The mixtures were filtered after shaking for 60 s. The filtrates were assayed for drug. Drug resinates are insoluble hence, even resinate of bitter drugs have virtually no taste. With the correct selection of ion exchange resin, the drug is not released in the mouth so that the patient does not taste the drug when it is swallowed. The percentage drug dissolved was found to be 1.96% ± 0.50 at a drug–resin complex ratio of 1:2.

2.2.3.6 X.R.P.D studies

The experiments were conducted on pure drug, pure resin, physical mixture of drug and resin and drug–resin complex for X-ray powder diffraction. The X-ray diffractograms were prepared by using Philips X’Pert PROP analytical XRD machine model PW1780.

The drug sample received from Adroit Pharmaceuticals complies with the compendial specifications for identification and other tests, and is suitable for present studies. Previously reported spectrophotometric methods of analysis of doxylamine succinate was found suitable for the present work and obeys Beer–Lambert's law in working range in all the media i.e., Distilled water, 0.01 N hydrochloric acid, 0.1 N hydrochloric acid and simulated salivary fluid.

The first step for purification of resin was done by washing with absolute ethanol, ethanol and water mixture and final washing with water to remove impurities associated with industrial scale, manufacturing or absorbed during storage or handling. For rapid release of drug, weak acid cation exchange carboxylic acid resins were tried. Preparation of resinate is normally done by two techniques (1) Bateh and (2) Column technique, but resinates were prepared using batch method.

Among three different resins viz. Indion 204, Indion 234 and Indion 414, the Indion 234 gave highest amount of drug loading (89.58% ± 0.26) and taste masking, because of its swelling and hydration properties hence Indion 234 was selected for further studies. Before designing a suitable delivery system, the main challenge is to optimize the conditions of resinate preparation, in order to obtain the desired drug loading in the resinates. Various processing parameters, viz. drug–resin ratio, pH, temperature and drug concentration, affected either rate or extent of loading of doxylamine succinate on Indion 234.

Study on effect of drug–resin ratio suggests higher drug loading at drug to resin ratio 1:1 and above. The plot of% drug loaded Vs time demonstrates that% uptake of drug from solution is highest for the ratio 1:2 i.e., 88.63% ± 1.39, for this reason drug–resin ratio 1:2 was selected as optimized ratio. Doxylamine succinate–Indion 234, complexation involves the exchange of ionizable drug and metal ions in resin, which in turn depends on the pKa of drug and resin. Such a mode of complexation between amino group of doxylamine succinate and –COO-K⁺ functionality of Indion 234 can be affected by the pH of the reacting media. The complexation was enhanced with increasing pH from 3 to 7. A maximum of 80.87% ± 0.26 wt/wt drug loading was obtained at pH 5 (i.e., at pKa of doxylamine succinate).

As shown in Fig. 3, as pH increased above 5 the percentage of drug loading decreased. The pH of the solution affects both solubility and the degree of ionization of drug and resin. The results can be attributed to the fact that doxylamine succinate has a pKa 4.4 and hence will have maximum solubility and complete ionization in this range. The decreased complexation at lower pH is due to excess H⁺ ions in the solution, which have more binding affinity to the –COO groups of resin and compete with the drug for binding.

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Figure 3

Effect of pH on drug loading.

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The temperature also affected the complexation. Highest drug loading on resin occurred (90.71% ± 0.70) at temperature 50 °C. Increased temperature during complexation increases ionization of drug and resin. High temperatures may also cause swelling of resin, higher temperatures tend to increase the diffusion rate of ions by decreasing the thickness of exhaustive exchange zone. Drug concentration per ml of loading solution was found to affect the loading time and had no appreciable effect on extent of uptake. Drug loading was faster at higher drug concentration, probably because of efficient competition for binding site with other ions in solution. Thus higher drug concentration can be used to reduce the processing time and larger batches can be processed in relatively smaller vessels. The extent of drug loading was faster at drug concentration (4 mg/ml) i.e., 91.47% ± 0.46. Complexation between the drug and resin is essentially a process of diffusion of ions between the resin and surrounding drug solution.

The results reveal that a 30-min swelling time of Indion 234 in deionized water gave the maximum doxylamine succinate loading above 80%. The swelling and hydration properties of Indion 234 affect the rate of Ion exchange, which in turn affect the percentage drug loading. In unswollen resin matrix, the exchangeable groups are latent and coiled towards the backbone, hence less drug loading efficiency. The percentage of drug loading stirring time was studied. This study revealed that as time increased the K_DM values increased rapidly up to 20 min, it is surprising to note the high exchange rate between 20 and 30 min. This finding may indicate the significant involvement of Vander Waals forces or chemisorption taking place along with exchange during complexation. Increasing the stirring time above 30 min did not further increase the K_DM values. Hence 30 min contact time between drug and resin could be optimized to equilibrate the ion exchange process to achieve maximum drug loading. This study indicated that optimum ion exchange could be completed in a short period of 30 min.

Doxylamine succinate release from drug–resin adsorbate was observed using United States Pharmacopoeia USP 24 type II dissolution apparatus and drug release was 97.37% ± 2.88 within 30 min.

In vitro drug release in average salivary pH of 6.7 was less than 5% within 60 s. The presence of exchangeable ions of ionizable electrolytes in salivary fluid may be responsible for this release. Resinate is stable in salivary pH for a period of administration. The amount released is insufficient to impart bitter taste while the formulation passes through the mouth to further parts of gastrointestinal tract.

A drug–resin complex is made from the bitter drug and ion exchange resins. The nature of the complex is such that the average pH of 6.7 and cation concentration at about 40 meq/lit in saliva are not able to break the drug–resin complex but it is weak enough to be broken down by the hydrochloric acid present in the stomach, thus the drug–resin complex is absolutely tasteless and stable, with no aftertaste. The complexation of doxylamine succinate and Indion 234 produces amorphous tasteless drug resinate. Taste evaluation in volunteers found the DRC to be tasteless and agreeable with maximum acceptability.

The XRPD pattern of pure drug contained a number of sharp peaks, while the resin showed a diffused peak. The XRPD patterns of the physical dispersions showed simply the sum of the characteristic peaks were observed in the XRPD patterns for the complexes regardless of presence of drug. According to the data from XRPD, the molecular state of pure drug was crystalline, but that of the resin was amorphus. The molecular state of the drug prepared as drug–resin complexes was changed from the crystalline to the amorphous state. These results demonstrated that the entrapped molecule of drug was dispersed monomolecularly in the resin bead. In the case of physical dispersions of drug and Indion 234, drug molecules are outside the resin beads. Thus, DRC is amorphous in nature and shows faster dissolution due to improved solubility. FTIR spectra of pure drug, pure resin, physical mixture of drug and resin and resinate confirms the complexation between drug and resin, and support the findings of XRPD studies. The time intensity study adopted for taste evaluation reviled considerable masking of bitter taste of doxylamine succinate, which makes Indion 234 suitable for taste masking of doxylamine succinate.

2.2.5.1 Angle of repose

The flow characteristics are measured by angle of repose. Improper flow of powder is due to frictional forces between the particles. These frictional forces are quantified by angle of repose. Angle of repose is defined as the maximum angle possible between the surface of a pile of the powder and the horizontal plane.

By definition $$\tan \theta =\frac{h}{r}$$ $$\theta ={\tan }^{-1}\frac{h}{r}$$ where h is the height of pile; r is radius of the base of the pile; θ is the angle of repose.

2.2.5.2 Bulk density

It is defined mathematically as $$\text{Bulk density}(\rho )=\frac{\text{mass of a powder}(w)}{\text{bulk volume}(V_b)}$$

When particles are packed loosely, lots of gaps between particles are observed. Hence bulk volume increases making the powder light. Based on bulk volume, powders are classified as “light” and “heavy”. Light powders have high bulk volume. On the other hand, smaller particles may sift between the larger particles, the powder assume low bulk volume or high bulk density. Such powders are called heavy powders. The bulk density depends on particle size distribution, shape and cohesiveness of particles.

A powder (about 60 g) is passed through a standard sieve No. 20. A weighed amount (approximately 50 g) is introduced into a 100 ml graduated cylinder. The cylinder is fixed on the Bulk density. Apparatus and the timer knob is set (regulator) for 100 tappings. The volume occupied the powder is noted. Further, another 50 taps may be continued and the final volume is noted. For reproducible results, the process of tapings may be continued until concurrent volume is achieved. This final volume is the bulk volume. Then bulk density is calculated using equation. Bulk volume is also measured by dropping the cylinder (containing powder) onto a hard wooden surface 3 times from a height of 1 inch at 2 s intervals. Sometimes, to get an appropriate volume, the container has to be dropped or tapped 500 times.

2.2.5.3 Tapped density

Tapped density was determined by USP method II. The powder sample under test was screened through sieve No. 18 and 10 g of tablet bend was filled in 100 ml graduated cylinder of tap density tester (Electrolab, ETD 1020). The mechanical tapping of the cylinder was carried out using tapped density tester at a nominal rate of 250 drops per minute for 500 times initially and the initial tapped volume (V_a) was noted. Tapping was proceeded further for additional 750 times and volume was noted. The difference between two tapping volumes was calculated. Tapping was continued for additional 1250 times if the difference is more than 2%. This was continued in increments of 1250 taps until difference between volumes of subsequent tapings was less than 2%. This volume was noted as, the final tapped volume (V_b).

The tapped density (Dt) was calculated in g/ml by the formula, $$\mathit{Dt}=M/V_b$$ where M is the weight of sample powder taken; V_b is tapped volume.

Determinations were carried out in 3 replicates. The mean value of three determinations are considered.

2.2.5.4 Compressibility

Carr's consolidation index: It is defined as: $$\text{Consolidation index}=\frac{\text{tapped density}-\text{fluff density}}{\text{tapped density}}\times 100$$

This property is also known as compressibility. It is indirectly related to the relative flow rate, cohesiveness and particle size. It is simple, fast and popular method of predicting powder flow characteristics.

Fluff (poured) density is the ratio of mass of powder to the fluff volume. Fluff volume is the volume occupied by a certain mass, when gently poured into a measuring cylinder.

Tapped density is the ratio of mass of powder to the tapped volume. Tapped volume is the volume occupied by the same mass of the powder after a standard tapping of a measure.

Compressibility index can be a measure of the potential strength that a powder could build up in its arch in a hopper and also the ease with which such an arch could be broken.

Using a suitable adhesive, the base of a 10 ml tarred measuring cylinder is fixed to the standard rubber bung at the top of the 250 ml cylinder. A powder sample (about 5.0 g) is transferred into the tarred 10 ml cylinder with the help of a funnel. The 250 ml measuring cylinder is placed on the tapping apparatus. The initial volume occupied by the powder is denoted as V₀.

The contents are tapped in the following order, 2, 4, 6, 8, 10, 20, 30 and 50 taps. After completing the tapings, the volume is denoted as V₂, V₄ … V_50.

The powder is carefully collected from the cylinder and weighed (W) $$\text{Fluff density}({\rho }_b\text{minimum})=W/V_0\text{g}/\text{cc}$$ $$\text{Tapped density}({\rho }_b\text{maximum})=W/V_{50}\text{g}/\text{cc}$$

2.2.5.5 Powder flowability

Before tablating the flowability of the mix ingredients of each formulation was studied. Although the pure doxylamine succinate was non flowable the addition of excipients resulted in a formation with percent compressibility between 12–16 and angle of repose between 20–30 indicating that flowability had significantly improved (Table 7).

2.2.6.1 Weight variation

With a tablet designed to contain a specific amount of drug in a specific amount of tablet formula, the weight of the tablet being made is routinely measured to help ensure that a tablet contains the proper amount of drug. In practice, composite samples of tablets (usually 10) are taken and weighed throughout the compression process. The composite weight divided by 10, however, provides an average weight but contains the usual problems of averaged values. Within the composite sample that has an acceptable average weight, there could be tablets excessively overweight or underweight. To help alleviate this problem the United States Pharmacopoeia (USP)/National Formulary (NF) provides limits for the permissible variations in the weights of individual tablets expressed as a percentage of the average weight of the sample. The USP weight variation test is run by weighing 20 tablets individually, calculating the average weight, and comparing the individual tablet weights to the average. The tablets meet the USP test if no more than 2 tablets are out side the percentage limit and if no tablet differs by more than 2 times the percentage limit. The weight variation tolerances for uncoated tablets differ depending on average tablet weight.

2.2.6.2 Hardness

The hardness of a tablet is indicative of its tensile strength and is measured in terms of load/pressure required to crush it when placed on its edge. A number of handy hardness testers such as Mosanto type or Pfizer type are currently in use. Hardness of about 5 kg is considered to be minimum for uncoated tablets for mechanical stability. The hardness is a function of physical properties of granules like their hardness and deformation under load, binders and above all the compressional force. The hardness has influence on disintegration and dissolution times and is as such a factor that may affect bioavailabilities.

2.2.6.3 Friability

Generally it refers to loss in weight of tablets in the containers due to removal of fine particles from their surfaces. However, in wider sense chipping and fragmentations can also be included in friability. Friability generally reflects poor cohesion of tablet ingredients. Standard devices have been fabricated to measure friability. Generally such instruments, marketed as ‘Friability Test Apparatus’ or ‘Friabilators’, consist of a circular plastic chamber, divided into 2–3 compartments. The chamber rotates at a speed of 25 r.p.m. and drops the tablets by a distance of 15 cm. Preweighed tablets are placed in the apparatus, which is given 100 revolutions after which the tablets are weighed once again. The difference in the two weights represents friability. The weight loss should not be more than one per cent.

2.2.6.4 Wetting time and water absorption ratio

The procedures similar to those used Bi et al., where used to measure tablet wetting time and water absorption ratio. A piece of tissue paper folded twice was placed in a small petridish containing 6 ml of water. A tablet was kept on the paper and time required for complete wetting was measured. The wetted tablet was then weighed.

Water absorption ratio, R, was determined using the following equations: $$R=\{(W_a-W_b)-W_b\}\times 100$$ where, W_b = weight of tablet before water absorption, and W_a = weight of tablets after absorption.

2.2.6.5 Disintegration time

In vitro disintegration time of tables from each formulation were determined by using digital tablet disintegration apparatus. In vitro disintegration test was carried out at 37 ± 2 °C in 900 ml distilled water.

2.2.6.6 Content uniformity

Transfer 1 finely powdered tablet to a 100 ml volumetric flack containing 65 ml of 0.1 N hydrochloric acid, Shake frequently during a 10 min period, dilute with 0.1 N hydrochloric acid to volume, and mix. Allow the insoluble material to settle, and filter, discarding the first 20 ml of the filtrate. Dilute a Portion of the subsequent filtrate quantitatively and stepwise, if necessary, with 0.1 N hydrochloric acid to provide a solution containing approximately 25 μg of doxylamine succinate per ml. Concomitantly determine the absorbances of this solution and of a standard solution of USP doxylamine Succinate RS in the same medium having a known concentration of about 25 μg per ml in 1-cm cells at the wavelength of maximum absorbance at about 262 nm, with a suitable spectrophotometer, using 0.1 N hydrochloric acid as the blank. Calculate the quantity in mg, of C₁₇H₂₂N₂O·C₄H₆O₄ in the tablet taken by the formula: $$(\mathit{TC}/D)(\text{AU/AS})$$ in which; T is the labeled quantity in mg, of doxylamine succinate in the tablet, C is the concentration, in μg per ml of USP doxylamine succinate RS in the standard solution, D is concentration, in μg per ml doxylamine succinate in the solution from the tablet, based on the labeled quantity per tablet and the extent of dilution and AU and AS are the absorbances of the solution from the tablet and the standard solution, respectively, results are reported in Table 8.

2.2.6.7 Dissolution studies

The in vitro dissolution studies were carried out using USP apparatus type II at 50 rpm. The dissolution medium used was 0.01 N hydrocloric acid (900 ml) maintained at 37 ± 0.5 °C. Aliquots of dissolution media were withdrawn at different intervals and content of doxylamine succinate was measured by determining absorbance at 262 nm (Table 9). The dissolution experiments were conducted in triplicate. Not less than 80% (Q) of the labeled amount of C₁₇H₂₂N₂O·C₄H₆O₄ is dissolved in 30 min. The comparative results are shown as Fig. 4.

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Figure 4

Dissolution study of different batches.

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2.2.6.8 Comparison of optimized formulation with conventional marketed tablet

In vitro dissolution studies for batch F₅ and conventional tablet were carried out using USP apparatus type II at 50 rpm, which shows that the drug release was more than 80% within 15 min which is better than conventional marketed tablet. The results are shown in Table 10, a plot of comparison is shown in Fig. 5.

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Figure 5

Comparison of optimised formulation with conventional marketed tablet.

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2.2.6.9 Stability study

Stability study was conducted by storing tablets at 40 °C ± 2 °C/75 °C ± 5% relative humidity for three months (Gohel and Jogani, 2005). The content and dissolution behaviours from orodispersible tablets were tested monthly for three months (Tables 11–14).

Each tablets was individually weighed and wrapped in a aluminium foil and packed in black PVC bottle and put at above specified conditions in a heating humidity chamber for three months. After each month tablet sample was analysed for hardness, disintegration, time, dissolution and drug content. The results are shown below, comparative account is given in the form of plots (Figs. 6 and 7).

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Figure 6

Dissolution profile for 40 °C.

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Figure 7

Dissolution profile for 75 °C.

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