Oral dissolvable films (ODFs) of diclofenac sodium intended for osteoarthritis were prepared using
Fast dissolving drug delivery systems like oral dissolvable films (ODFs) and fast disintegrating tablets (FDTs) were introduced in the late 1970s as alternative dosage forms for paediatric and geriatric patients who have difficulties in swallowing conventional oral solid dosage forms such as tablets and capsules [
ODFs are easy to transport and offer fast, safe, and accurate dosing without the need for water or any measuring device. Also, dysphagic, schizophrenic, and dementia patients are able to use ODFs with little or no difficulty [
Gums are pathological compounds produced by certain plants as a result of mechanical injury or due to undesirable climatic conditions, such as drought [
Osteoarthritis is the third leading diagnosis in the aged population [
This study was aimed at developing oral dissolvable films of diclofenac sodium using
Diclofenac sodium was received as a gift from Trade Winds Chemists (Kumasi, Ghana). Hydroxypropyl methylcellulose (HPMC) E15 (viscosity of 2% solution at 15 cPs) was obtained as a gift from UK Chemicals Ltd. (Kumasi, Ghana). Aspartame was a gift from Aspee Pharmaceuticals Ltd. (Kumasi, Ghana). Pineapple flavour and titanium dioxide were supplied by Kinapharma Ltd. (Accra, Ghana). Glycerol, Tween 80, and citric acid were obtained from the chemical stores of the Departments of Pharmaceutics and Pharmaceutical Chemistry, KNUST (Kumasi, Ghana). All other reagents used were of analytical grade. Crude
Crude
The moisture content and insoluble matter in the gums were determined using British Pharmacopoeia methods [
One gram of the gum was dispersed in sufficient distilled water, with occasional agitation, to form 1% w/v gum mucilage. The pH of the resultant mucilage was determined with a calibrated Eutech pH meter (pH 510, pH/mV/°C meter, Singapore) at 25°C. The total ash, acid insoluble ash, and water soluble ash of the gums were determined using official methods [
The true density of the gums was determined by liquid displacement method at 25°C [
One gram of the gum powder was weighed into a 10 mL measuring cylinder. The initial volume of the gum was noted after which distilled water was added to the 10 mL mark. The cylinder was stoppered, mixed lightly, and allowed to stand for 24 h and the final volume occupied by the gum sediment was noted. The swelling index was calculated as follows:
The charring temperature was determined by the open capillary method using the Stuart melting point apparatus (Bibby Scientific Ltd., UK). An open capillary tube was sealed using a Bunsen burner. The tube was packed by pressing the open end gently into a sample of the dry powder gum. The gum was transferred from the open end to the bottom of the tube by gently tapping the bottom on the bench. The sample tube was then inserted into the melting point apparatus and the temperature at which the gum sample changed colour was determined.
The viscosity of 5, 10, 20, 30, and 40% gum mucilage was measured with a Brookfield viscometer (Brookfield Engineering Laboratories, Inc., Middleboro, USA) at 25°C and shear rate of 30 rpm. The effect of temperature on the viscosity of 40% gum mucilage was also studied at 25, 50, 65, 75, and 85°C with the Brookfield viscometer at a shear rate of 30 rpm.
The mineral and toxic ion contents of the gums, namely, iron (Fe), copper (Cu), zinc (Zn), manganese (Mn), cadmium (Cd), lead (Pb), mercury (Hg), and arsenic (As), were determined with an atomic absorption spectrophotometer (AAS) (Buck Scientific Model 210V GP). The gums were subjected to dry ash digestion and the clear supernatant digest after centrifugation was used for the analysis. The file for the AAS analysis and hollow cathode lamps were set as follows: Fe at 248.3 nm, Cu at 324.8 nm, Zn at 213.9 nm, Mn at 279.5 nm, Cd at 228.9 nm, Pb at 283.3 nm, Hg at 253.7 nm, and Ar at 193.7 nm. A calibration curve was plotted for each of the elements to be analyzed from the stock standards. The stock standard followed by the sample solutions was analyzed for the elements. The determinations were done in triplicate for each supernatant digest. The contents of potassium and sodium in the gums were determined by flame photometry (Jenway flame photometer PFP7) at wavelengths of 766 nm and 589 nm, respectively. The content of phosphorus was evaluated using the phosphovanadomolybdate method [
Diclofenac sodium ODFs were prepared using the solvent casting method [
Composition of diclofenac sodium ODF formulations.
Code |
|
HPMC (g) |
|
|
Gly (g) | Tw (g) | Fla (g) | Asp (g) | Tit (g) | CA (g) | Water (mL) |
---|---|---|---|---|---|---|---|---|---|---|---|
F1 | 4 | 3 | — | — | 5 | 1 | 5 | 1 | 1 | 1 | 100 |
F2 | 4 | 2 | 2 | — | 5 | 1 | 5 | 1 | 1 | 1 | 100 |
F3 | 4 | 2 | — | 5 | 5 | 1 | 5 | 1 | 1 | 1 | 100 |
F4 | 4 | — | 5 | — | 5 | 1 | 5 | 1 | 1 | 1 | 100 |
F5 | 4 | — | 2 | 5 | 5 | 1 | 5 | 1 | 1 | 1 | 100 |
F6 | 4 | — | 10 | 5 | 1 | 5 | 1 | 1 | 1 | 100 | |
F7 | 4 | 1 | 2 | 5 | 5 | 1 | 5 | 1 | 1 | 1 | 100 |
All prepared films were checked for their appearances, whether uniform or not, and for the presence or absence of air bubbles, and so forth. The thickness of five randomly selected 2 cm × 2 cm films from each ODF formulation was determined using a digital caliper (Powerfix, Milomex Ltd., UK). The measurements were taken along various planes of the films and the mean and standard deviation were calculated [
The individual weights of ten randomly selected 2 cm × 2 cm films were determined using an analytical balance (Adam Equipment, UK). The average weight and standard deviations were calculated. The pH of the films was determined by dissolving a 2 cm × 2 cm film in 10 mL of distilled water. The pH of the resulting solution was measured using a standardized Eutech pH meter (pH 510, pH/mV/°C meter, Singapore). The mean of five determinations of each film was calculated.
A Bruker FTIR spectrophotometer (Alpha-Platinum ATR, Jos Hansen & Soehne GmbH, Hamburg, Germany) run by the Opus software (Version 7.2 Build 7.2. 139. 1294) was set to baseline to format previous entries that may interfere with the determination. About 0.1 g of diclofenac sodium was loaded onto the stage directly on top of the platinum. The force gauge was pulled closer to the sample to compress the sample. When the setup was ready, the Opus software generated the spectrum of the loaded sample on the monitor of a computer. The FTIR spectra of both
The petri dish method was employed in the determination of the disintegration time of the ODFs. Five randomly selected 2 cm × 2 cm films were placed into 25 mL distilled water in a petri dish at
Five randomly selected 2 cm × 2 cm diclofenac sodium ODFs each containing ~50 mg diclofenac sodium were placed in separate conical flasks containing 70 mL of 0.1 M sodium hydroxide. The flasks were shaken for 15 min using a shaker. Sufficient quantities of 0.1 M NaOH were added to produce 100 mL in each flask. The resultant solutions were filtered and 2 mL of each filtrate was diluted to 100 mL with 0.1 M NaOH. The drug concentrations were evaluated spectrophotometrically (T90 UV/VIS spectrometer, PG Instruments Ltd., UK) at a wavelength of 276 nm using the regression data of the calibration curve (
The mechanical properties of 2 cm × 2 cm ODFs were evaluated using a Brookfield Texture Analyzer CT3-100 with TexturePro CT Software (Brookfield Engineering Lab. Inc., Middleboro, MA, USA), fitted with TA-DE and TA-DGA probes and equipped with a 10 kg load cell. The required test parameters were entered into the Texture Loader Software and the appropriate mode was chosen. In the measurement of tensile strength and elastic modulus, a randomly selected film was held between two clamps of probe TA-DGA using low pressure clips, allowing a distance of 3 cm between the sample surface and the base of the probe. For the elongation at break, a film was clamped between the accessory fixtures of probe TA-DE. During measurement, the film was pulled at a rate of 2 mm/s. The force at break and elongation were shown on the CT3 display when the film broke. With an attached computer and TexturePro CT software, the mechanical parameters, namely, tensile strength, elastic modulus, and percentage elongation, were obtained. The experiment was carried out in triplicate for each ODF formulation and the average and standard deviations were calculated [
Dissolution efficiency (DE), difference (
The dissolution efficiency was calculated using the equation
The difference and similarity factors were calculated using the following equations:
The drug release data were also subjected to one-way ANOVA followed by Dunnett’s multiple comparison test using GraphPad Prism Version 5.00 (GraphPad Software, Inc., USA). Paired samples with
The drug release data were fitted into the zero-order, first-order, Higuchi, and Hixson-Crowell kinetic models to determine the release mechanism [
The physicochemical properties of the purified
Comparative physicochemical properties of purified
Parameter | Type of gum | |
---|---|---|
|
|
|
Extraction yield (%) | 39.38 ± 2.35 | 67.50 ± 2.98 |
Moisture content (%) | 12.42 ± 2.10 | 13.92 ± 1.51 |
Insoluble matter (%) | 0.275 ± 0.041 | 0.282 ± 0.013 |
pH (1% w/v @ 25°C) | 5.00 ± 0.12 | 3.84 ± 0.09 |
Total ash (% w/w) | 7.853 ± 0.064 | 5.603 ± 0.023 |
Water soluble ash (% w/w) | 1.303 ± 0.023 | 1.200 ± 0.017 |
Acid insoluble ash (% w/w) | 0.600 ± 0.017 | 0.607 ± 0.012 |
Solubility (%) | ||
Cold water | 1.273 ± 0.064 | 0.380 ± 0.020 |
Warm water | 1.747 ± 0.083 | 0.527 ± 0.064 |
Acetone | 0.110 ± 0.044 | 0.127 ± 0.031 |
Chloroform | 0.070 ± 0.062 | 0.020 ± 0.020 |
Ethanol | 0.093 ± 0.023 | 0.087 ± 0.042 |
Swelling index (%) | 611.29 ± 4.07 | 477.97 ± 8.67 |
True density (g/mL) | 1.363 ± 0.012 | 1.412 ± 0.073 |
Temperature of charring (°C) | 258.33 ± 2.89 | 242.67 ± 2.52 |
The swelling capacity is an important characteristic of ODFs as the dosage form will have to absorb water, increase in size, and disintegrate in order to release the drug for dissolution and subsequent oromucosal absorption [
Elemental analysis of the two gums showed the presence of the macrominerals calcium, magnesium, sodium, phosphorus, and potassium and the microminerals iron, copper, zinc, and manganese (Table
The mineral and toxic metal ion content of
Parameter | Type of gum | |
---|---|---|
|
|
|
|
||
Iron (mg/100 g) | 16.450 ± 0.087 | 9.640 ± 0.069 |
Copper (mg/100 g) | 3.240 ± 0.069 | 2.087 ± 0.023 |
Manganese (mg/100 g) | 18.933 ± 0.058 | 2.637 ± 0.064 |
Zinc (mg/100 g) | 7.883 ± 0.029 | 6.633 ± 0.058 |
Calcium (g/100 g) | 0.413 ± 0.012 | 0.870 ± 0.035 |
Magnesium (g/100 g) | 0.633 ± 0.029 | 0.847 ± 0.046 |
Potassium (g/100 g) | 2.777 ± 0.064 | 0.193 ± 0.006 |
Sodium (g/100 g) | 0.133 ± 0.012 | 0.070 ± 0.000 |
Phosphorus (g/100 g) | 0.070 ± 0.000 | 0.103 ± 0.006 |
|
||
Nitrogen (g/100 g) | 1.137 ± 0.012 | 0.560 ± 0.017 |
Carbon (g/100 g) | 45.903 ± 0.023 | 47.303 ± 0.040 |
|
||
Lead ( |
0.010 ± 0.000 | Nil |
Mercury ( |
0.005 ± 0.007 | Nil |
Cadmium ( |
0.015 ± 0.007 | 0.005 ± 0.007 |
Arsenic ( |
Nil | 0.012 ± 0.002 |
Cyanide ( |
Nil | Nil |
The elemental analysis showed negligible amounts of the toxic metals cadmium, lead, mercury, cyanide, and arsenic in the two gums. These toxic metals have no known function in the body but are very harmful to the proper functioning and metabolic activities of the human body. The near absence of these toxic metals gives a good indication of the possible safety of the gums when used as pharmaceutical excipients.
Figure
Effect of concentration on the viscosity of
Effect of temperature on the viscosity of
In the preparation of diclofenac sodium ODFs, HMPC,
Table
Physicochemical properties of diclofenac sodium ODF formulations.
Code |
|
Thickness (mm), |
pH, |
Disintegration time (s), |
Assay (%), |
---|---|---|---|---|---|
F1 | 0.186 ± 0.019 | 0.128 ± 0.013 | 4.66 ± 0.452 | 43.19 ± 0.077 | 98.74 ± 0.448 |
F2 | 0.250 ± 0.016 | 0.128 ± 0.015 | 5.08 ± 0.181 | 37.16 ± 0.043 | 99.46 ± 0.337 |
F3 | 0.194 ± 0.023 | 0.142 ± 0.008 | 4.82 ± 0.084 | 41.23 ± 0.070 | 99.94 ± 0.388 |
F4 | 0.208 ± 0.019 | 0.138 ± 0.023 | 3.80 ± 0.035 | 40.32 ± 0.081 | 100.41 ± 0.212 |
F5 | 0.254 ± 0.011 | 0.126 ± 0.013 | 3.09 ± 0.026 | 38.33 ± 0.053 | 99.68 ± 0.542 |
F6 | 0.116 ± 0.011 | 0.108 ± 0.008 | 3.62 ± 0.060 | 43.13 ± 0.058 | 97.58 ± 0.231 |
F7 | 0.298 ± 0.095 | 0.174 ± 0.011 | 5.23 ± 0.043 | 47.45 ± 0.050 | 98.82 ± 0.734 |
The pH of the films was determined to understand their possible effect on the mucous membrane of the mouth upon usage of the dosage form. The pH of a product is determined by the drug and the excipients used in the formulation [
ODFs are required to release the drug in a controlled and reproducible manner and the primary step towards drug release is through disintegration of the films. The average disintegration time for the formulations was 37.16 to 47.45 s. Although no official specifications and guidelines for the disintegration time of ODFs exist [
Figure
FTIR spectra of pure diclofenac sodium and
Pharmaceutical ODFs are required to exhibit good mechanical properties in order to maintain their integrity during handling, packaging, and transportation. The mechanical properties can be influenced by the film forming polymer, the technique of film fabrication, and the type and amount of plasticizer used. Plasticizers confer pliability to films and greatly improve their mechanical properties [
Mechanical properties of diclofenac sodium ODF formulations (mean ± SD,
Code | Tensile strength (MPa) | Elastic modulus (MPa) | Elongation at break (%) | Folding endurance |
---|---|---|---|---|
F1 | 5.95 ± 0.976 | 4.20 ± 0.786 | 17.87 ± 0.432 | 85 ± 1.57 |
F2 | 6.32 ± 0.542 | 3.89 ± 0.321 | 17.64 ± 0.156 | 103 ± 2.06 |
F3 | 6.51 ± 0.985 | 4.39 ± 0.465 | 13.49 ± 0.768 | 54 ± 1.56 |
F4 | 5.67 ± 0.231 | 4.05 ± 0.654 | 15.91 ± 0.563 | 67 ± 1.45 |
F5 | 6.14 ± 0.331 | 4.46 ± 0.943 | 10.73 ± 0.105 | 79 ± 2.15 |
F6 | 7.32 ± 0.432 | 4.86 ± 0.543 | 8.20 ± 0.445 | 39 ± 0.98 |
F7 | 7.19 ± 0.652 | 5.11 ± 0.213 | 7.65 ± 0.154 | 46 ± 1.57 |
Elastic modulus describes the stiffness of films [
The exertion of stress on a film causes the film to stretch. This effect called strain is expressed as the change in length of a film divided by its initial length before the applied strain [
Folding endurance expresses the capacity of the film to resist breaking when folded repeatedly along the same plane. High folding endurance values portray considerable mechanical strength of the film. It is directly regulated by the type and amount of plasticizer used in the formulation. The folding endurance of the films was in the order, F6 < F7 < F3 < F4 < F5 < F1 < F2. Folding endurance of 300 is considered satisfactory for oral films [
Figure
Drug release profiles of diclofenac sodium ODF formulations in phosphate buffer pH 6.8 at 37°C (mean ± SD,
Table
The difference factor (
Code | Difference factor ( |
Similarity factor ( |
Dissolution efficiency (DE) [%] |
---|---|---|---|
|
— | — | 95.85 |
F2 | 7 | 61 | 91.88 |
F3 | 7 | 55 | 89.27 |
F4 | 2 | 89 | 89.37 |
F5 | 5 | 66 | 91.84 |
F6 | 4 | 70 | 93.01 |
F7 | 27 | 33 | 82.85 |
The difference factor (
Data of one-way ANOVA followed by Dunnett’s multiple comparison test on drug release profiles of different ODF formulations.
Code | Statistical significance |
---|---|
F1 versus F2 | NS |
F1 versus F3 | NS |
F1 versus F4 | NS |
F1 versus F5 | NS |
F1 versus F6 | NS |
F1 versus F7 | SD |
NS = no significant difference between the two formulations (
The kinetic data for the diclofenac sodium ODFs are shown in Table
Drug release kinetic models of diclofenac sodium ODF formulations.
Code | Zero-order model | First-order model | Higuchi model | Hixson-Crowell model | ||||
---|---|---|---|---|---|---|---|---|
|
|
|
|
|
|
|
| |
F1 | 32.54 | 0.8685 | 0.163 | 0.8580 | 34.46 | 0.9250 | 0.505 | 0.8615 |
F2 | 60.09 | 0.9834 | 0.979 | 0.9736 | 63.04 | 0.9989 | 0.865 | 0.9651 |
F3 | 87.18 | 0.9097 | 0.428 | 0.8860 | 85.29 | 0.9575 | 1.497 | 0.8942 |
F4 | 29.08 | 0.9793 | 0.146 | 0.9755 | 30.11 | 0.9938 | 0.976 | 0.9770 |
F5 | 57.79 | 0.9464 | 0.946 | 0.9400 | 58.80 | 0.9722 | 0.955 | 0.9601 |
F6 | 51.60 | 0.9144 | 0.266 | 0.9059 | 55.71 | 0.9554 | 0.893 | 0.9089 |
F7 | 92.40 | 0.9853 | 0.874 | 0.9704 | 96.24 | 0.9941 | 1.896 | 0.9753 |
In can be concluded from the study that
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors gratefully acknowledge the technical assistance of the technicians in the Departments of Pharmaceutics and Pharmaceutical Chemistry, KNUST, Kumasi, Ghana.