Despite of numerous innovations in drug delivery method, the oral route continues to be the preferred route for delivering therapeutic agents due to its accurate dosage, low-cost therapy, self-medication, and ease of self-administration leading to high level of patient compliance. The hard gelatin capsules and conventional tablets are the most commonly used dosage forms. Geriatric and pediatric patients may have difficulties in chewing or swallowing pharmaceuticals that are intended for oral administration
Precise measurements were taken with the use of a Sartorius weighing balance, while moisture content was analyzed with a Sartorius moisture analyzer. Humidity levels were monitored with an Equimox hygrometer and tablet compression was performed using two machines: the Rimek Minipress (12 Station) and the Cadmach (16 Station). Disintegration testing was carried out with an Electrolab USP disintegration tester, and friability was assessed using an Electrolab USP friabilator. Bulk and tap densities were measured with an Electrolab USP apparatus. Stability studies were conducted in a Newtronics stability walk-in chamber. Infrared spectroscopy was performed with a Jasco FTIR, and HPLC (high-performance liquid chromatography) analysis was conducted using an Agilent HPLC system.
The physicochemical properties of the vitamins were evaluated, including their description, crystallinity, odor, solubility, identification by infrared spectroscopy (IR), loss on drying, melting point, heavy metals content, and assay.
The formulation used APIs from Strides Arcolab: Calcium Pantothenate, Folic Acid, Nicotinamide, Thiamine Hydrochloride, Riboflavin, Pyridoxine Hydrochloride, Cyanocobalamin, and Ascorbic Acid.
Excipients were chosen to enhance disintegration and ensure compatibility with vitamins, including diluents, effervescent mixture, super disintegrants, taste masking agents, sweeteners, flavourings, lubricants, and glidants.
The formulation included several excipients, each with a specific role: Isomalt (Galen IQ) as a diluent, Veegum-F (Magnesium Aluminium Silicate) (Pioma Chemicals) as a taste-masking agent, Tartaric Acid, Sodium Bicarbonate, and Citric Acid (Strides Acrolab) for the effervescent mixture, Crospovidone and Croscarmellose Sodium (Strides Acrolab) as super disintegrants, Orange Flavour (Givovidan & Sonorome) and Menthol (Strides Acrolab) for flavouring and taste bud desensitization, Sucralose and Liquorice (Strides Acrolab) as sweeteners and Magnesium Stearate and Talc (Strides Acrolab) as a lubricant and glidant, respectively.
Infra-red spectroscopy was used to identify functional groups in the drug and excipients to confirm their chemical identity and compatibility.
Water-soluble B vitamins were chosen as ideal candidates for fast-dissolving tablets for formulation. The selected vitamins include Calcium Pantothenate (B5), Folic Acid (B9), Niacinamide (B3), Thiamine Hydrochloride (B1), Riboflavin (B2), Pyridoxine Hydrochloride (B6), Cyanocobalamin (B12), and Ascorbic Acid (C). Fast-dissolving tablets of the Vitamin B Complex were prepared using the method of direct compression.
All ingredients, except the super disintegrant, magnesium stearate, and talc, were sieved through a #40 mesh. The APIs, Veegum-F, and isomalt were mixed in small portions to achieve uniformity. Super disintegrant, magnesium stearate, and talc were sieved through a #60 mesh. Both mixtures were blended in an octagonal blender for 15-20 minutes, then compressed using a hydraulic press. The compression force was adjusted to achieve tablet hardness of 30-40 Newtons, with tablet weight kept constant at 550 mg for formulations F1 to F3.
Effervescent tablet preparation required maintaining at 20-30% RH and temperatures below 30°C. Ingredients, except for the effervescent mixture, magnesium stearate, and talc, were sieved through a #40 mesh. APIs, Veegum-F, and isomalt were blended in small portions to achieve uniformity. The effervescent mixture, magnesium stearate, and talc were sieved through a #60 mesh. Both mixtures were then blended in an octagonal blender for 15-20 minutes before immediate compression. Tablets were compressed with a hydraulic press to achieve a hardness of 30-40 Newtons, with a constant weight of 550 mg for formulations F4 to F7 (
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Thiamine Hydrochloride (B1) |
2.1 |
2.1 |
2.1 |
2.1 |
2.1 |
2.1 |
2.1 |
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Riboflavin (B2) |
1.95 |
1.95 |
1.95 |
1.95 |
1.95 |
1.95 |
1.95 |
|
Niacinamide (B3) |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
Calcium Pantothenate (B5) |
7.5 |
7.5 |
7.5 |
7.5 |
7.5 |
7.5 |
7.5 |
|
Pyridoxine Hydrochloride (B6) |
1.95 |
1.95 |
1.95 |
1.95 |
1.95 |
1.95 |
1.95 |
|
Folic Acid (B9) |
0.6 |
0.6 |
0.6 |
0.6 |
0.6 |
0.6 |
0.6 |
|
Cyanocobalamine (B12) |
0.3 |
0.3 |
0.3 |
0.3 |
0.3 |
0.3 |
0.3 |
|
Ascorbic Acid (Vit C) |
78 |
78 |
78 |
78 |
78 |
78 |
78 |
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Crospovidone |
10 |
---- |
10 |
---- |
---- |
---- |
---- |
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Croscarmellose Sodium |
---- |
10 |
10 |
---- |
---- |
---- |
---- |
|
Tartaric Acid |
---- |
---- |
---- |
10 |
30 |
40 |
30 |
|
Citric acid |
---- |
---- |
---- |
2 |
5 |
10 |
5 |
|
Sodium Bicarbonate |
---- |
---- |
---- |
10 |
60 |
80 |
60 |
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Orange Flavour |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
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Menthol |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
|
Sucralose |
25 |
25 |
25 |
25 |
25 |
25 |
25 |
|
Liqorice |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
Isomalt |
256.2 |
256.2 |
246.2 |
244.2 |
171.2 |
136.2 |
287.6 |
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Veegum-F |
116.4 |
116.4 |
116.4 |
116.4 |
116.4 |
116.4 |
---- |
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Talc |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
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Magnesium Stearate |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
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Total |
550 |
550 |
550 |
550 |
550 |
550 |
550 |
The purpose of the evaluation was to analyse the physicochemical properties and other characteristics of the developed formulations.
Effervescent components are highly hygroscopic, so pre-compression parameters were maintained below 40% RH to prevent moisture absorption.
Bulk density is the ratio of the powder's mass to its bulk volume. It is measured by pouring weighed, sieved powder into a measuring cylinder and noting the initial volume, which is used in the calculation and expressed in g/cc.
Tapped density is the mass-to-tapped volume ratio of powder. Fifty grams of blend were placed in a 250 ml flask, and the volume was measured after 100 taps expressed in g/cc.
The angle of repose is the maximum angle between a powder pile's surface and the horizontal. Powders were allowed to flow through a funnel and form a heap. The angle was calculated from the heap's height and radius. An angle <25° indicates excellent flow, 25-30° good flow, 30-40° passable, and >40° poor flow.
Powder flowability is assessed by comparing bulk density (Db) and tapped density (Dt) to calculate the compressibility index. Compressibility ranges indicate flow properties: 5-15% for excellent, 12-16% for good, 18-21% for fair, 23-25% for poor, 33-38% for very poor, and >40% for extremely poor flow.
The ratio of tapped density to the bulk density was calculated by Hausner’s ratio.
Directly compressed tablets were examined under the magnifying lens for the shape of the tablet.
The measurements for the thickness and diameter were taken using calibrated digital vernier callipers, with 3 tablets from each formulation being randomly chosen and individually measured.
Hardness, indicating a tablet's ability to withstand mechanical shocks, was measured in Newtons using a digital hardness tester. A random selection of three tablets was done for testing.
friability was measured using a Roche Friabilator. Ten tablets were weighed (WI), placed in the friabilator, and rotated at 25 rpm for 4 minutes or 100 revolutions. The tablets were weighed again (WF) and % friability wascalculated. A friability <1% was considered acceptable.
Ten tablets from each batch were weighed individually to check weight variation, allowing minor deviations as per U.S. Pharmacopoeia standards.
Content uniformity was conducted using HPLC method.
For formulations with super disintegrants, a Petri dish (5.5 cm diameter) with 6 ml methylene blue dye was used. A tablet placed in the center was observed, and the time to wet the tablet's surface was recorded as wetting time.
A tablet was placed in 10 ml of water at 37±0.5°C, and the time for complete dispersion was measured.
The study was conducted at 40%, 60%, and 75% RH at 25°C. Five clean Petri dishes were weighed (W1). Ten tablets per dish were weighed (W2). Dishes were placed in a desiccator with a saturated salt solution for each RH and sealed. Initial time was recorded as '0', and weights were measured at 2, 4, 6, 8, 24, 32, and 48 hours. The solubility and relative humidity of Potassium Carbonate was 1.15 g/ml at 40% RH, Sodium Bromide was 1.16 g/ml at 60% RH and Sodium Chloride was 0.37 g/ml at 75% RH.
The HPLC system, an Agilent equipped with a Photo Diode Array detector, used an Inertial ODS-3V column (250 × 4.6 mm, 5 µm). The column oven was set to 25°C, with a flow rate of 1 mL/min. The analysis was performed at wavelengths of 210 and 268 nm, with an injection volume of 5 µL and a run time of 25 minutes. The mobile phase for the HPLC analysis consisted of two components: Mobile Phase A was a potassium dihydrogen phosphate buffer (pH 2.5), and Mobile Phase B was 100% HPLC-grade methanol.
Dissolved 20.7 mg Vitamin B2 and 30.24 mg Vitamin B6 in a 20 ml volumetric flask and filled to volume with water.
Dissolved 6.533 mg Vitamin B1 and 81.02 mg sodium bicarbonate in a 10 ml volumetric flask and filled to volume with water.
Combined 7.501 mg of Vitamin B1, 40.35 mg of Vitamin B3, 15.78 mg of Vitamin B5, 200.5 mg ascorbic acid, 5 ml of Preparation 1, and 1 ml of Preparation 2 in a 50 ml volumetric flask, shook, and filled to volume with water.
Dissolved 5 mg Vitamin B11 in a 50 ml volumetric flask with 25 ml water and 3-4 sodium carbonate crystals, stirred until dissolved, and filled to volume with water.
Weighed 20 Vitamin ‘B’ Complex tablets and recorded their weight. Triturated the tablets in a clean mortar. Weighed 550 mg of the powder blend, transferred it into a 100 ml amber volumetric flask, and mixed with water. Adjusted the volume with water. Equilibrated the chromatographic system with a gradient program by injecting the blank solution, followed by 10 µl of the standard preparation four times. Ensured that the % RSD for each component was within 5%. Injected 10 µl of the sample preparation, identified each peak by comparing retention times with the standard, and calculated the amount of each ingredient.
The International Conference on Harmonization (ICH) Guidelines on “Stability Testing of New Drug Substances and Products” (QIA) outline stability test requirements for drug registration in the EU, Japan, and the USA. The International Conference on Harmonization guidelines specify that long-term testing is at 25°C ± 2°C with 60% RH ± 5% for 12 months, and accelerated testing is at 40°C ± 2°C with 75% RH ± 5% for 6 months. In this study, stability testing was conducted at 40°C and 75% RH for 2 months. The formulation was packed in moisture-proof containers with silica gel to prevent moisture uptake and stored at 25°C ± 2°C / 60% RH ± 5% for 12 months and 40°C / 75% RH for 6 months. Only the first 2 months of stability results at 25°C ± 2°C / 60% RH and 40°C / 75% RH were reported.
The Samples of Vitamin ‘B’ Complex along with Ascorbic acid were tested for physiochemical properties which complied for in house specifications (
The present study aimed to develop taste-masked formulations of fast-dissolving Vitamin tablets. Vitamin dosages were determined on the basis of "Recommended Dietary Allowance" (RDA), which establishes the nutritional levels needed to meet the requirements of nearly all healthy individuals
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1 |
Description |
White or practically white |
White |
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2 |
Form |
Crystalline powder |
Crystalline powder |
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3 |
Odour |
Characteristic odour |
Complies |
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4 |
Solubility |
Freely soluble in water; soluble in glycerin; slightly soluble in ethanol (95%); practically insoluble in ether. |
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5 |
Identification by IR |
The infrared absorption spectrum of the sample must be concordant with the standard spectrum |
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6 |
Loss on drying |
Not more than 3.0%, determined on 1 g by drying in an oven at 105o |
1.2 % |
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7 |
Heavy metals |
Not more than 20 ppm, on 1.0 g dissolved in 25 ml of water |
5 ppm |
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8 |
Residue on ignition |
Not more than 0.15 % |
0.060 % |
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9 |
Assay |
97.0 - to 103 % |
100 % |
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1 |
Description |
Yellow to yellowish-orange |
Yellow |
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2 |
Form |
Crystalline powder |
Crystalline powder |
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3 |
Odour |
Characteristic odour |
Complies |
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4 |
Solubility |
Practically insoluble in cold water and in most organic solvents; very slightly soluble in boiling water; soluble in dilute acids and in alkaline solutions |
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5 |
Identification by IR |
The infrared absorption spectrum of the sample must be concordant with the standard spectrum |
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6 |
Sulphated ash |
Not more than 0.5% |
0.00 |
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7 |
Assay |
99-102 % |
100% |
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|
1 |
Description |
Colourless crystals or white |
White powder |
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2 |
Form |
Crystalline powder |
Crystalline powder |
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3 |
Odour |
Faint and characteristic |
Complies |
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4 |
Solubility |
Freely soluble in water and in ethanol (95%); slightly soluble in chloroform and in ether. |
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5 |
Identification by IR |
The infrared absorption spectrum of the sample must be concordant with the standard spectrum |
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6 |
Heavy metals |
Not more than 30 ppm, |
5 ppm |
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7 |
Melting point |
Melts between 128o and 131o |
Complies |
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|
8 |
Assay |
97.5-102 % |
99.5 % |
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|
1 |
Description |
Colourless crystals or white |
White powder |
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2 |
Form |
Crystalline powder |
Crystalline powder |
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3 |
Odour |
Characteristic |
Complies |
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|
4 |
Solubility |
Freely soluble in water and in ethanol (95%); slightly soluble in chloroform and in ether. |
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|
5 |
Identification by IR |
The infrared absorption spectrum of the sample must be concordant with the standard spectrum |
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6 |
Heavy metals |
Not more than 20 ppm, |
10 ppm |
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7 |
Loss on Drying |
Not more than 5.0%, determined on 1 g by drying in an oven at 105o |
1.5% |
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|
8 |
Assay |
98.5 to 101.0% |
99.5 % |
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|
1 |
Description |
Powder |
Powder |
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2 |
Colour |
Orange yellow |
Complies |
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3 |
Solubility |
Very slightly soluble in water; more soluble in saline solution than in water; practically insoluble in chloroform, in ethanol (95%) and in ether. |
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4 |
Specific rotation |
-135 to -1150 |
-127 |
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5 |
Loss on drying |
Max 1.5% |
0.7 |
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6 |
Sulphated ash |
Max0.10% |
0.02 |
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7 |
Heavy metals |
10 ppm |
complies |
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|
8 |
Lead |
<=2 ppm |
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|
1 |
Description |
White or practically white |
White |
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2 |
Form |
Crystalline powder, pallets or rods |
Crystalline powder |
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3 |
Odour |
Acidic, with slightly bitter saline taste almost odourless |
Complies |
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4 |
Solubility |
Freely soluble in water and in ethanol (95%); slightly soluble in chloroform and in ether. |
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5 |
IR |
Complies |
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6 |
Residue on ignition |
Not more than 0.15 % |
0.060 % |
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|
7 |
Assay |
97.0- to 103 % |
100 % |
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|
1 |
Description |
Crystalline powder or Small crystals |
Crystalline powder |
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2 |
Coloration of aqueous solution (0.050g + 25 ml) |
Red |
Red |
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3 |
Loss on Drying |
<= 3.0 % |
1.5 % |
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|
4 |
Solubility |
Sparingly soluble in water and in ethanol (95%); practically insoluble in chloroform, in acetone and in ether. |
Complies |
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5 |
Related substances (HPLC) |
<=3.0 % |
0.9 % |
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6 |
Assay by spectroscopy |
97.0 to 100.5 % |
99.8 % |
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|
1 |
Appearance |
Powder |
Powder |
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2 |
Colour |
White |
White |
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3 |
Loss on Drying |
0 to 0.1 % |
0.01 % |
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4 |
Heavy metals |
0-10 ppm |
<10 ppm |
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5 |
Iron |
0-2 ppm |
1.22 ppm |
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6 |
Copper |
0-5 ppm |
2.546 ppm |
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7 |
Lead |
0-2 ppm |
0.394 ppm |
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|
8 |
Arsenic |
0-3 ppm |
1.754 ppm |
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|
9 |
Mercury |
0-1 ppm |
0.698 ppm |
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10 |
Oxalic Acid |
0-0.2 ppm |
0.146 ppm |
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Assay |
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|
11 |
Through USP 20 (850u) |
100 to100 % |
100 % |
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12 |
Through USP 100 (150u) |
0 to 70 % |
22 % |
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1. |
Vitamin B Complex + 10mg Crospovidone [F1] |
Complies |
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2. |
Vitamin B Complex + 10mg Croscarmellose Sodium [F2] |
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3. |
Vitamin B Complex + 10mg Crospovidone +10mg Croscarmellose Sodium [F3] |
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4. |
Vitamin B Complex + 10 mg Tartaric Acid + 2 mg Citric acid + 10mg Sodium Bicarbonate [F4] |
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5. |
Vitamin B Complex + 30 mg Tartaric Acid + 5 mg Citric acid + 60mg Sodium Bicarbonate [F5] |
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6. |
Vitamin B Complex + 40 mg Tartaric Acid + 10 mg Citric acid + 80mg Sodium Bicarbonate [F6] |
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7. |
Vitamin B Complex + 30 mg Tartaric Acid + 5 mg Citric acid + 60 mg Sodium Bicarbonate [F7] |
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The recommended daily intake of vitamins varies by age and physiological condition. For adults aged 31-50 years, it is: Calcium Pantothenate 5 mg, Folic Acid 0.4 mg, Nicotinamide 16 mg, Thiamine Hydrochloride 1.2 mg, Riboflavin 1.3 mg, Pyridoxine Hydrochloride 1.3 mg, Cyanocobalamin 0.2 mg, and Ascorbic Acid 60 mg. For children aged 4-8 years: Calcium Pantothenate 3 mg, Folic Acid 0.2 mg, Nicotinamide 8 mg, Thiamine Hydrochloride 0.6 mg, Riboflavin 0.6 mg, Pyridoxine Hydrochloride 0.6 mg, Cyanocobalamin 0.08 mg, and Ascorbic Acid 37 mg. Pregnant and lactating women require: Calcium Pantothenate 6-7 mg, Folic Acid 0.5-0.6 mg, Nicotinamide 17-18 mg, Thiamine Hydrochloride 1.4 mg, Riboflavin 1.4-1.6 mg, Pyridoxine Hydrochloride 1.9-2 mg, Cyanocobalamin 0.8-1 mg, and Ascorbic Acid 87 mg daily. Due to the sensitivity of vitamins to light and environmental conditions, excess quantities, or "overages," are added to ensure sufficient levels
After finalizing the vitamin doses, various trials were performed using both super disintegrants and effervescent mixtures. Although formulations were prepared, a bitter taste from the vitamins was a problem. To mask the taste, Magnesium Aluminium Silicate (VEEGUM-F) was used. VEEGUM-F, a directly compressible grade, was chosen as the taste-masking agent. Its concentration was optimized by trial and error, with a final ratio of 1:1, meaning an equal proportion of vitamins and VEEGUM-F. Seven formulations were prepared: the first three used combinations of two super disintegrants or single super disintegrants; the next three used different concentrations of effervescent mixtures; and the final formulation used the effervescent concentration from the seventh formulation without the taste-masking agent.
The dosage form development involved trials with varying excipient percentages to optimize the formula. Due to the high dose of active ingredients, the goal was to minimize excipients to reduce tablet size for patient compliance and cost-effectiveness. Formulation F-1 used Crospovidone alone as a super disintegrant but had a disintegration time (Dt) of 165 seconds and a bitter taste. The next formulation used Croscarmellose Sodium but still had a DT of 140 seconds and bitterness. The third approach combined Crospovidone and Croscarmellose Sodium, reducing Dt to 103 seconds but increasing bitterness. The fourth approach used a 1:1 ratio of tartaric acid and sodium bicarbonate, reducing Dt to 95 seconds. In the fifth approach, a 1:2 ratio of tartaric acid and sodium bicarbonate further decreased DT to 80 seconds with improved taste and mouthfeel, effectively masking the bitterness. The sixth approach, with a 1:2 ratio of tartaric acid and sodium bicarbonate, reduced Dt to 45 seconds but resulted in an unacceptably tart taste. The seventh approach used the effervescent concentration from F-5 but removed VEEGUM-F, resulting in an undesirable taste. Finally, F-5, which had acceptable assay results, was selected as the optimized formulation and subjected to stability studies (
The stability studies followed ICH guidelines. Long-term testing was conducted at 25°C ± 2°C with 60% RH ± 5% for 12 months, and accelerated testing at 40°C ± 2°C with 75% RH ± 5% for 6 months. Reports from the first two months were within acceptable limits, prompting continuation of the study for the next six months (
The research aimed to create a novel injectable dosage form of betamethasone acetate, which is insoluble in water. The project aimed to overcome its drawbacks and create a stable formulation as a depot injectable suspension. Surfactants like polysorbate 80 and PEG 3350 were selected to improve syringibility, resuspendibility, and sedimentation characteristics. Monobasic and dibasic sodium phosphate were used as buffers, disodium edeate as a complexing agent, and benzalkonium chloride as a preservative. The batch-II formulation was chosen due to its good appearance, syringibility, resuspendibility, drainage, zeta potential, assay, pH, and related impurities. The drug release from the suspension was prolonged for 24 hours. Stability studies were conducted for three months, revealing the formulation's stability.