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Formulation of Vitamin D3 + Calcium tablets and evaluation of Physical and chemical Properties

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Der Pharmacia Lettre, 2016, 8 (12):193-199
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ISSN 0975-5071
USA CODEN: DPLEB4
193
Scholar Research Library
Formulation of Vitamin D3 + Calcium tablets and evaluation of Physical and
chemical Properties
Amit Sarker*
1
, Md. Mahmudul Hasan
1
, Md. Iftekhar Hussain
1
, Riazul Haque Tuhin
1
,
Taslima Begum
1
and Prozzal Roy
2
1
Department of Pharmacy, Primeasia University, Star Tower, 12 Kemal Ataturk Avenue, Banani, Dhaka-1213,
Bangladesh
2
Department of Pharmacy, University of Development Alternative(UODA), 80 Satmasjid Road, Dhaka -1209,
Bangladesh
_____________________________________________________________________________________________
ABSTRACT
The aim of this investigation was to develop Vitamin D3 and Calcium tablets by wet granulation method using
excipients and to compare the tablet properties with BP specification. The blend was compressed on a single punch
machine, tablets were subjected to various tests (weight variation, diameter and thickness, hardness, disintegration
and assay of the drug) and the results were also in compliance with the official specifications. All the physical
properties studied indicated that all excipients are good pharmaceutical excipients in tablets. The objective of this
work was to present Vitamin D3 in granular and tablet form with improved dispersability, to minimize the
complexity of formulations and to make cost effective product.
Keywords: Vitamin D3 and Calcium, tablet formulation, wet granulation.
_____________________________________________________________________________________________
INTRODUCTION
Vitamin D3(cholecalciferol) is derived from 7-dehyrocholesterol and involved in bone health. Scientists have
recognized that, depression, back pain, cancer, both insulin resistance and pre-eclampsia during pregnancy, impaired
immunity and macular degeneration are directly linked to the Vitamin D3 deficiency [1].Inadequate Vitamin D3
may cause secondary hyperparathyroidism that increases the risk of osteoporosis and fractures and change the
regulatory mechanisms of parathyroid hormone (PTH) [2]. Other types of condition such as high blood pressure,
fibromyalgia, diabetes, multiple sclerosis, rheumatoid arthritis has been linked to the low levels of Vitamin D3
[3,4,5]. Vitamin D3 deficiency is responsible psychiatric and neurologic disorders and associated with low mood
[6]. Vitamin D3 improves bone health and deficiency causes a painful bone disease known as osteomalacia.
Deficiency of Vitamin D3 also causes exacerbates muscle weakness and turn to fractures [7]. There is a relationship
between the intakes of calcium, either alone or in combination with vitamin D, and reducing the loss of bone mineral
density (BMD). Reduction in the risk of bone fractures are related to the reducing the loss of BMD. Calcium and
vitamin D may also reduce the loss of bone mineral in post-menopausal women [8]. Bone mineral density (BMD) or
incidence of osteoporotic bone fractures can be changed by the combination of calcium and vitamin D. The
combination of calcium and vitamin D can be effective in the prevention and treatment of steroid-induced
osteoporosis in adults (older than 18 years) [9,10,11,12].
Amit Sarker et al Der Pharmacia Lettre, 2016, 8 (12):193-199
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The objective of the present study is to develop a formulation of Calcium and Vitamin D3 tablet by wet granulation
process and evaluation of its Physical and chemical properties.
MATERIALS AND METHODS
Materials: Chemicals that were used for formulation are given in table 1. All chemicals were procured from
commercial sources.
Table 1: Amount of Active and Excipients
Chemicals Amount (per tablet)
1 Calcium Carbonate 1250 mg
2 Vitamin D3 2.00 mg
3 Maize Starch (as paste) 25 mg
4
Maize Starch( as
dry mix)
25.00 mg
5
Lactose monohydrate
25.00 mg
6 Sodium Methyl paraben 1.00 mg
7 Sodium Propyl paraben 0.24 mg
8 Povidone K-30 16.00 mg
9 Purified talc 2.00 mg
Magnesium stearate
2.00 mg
Maize Starch dry
45.00 mg
Preparation Method:
Wet granulation method was used to prepare the tablets. Mass mixer was used to mix the Calcium Carbonate,
Lactose monohydrate and Maize Starch. These materials were passed through 40-mesh size screen and mix for 20
minutes. Make a solution of Povidone K-30 in hot DM water. Stirring was continued until making a clear solution.
Slurry wass prepared by using Maize Starch, Sodium Methyl paraben and Sodium Propyl paraben. This slurry was
added in clear solution of Povidone K-30. This mixture was called paste. Then paste was added in mass mixer and
makes a wet mass which mixed for 10 minutes. Wet mass was dried in Fluid Bed Dryer (FBD) at 70-75
o
C for 30
minutes and then transfer into the multi mill to reduce the size. Finally it was again transferred to Fluid Bed Dryer
(FBD) for final drying at 60-65
o
C for 10 minutes.
Methods for Evaluation of Tablet Properties
Tablets properties were evaluate by using BP and by non-pharmacopoeial tests.
Weight variation test
20 tablets were used to carry out the weight variation test. 20 tablets were weighed individually on an digital balance
(Digital Balance, Model No. Ek 6001, Origin: Precisa, Switzerlant) and calculate the average weight. Individual
weight was compared with average weight.
Length, Width and Thickness
Micrometer screw gauge was used to determine the length, width and thickness of each tablet. Random samples of
10 tablets were selected and their length, width and thickness was calculated in mm.
Hardness:
Hardness test was done to measure the tablet crushing strength. Hardness of randomly selected 10 tablets was
measured using Hardness Tester (Model No. HT-50, Origin: Thermonic, India).
Friability:
Friabilator (Friability Machine, Model No. 902, Origin: Electronic, India) was used to determine the Friability of
tablets. This consists of a plastic chamber that revolves at 25 rpm. After operation tablets were reweighed.
Disintegration Test
Six tablets were putting in basket rack assembly (Disintegration Test Apparatus, Model No.: D-17, Origin:
Electronic, India) to measure the Disintegration time. Six disks were used to avoid floating of tablets in 900 ml
distill water maintained at 37±2ºC.
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Assay:
Assay for calcium (Titrimetric Method)
Reagents:
1. Ammonia buffer P
H
10.9: Prepared by dissolving 67.5 g of ammonium chloride in sufficient 10 M ammonia to
produce 1000 ml.
2. Mordent black II triturate: Prepared by mixing 1 part of mordent black II with 99 parts of sodium chloride.
Procedure:
20 tablets were crushed into fine powder. About 88mg of tablet powder(About 88 mg of tablet powder is equivalent
to about 30mg of calcium) was taken in a conical flask with 5ml dilute hydrochloric acid and 30ml of water. Boiled
the solution for 2 minutes; allowed for cooling and diluting up to 50 ml with water. 10 ml of ammonia buffer (p
H
10.9) was added. Titration was done with 0.05M disodium edentate(Each ml of 0.05M disodium edentate is
equivalent to 2.004mg of elemental calcium or 5.004mg of calcium carbonate) using mordant black II triturate as
indicator until the color change from pink to blue.
Content of elemental calcium per tablet was calculated by using following equation:
=V × F × 2.004 × W

V=Volume of 0.05M disodiumedetate required in ml.
F= factor of the titre.
WT= weight of sample taken in mg.
W=average weight of the tablet taken in mg.
Assay For Vitamin D
3
(HPLC method):
Mobile Phase: Acetonitrile : methanol = 91 : 09
Chromatographic system
Flow rate: 1.5ml/min
Column: Octadecylsilyl silica gel for liquid Chromatography (C
18
). (size: 4.6mm×250mm, 5µm).
Detector: 265nm, UV
Injection volume: 20µl
Temperature: 40
0
C
Standard Preparation: Accurately about 100mg of Cholecalciferol was taken in 100ml volumetric flask. 30ml of
methanol was added and then sonication for proper dissolve .Volume up to 100 ml was completed by using
methanol and mix well. About 2ml of this solution was diluted to 50 ml by using same diluent.
Sample Preparation: 20 tablets were crushed into fine powder. 1215 mg of those powder was taken into 50 ml
volumetric flask. 30 ml of methanol was added and sonicated for dissolve. Finally volume up to 50ml was filled
with same solvent methanol.
Chromatographic Procedure: Before injection, filtration was done through 0.2µ syringe filter. Separately 20 µl of
prepared sample were injected into the chromatograph. Chromatograms were recorded and measure the responses
for major peaks. The content of cholecalciferol was calculated by using following equation:
Calculation: Content of Cholecalciferol(IU)


×


×

×


×


× Wmg/tablet
=X IU of Cholecalciferol.
Where,
AT= Area of sample preparation.
AS= Area of standard preparation.
WT= Weight of sample in mg.
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WS= Weight of Standard Cholecalciferol (vitamin D
3
) in mg.
Ps=Potency of vitamin D
3
standard.(100000 IU/gm)
W=Average weight of tablet.
100000 IU/gm
1mg=100 IU
2mg=200 IU =one tablet contain 200 IU vitamin D3
RESULTS AND DISCUSSION
Wet granulation process was used to prepare the Calcium Carbonate and vitamin D
3
tablets by using different types
of excipients (table 1). Tablet properties were evaluated by performing various tests. The result of weight variation
test was + 0.76% and -1.42%. The weight variation test is alternative to content uniformity test that assure the
therapeutic utility [13]. Weight variation test is an also an indicator of variations in the drug content [14]. Standards
and specifications have given in Pharmacopoeias that provide permissible limits for weight variation. Result of
length, width and thickness was 19.4 mm, 9.2 mm and 5.9 mm respectively whereas the permissible limit according
to BP is19.2 mm – 19.4 mm for length, 9.0 mm – 9.2 mm for width and 5.6-6 mm for thickness. The result of
hardness was 10 kg (permissible limit is not less than 4.0 kg) which meet the permissible limit. Friability test
indicates the mechanical strength. According to Pharmacopoeia friability for compressed tablet is not more than
1.0%. The result of Calcium and Vitamin D3 tablet was 0.14%. After physical tests the tablets were subjected to
chemical tests. Assay, disintegration and tests were carried out for evaluation of chemical properties. Availability of
a drug for dissolution and absorption is determined by evaluation of disintegration [15]. The result showed that
tablets took 5 minutes to disintegrate (permissible limit is not more than 15 minutes). Content of Cholicalciferol was
determined by HPLC method and the result was 202.4 IU (permissible limit is 180.0 IU -330.0 IU). The Calcium
content was assayed by Titrimetric Method and result was 497.07 mg (permissible limit is 450.0 mg -550.0 mg). All
results are given in table 2.
Calculation:
Content of elemental Calcium:
=
××.×

= 15.1× 0.986 × 2.004 × 1414.4/ 84.9 mg/tablet
= 497.07 mg/tablet
V= Volume of 0.05M disodium EDTA in ml = 15.1
F = Factor of the titrant = 0.986
W = Average weight of tablet in mg = 1414.4
WT = Weight of sample in mg = 84.9 mg
Content of Cholicalciferol :


×


×

×


×


× Wmg/tablet
= 28304/28455 × 99.0/100 × 2/50 × 50/ 1400 × 100000/100 × 1414.4 mg/Tablet
= 2.024 mg/Tablet
= 202.4 IU ( 2 mg = 200 IU)
Where,
AT = Area of sample preparation = 28304
AS = Area of standard preparation = 28455
WT = Weight of sample in mg = 1400
WS = Weight of Cholicalciferol(Vitamin D3) standard in mg = 99.0 mg
Ps = Potency of Cholicalciferol(Vitamin D3) standard (100000 IU)
W = Average weight of tablet = 1414.4 mg
Amit Sarker et al Der Pharmacia Lettre, 2016, 8 (12):193-199
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Figure1: Chromatogram of Vitamin D3 tablet(sample)
Amit Sarker et al Der Pharmacia Lettre, 2016, 8 (12):193-199
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Figure 2: Chromatogram of Vitamin D3 tablet(Standard)
Table 2: Physical and Chemical properties of Calcium and Vitamin D3 tablets
Sl.No.
Tests
Specifications
Results
1 Average weight /tablet 1388.7 mg to 1445.3 mg 1414.5 mg
2 Weight variation + 5.0-% + 0.76% and -1.42%.
3 Length 19.2 mm – 19.4 mm 19.4 mm
4 Width 9.0 mm – 9.2 mm 9.2 mm
5 Thickness 5.6 mm-6.0 mm 5.9 mm
6
Hardness
Not less than 4.0 kg
10 kg
7
Friability
Not more than 1.0%
0.14%
8 Disintegration time Not more than 15 minutes 5 min
9 Assay:
a. Content of elemental Calcium per tablet
450.0 mg -550.0 mg 497.07 mg
b.
Content of Vitamin D3 per tablet 180.0 IU -330.0 IU 202.4 IU
CONCLUSION
In the present work, vitamin D3 and calcium tablets were manufactured successfully that fulfills all the
pharmacopoeial limits. This type of study not only for this combination but also be done on other drugs. Present data
would be used as a reference for future work.
Amit Sarker et al Der Pharmacia Lettre, 2016, 8 (12):193-199
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Scholar Research Library
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Article
Full-text available
Vitamin D is a hormone that controls phosphorus, calcium, and bone metabolism and neuromuscular function. Vitamin D synthesis is a process in which the skin, liver, and kidney are sequentially involved. The vitamin D pool is completed by the amount taken with food and supplements. Vitamin D deficiency causes osteopenia, precipitates and exacerbates osteoporosis, causes a painful disease, osteomalacia, and increases muscle weakness, which worsens the risk of falls and fractures. A high prevalence of vitamin D insufficiency exists in the apparently healthy population, osteoporotic patients, and patients with prior fractures. Factors contributing to low vitamin D levels include low sunlight exposure, decreased skin synthesis and intestinal absorption, and inadequate diet. The simplest way to correct hypovitaminosis is adequate nutrition and supplements. However, few patients with osteoporosis and/or fractures, receive adequate supplements. Vitamin D insufficiency may alter the regulatory mechanisms of parathyroid hormone and may induce a secondary hyperparathyroidism that increases the risk of osteoporosis and fractures, although the necessary degree of this is not established. Monitoring of serum 25-hydroxyvitamin D levels is the only way to assess vitamin D status. The ideal healthy blood levels of 25-hydroxyvitamin D are controversial, although a range from 30 to 60ng/mL is widely accepted. The role of vitamin D supplementation is to provide humans with the nutrient in an amount closer to the biological norm for our species. This amount of vitamin D results in optimal function of many aspects of health, including balance and muscle strength, thus reducing the risk of fracture beyond what is possible via the quality and quantity of bone itself.
  • R Vieth
  • Y Ladak
  • P G Walfish
Vieth R, Ladak Y, Walfish PG. J Clin Endocrinol Metab. 2003 Jan;88(1):185-91.
  • J Lappe
  • D Travers-Gustafson
  • K Davies
  • R Recker
  • R Heaney
Lappe J, Travers-Gustafson D, Davies K, Recker R, Heaney R. American Journal of Clinical Nutrition. 2007, June 8;85(6):1586-1591.
  • L M Bodnar
  • J M Catov
  • H N Simhan
  • M F Holick
  • R W Powers
  • J M Roberts
Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM. J Clin Endocrinol Metab. 2007 May 29.
  • Z Maghbooli
  • A Hossein-Nezhad
  • F Karimi
  • A R Shafaei
  • B Larijani
Maghbooli Z, Hossein-Nezhad A, Karimi F, Shafaei AR, Larijani B. Diabetes Metab Res Rev. 2007 Jul 2.
  • C H Wilkins
  • Y I Sheline
  • C M Roe
  • S J Birge
  • J C Morris
Wilkins CH, Sheline YI, Roe CM, Birge SJ, Morris JC. Am. J Geriatr Psychiatry. 2006 Dec;14(12):1032-40.
Nutrition and Allergies on a request from Abtei Pharma Vertriebs GmbH on the scientific substantiation of a health claim related to Calcium plus Vitamin D3 chewing tablets and reduction of the risk of osteoporotic fractures by reducing bone loss
Scientific Opinion of the Panel on Dietetic Products, Nutrition and Allergies on a request from Abtei Pharma Vertriebs GmbH on the scientific substantiation of a health claim related to Calcium plus Vitamin D3 chewing tablets and reduction of the risk of osteoporotic fractures by reducing bone loss. The EFSA Journal, 2009, 1180, 1-13.
  • A Avenell
  • W J Gillespie
  • L D Gillespie
  • O Connell
Avenell A, Gillespie WJ, Gillespie LD, O'Connell DL. The Cochrane Database of Systemic Reviews 3, 2005,CD000227.
  • S Boonen
  • P Lips
  • R Bouillon
  • H A Bischoff-Ferrari
  • D Vanderschueren
  • P Haentjens
Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P. The Journal of Clinical Endocrinology and Metabolism 2007,92 (4),, pp. 1415-1423.
The Cochrane Database of Systemic Reviews 2
  • J Homik
  • M E Suarez-Almazor
  • B Shea
  • A Cranney
  • G Wells
  • P Tugwell
Homik J, Suarez-Almazor ME, Shea B, Cranney A, Wells G, Tugwell P. The Cochrane Database of Systemic Reviews 2, 1998, CD000952