Different Brands Of Cholecalciferol Tablets Biology Essay

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ABSTRACT:

The basic purpose of my work was to develop accelerated stability-indicating Non-Pharmacopoeial method for assay of Cholecalciferol tablets and to understand the drug assay stability at different intervals at accelerated climatic condition.

In accelerated stability study, minimum of 3 points including the initial and final time points (e.g., 0, 3, 6 months) from a 6 month study were analyzed. Accelerated study conditions comprised of 40± 2°C/75± 5%RH for 6 months. The assay results data was analyzed by comparison between different commercial brands and were found to be sensitive to elevated temperatures as well as to high relative humidity. In my study, I analyzed that the active ingredient should have best result in ambient climate while in accelerated climate, there were little bit degradation of active drug material (Cholecalciferol).

INTRODUCTION:

Degradation during storage and transportation is of particular vital issue in tropical countries. Indeed, shelf life (an expiry date) determined for a temperate climate may be inappropriate in a tropical region even when high standards of packaging are met. For this purpose, particular importance is accorded to visual inspection of dosage forms, since this frequency provides a first vital indication of degradation which may be due to poor manufacture, tampering etc.

Because the distribution environment is highly variable, products must be distributed in a manner that ensures the drug product quality will not be adversely affected. The effect of possible temperature and relative humidity fluctuations, outside of labeled storage conditions, during transportation of drug products, can be evaluated on the basis of the stability analysis for that drug [1, 3].

No pharmaceutical product is stable indefinitely and certainly the majority of drug products are stable only for a limited time. The instability may be demonstrated as active drug or excipients degradation. Instability is thermodynamic phenomenon in nature of pharmaceutical formulations.

Vitamin D3 or Cholecalciferol commonly known as the "Sunshine vitamin" is essential for calcium metabolism and for bone health. The major physiological function of Cholecalciferol is to maintain the blood calcium and phosphorus levels within the normal range, metabolic functions are essential for most of the life process. Cholecalciferol is synthesized from 7-dehydrocholesterol in skin by the action of sunlight. Under UV ray between 290-315 nm, 7-dehydrocholesterol is converted to previtamins D3. However, it is thermodynamically unstable easily rearrange to more stable form, Vitamin D3 [4, 6, 10].

Cholecalciferol (Vitamin D3) undergoes degradation reactions at elevated temperatures and high humidity conditions [7].Our goal in this work was to expand investigation of degradation of various Cholecalciferol samples of tablets to a wider range of conditions than reported previously. Degradation of Cholecalciferol (Vitamin D3) tablets was compared to pure Cholecalciferol.

Cholecalciferol is the vitamin that mediates intestinal calcium absorption, bone calcium metabolism and very likely, muscle activity, usually acts as a hormone precursor [8].

Structure of Cholecalciferol:

Cholecalciferol-activated 7-dehydrocholesterol [9].

Cholecalciferol is also called as activated 7-dehydrocholestrol or vitamin D3. Their chemical formula is C27H44O and molecular weight is 384.7. Its melting point is 84°C to 88°C.It is white odorless crystals which are affected by air and light. It should be stored in a cool place in sealed glass containers in which the air has been replaced by an inert gas. Cholecalciferol should be protected from light [5]. It is oxidized and inactivated by moist air within a few days [8].

ACCELERATED STABILITY STUDY:

Accelerated study is the study designed to increase the rate of chemical degradation and/or physical change of a drug substance or drug product by using exaggerated storage conditions with the purpose of monitoring degradation reactions and predicting the shelf life under normal storage conditions.

The Stability test program comprised of test points (0, 3, 6 months) at given stability conditions. 15 packs of product are required to perform the complete analysis as per the accelerated stability specifications.

Oxidation is a well known chemical degradation pathway for Cholecalciferol. Oxygen, which participates in most oxidation reactions, is abundant in the environment to which Cholecalciferol is exposed, during either processing or long term storage.

Oxidation mechanisms for drug substances (Cholecalciferol) depend on the chemical structure of the drug and the presence of reactive oxygen species or their oxidants.

THE EFFECT OF TEMPERATURE, RELATIVE HUMIDITY AND LIGHT:

Temperature and Relative humidity universally affect the drug molecule but if we protect the drug from light from the start of manufacturing e.g., As Cholecalciferol (Raw material) is packed in aluminium container, while during drug manufacturing it is protected from light, then it is not necessary to check light as critical parameter during ASS of Cholecalciferol.

EVALUATION OF STABILITY DATA:

The data may clear so little degradation and so little variability that it is apparent from looking at the data that the requested re-test period will be granted. Under these circumstances, it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be enough.

An approach for examining the data on a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided confidence limit for the mean curve intersects the acceptance criterion. If analysis indicates that the batch-to-batch variability is small, it is advantageous to combine the data into one overall estimate.

As well as my study is concerned, I am dealing with a class of medicine that has one sided critical region for the statistical aspects of analysis that lies on the greater side of the normal curve. The value for the under study curve that get an increase from the standard (targeted or nominal value) set by official books, I find my critical value to the right hand tail of my normal curve.

This can be completed by first applying appropriate statistical tests, e.g., p values observed level of significance of rejection of more than 0.25 to the coefficient of the regression (we are regressed months with batches, it indicates that there is a 25% change in one variable to other) and zero time intercepts for the individual batches. If it is not suitable to combine data from several batches, the overall retest period should be based on the minimum time a batch can be expected to remain within acceptance criteria [2].

MATERIAL AND METHODOLOGY:

MATERIALS:

A-Drug Used:

1. Qalsan D Tablets manufactured by Novartis Pharma Pakistan.

2. Osam-D Tablets manufactured by Getz Pharma Pakistan.

3. Calgo Tablets manufactured by Horizon Pharma Pakistan.

B-Chemicals Used:

1. Cholecalciferol (Vitamin D3) powder supplied by Cure Pharma, Lahore Pakistan.

2. Formic acid supplied by BDH Laboratory England.

3. Methanol supplied by Lab scan Asia Co Ltd, Thailand.

4. Glacial Acetic Acid supplied by RCI Lab scan Ltd, Thailand.

5. Dinitrophenylhydrazin supplied by Cure Pharma, Lahore Pakistan.

6.Distilled water used was obtained from an all glass electrically heated still and kept stored in a 5 liters well leached and stopper bottle,pH 5.8±as determined by corning pH meter and surface tension 72± 0.2m Nm-1 at 20oC.

METHODOLOGY:

Drug Assay Procedure for Tablets:

Drug assay:

The assay for the active ingredient(s) in the formulations will be performed using U.V spectroscopic method (newly developed or non-pharmacopoeia method). The assays will be repeated three times and the results will be presented as the mean of 3 determinations (± standard deviation) at lambda () max 265nm.

Testing procedure for Tablets:

Preparation of standard solution: Take 100mg of VitaminD3 in 50ml of volumetric flask. Add 10ml formic acid in same volumetric flask and sonicate it for some time. Add methanol to make up the volume up to the mark (50ml).

Then, take 2ml from the stock solution into 100ml volumetric flask.Then,add 1ml of 2,4 dinitrophenylhydrazin compound in 100ml volumetric flask and make up the volume up to the mark up of the flask. Then, take absorbance at lambda max 265nm.

Blank=Methanol.

Preparation of sample: Take 100mg equivalent of Vitamin D3 in 50ml of volumetric flask. Add 10ml formic acid in same volumetric flask and sonicate it for some time. Add methanol to make up the volume up to the mark (50ml).

Then, take 2ml of filtrate solution, through filtration (0.45 micron filter) process, into 100ml volumetric flask. Then, add 1ml of 2, 4 dinitrophenylhydrazin compound in 100ml volumetric flask and make up the volume up to the mark up of the flask. Then, take absorbance at lambda max 265nm.

Blank=Methanol.

U.V spectroscopic method is used to determine the drug assay by using following formula

%Assay = Absorbance of sample x 100

Absorbance of standard

BEHAVIOUR OF INDIVIDUAL DRIGS:

Accelerated Stability Data:(Qalsan D Tablets)

STATISTICAL TESTING:

Statistical Data of Accelerated Stability Studies of Qalsan D Tablets in Two-way ANOVA: Responses versus Months, batches (Based on Assay result)

Source DF SS MS F P

Months 2 3.7727 1.88634 14.75 0.014

Batches 2 9.6977 4.84884 37.90 0.003

Error 4 0.5117 0.12793

Total 8 13.9821

S = 0.3577 R-Sq = 96.34% R-Sq(adj) = 92.68%

Individual 95% CIs For Mean Based on Pooled StDev

Months Mean -+---------+---------+---------+--------

0 101.493 (-------*-------)

3 100.497 (--------*-------)

6 99.927 (--------*-------)

-+---------+---------+---------+--------

99.40 100.10 100.80 101.50

Individual 95% CIs For Mean Based on Pooled StDev

Batches Mean -+---------+---------+---------+--------

1 100.443 (----*-----)

2 101.997 (-----*-----)

3 99.477 (-----*-----)

-+---------+---------+---------+--------

99.0 100.0 101.0 102.0

Results: Here, I have observed a p value of 0.014 for the average analysis of the affects of different methods for months. In this conditional probability, if my hypothesis is true, reveals that three methods significantly differ from each other in giving the response for the understudy assay result. My level of significance was set at 0.05 and the p value "the observed level of significance" is much less than 0.05.

In this research, I have also observed a p value of 0.003 for the average analysis of the affects of different methods for batches. In this conditional probability, if my hypothesis is true, reveals that three methods significantly differ from each other in giving the response for the understudy assay result. My level of significance was set at 0.05 and the p value "the observed level of significance" is much less than 0.05.

Statistical Data of Accelerated Stability Studies of Calgo Tablets in Two-way ANOVA: Responses versus Months, Batches (Based on Assay results)

Source DF SS MS F P

Months 2 92.917 46.4586 12.42 0.019

Batches 2 33.250 16.6252 4.45 0.096

Error 4 14.961 3.7402

Total 8 141.128

S = 1.934 R-Sq = 89.40% R-Sq(adj) = 78.80%

Individual 95% CIs For Mean Based on

Pooled StDev

Months Mean -------+---------+---------+---------+--

0 107.970 (-------*-------)

3 104.537 (------*-------)

6 100.120 (------*-------)

-------+---------+---------+---------+--

100.0 104.0 108.0 112.0

Individual 95% CIs For Mean Based on Pooled StDev

Batches Mean +---------+---------+---------+---------

1 102.180 (----------*---------)

2 103.657 (----------*---------)

3 106.790 (---------*---------)

+---------+---------+---------+---------

99.0 102.0 105.0 108.0

Results: Here, I have observed a p value of 0.019 for the average analysis of the affects of different methods for months. In this conditional probability, if my hypothesis is true, reveals that three methods significantly differ from each other in giving the response for the understudy assay result. My level of significance was set at 0.05 and the p value "the observed level of significance" is much less than 0.05.

In this case of research study, I have also observed a p value of 0.096 for the average analysis of the affects of different methods for batches. In this conditional probability, if my hypothesis is wrong, reveals that three methods significantly not differ from each other in giving the response for the understudy assay result. My level of significance was set at 0.05 and the p value "the observed level of significance" is greater than 0.05.

Statistical Data of Accelerated Stability Studies of Osam-D Tablets in Two-way ANOVA: Responses versus Months, Batches(Based on Assay result)

Source DF SS MS F P

Months 2 75.0064 37.5032 16.61 0.012

Batches 2 5.8756 2.9378 1.30 0.367

Error 4 9.0290 2.2572

Total 8 89.9110

S = 1.502 R-Sq = 89.96% R-Sq(adj) = 79.92%

Individual 95% CIs For Mean Based on

Pooled StDev

Months Mean ------+---------+---------+---------+---

0 103.613 (-------*-------)

3 99.857 (-------*-------)

6 96.547 (-------*-------)

------+---------+---------+---------+---

96.0 99.0 102.0 105.0

Individual 95% CIs For Mean Based on

Pooled StDev

Batches Mean -----+---------+---------+---------+----

1 101.147 (-----------*-----------)

2 99.383 (-----------*-----------)

3 99.487 (-----------*-----------)

-----+---------+---------+---------+----

98.0 100.0 102.0 104.0

Results: Here, I have observed a p value of 0.012 for the average analysis of the affects of different methods for months. In this conditional probability, if my hypothesis is true, reveals that three methods significantly differ from each other in giving the response for the understudy assay result. My level of significance was set at 0.05 and the p value "the observed level of significance" is much less than 0.05.

In this stability study, I have also observed a p value of 0.367 for the average analysis of the affects of different methods for batches. In this conditional probability, if my hypothesis is false, reveals that three methods significantly not differ from each other in giving the response for the understudy assay result. My level of significance was set at 0.05 and the p value "the observed level of significance" is much greater than 0.05.

RESULT AND DISCUSSION:

Three brands of Cholecalciferol (Vitamin D3) tablets i.e., (a) Qalsan D, (b) Calgo and (c) Osam-D containing 125, 125 and 400 IU respectively of Cholecalciferol were used in this study.

Qalsan D tablet in record of assay content had no degradation observed and was stable at temperature 40±2 oC and Relative humidity75±5% while Osam-D and Calgo in record of assay content show little bit degradation at given accelerated stability study parameters.

The brands of Cholecalciferol tablets were found to comply with the Pharmacopoeial requirements as shown in above table as regards to their variation in assay contents.

The assay content tests of tablet were carried out by using methanol as blank, formic acid and dinitrophenylhydrazin supply by reliable sources at max 265nm, using Double beam UV Spectrophotometer.

The percent of Qalsan D tablet samples of Batch 001, 002, 003 were analyzed and checked at month (0, 3, 6) at specific temperature and relative humidity.

From assay content behavior of these Cholecalciferol tablets, it is evident from above table, ASS data reveals that in first 6 months of Batch 001, results decreased from 100.89% to 100 %. In Batch 002, having 6 months study, results illustrated downward condition from 102.92% to 101.35%, while in Batch 003 having 6 months ASS, result move from 100.67% to 98.43%.

Similarly both "p" values of Qalsan D tablets were placed within the limit i.e., NMT 0.05, as shown in statistical data.

The percent of Calgo tablet samples of Batch 001, 002, 003 were analyzed and checked at month (0, 3, 6) at specific temperature and relative humidity.

From assay content behavior of these Cholecalciferol tablets, it is evident from above table, ASS data reveals that in first 6 months of Batch 001, results decreased from 105.63% to 98.19 %. In Batch 002, having 6 months study, results illustrated downward condition from 107.79% to 97.50%, while in Batch 003 having 6 months ASS, result move from 110.49% to 104.67%.

Similarly out of two "p" values, one "p" value of Calgo tablets was out of the limit while other meets the requirement, i.e., NMT 0.05, as shown in statistical data.

The percent of Osam-D tablet samples of Batch 001, 002, 003 were analyzed and checked at month (0, 3, 6) at specific temperature and relative humidity.

From assay content behavior of these Cholecalciferol tablets, it is evident from above table, ASS data reveals that in first 6 months of Batch 001, results decreased from 104.54% to 96.18 %. In Batch 002, having 6 months study, results illustrated downward condition from 102.69% to 97.27%, while in Batch 003 having 6 months ASS, result move from 103.61% to 96.19%.

Similarly out of two "p" values, one "p" value of Osam-D tablets was out of the limit while other meets the requirement, i.e., NMT 0.05, as shown in statistical data.

CONCLUTION:

From result and discussion, the main conclusions of the present investigation on the accelerated stability-indicating Non-Pharmacopoeial method for assay of different brands of Cholecalciferol tablet may be summarized as follows:

The assay stability of the Cholecalciferol tablet was investigated under various conditions. Cholecalciferol tablet samples were found to be sensitive to elevated temperatures as well as to high relative humidity. The most stable form is obtained in Qalsan D tablet formulations.

The Qalsan D tablet has stable Cholecalciferol molecule for 2 years while degradation of Cholecalciferol in Calgo tablet and Osam-D tablet highlights unstability of molecule under stress conditions and should be degraded completely before 2 years. The difference in assay contents with the progress of month and batch can be explained on the basis of oxidative degradation phenomenon. Three brands of tablets, accordingly of degree of oxidative degradation of Cholecalciferol are arranged in following sequences:

Qalsan D → Osam-D → Calgo.

SUGGESTION:

Some of the most complex tablet formulations include vitamins/multivitamins/minerals. These may be exposed to temperature and relative humidity during manufacturing, storage and administration causing vitamin interaction and loss of the individual vitamins.

In view of the sensitivity of Cholecalciferol and the influence of factors such as temperature, relative humidity, presence of other vitamins, in a multivitamin preparation, an evaluation of stability characteristics of Cholecalciferol extremely difficult.

This may be used to conduct further systematic studies on the evaluation of Cholecalciferol stability in tablet mixtures.

Identification of the unknown oxidative as well as degradative products of Cholecalciferol in tablet.

Development of Stability-determining methods for assay of a Cholecalciferol in the presence of its degradation product.

Study of the relationship of degradation rates with Non-Pharmacopoeial methods applied during analysis of Cholecalciferol tablet.

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