In Process quality control2, IPQC 2- the content uniformity BY LAW JIA JUIN



PARACETAMOL ASSAYED



THE PHARMACEUTICAL COMPANY CLAIMED THAT THE AMOUNT OF PURE PARACETAMOL PER TABLET IS 500MG



UV SPECTROMETER WE USED



INTERNAL STRUCTURE OF UV SPEC



A MODERN SOPHISTICATED INSTRUTMENT FOR MEASUREMENT OF CONTENT UNIFORMITY.



WRITTEN BY LAW JIA JUIN

Content of this article

1. OBJECTIVES
2. INTRODUCTION
3. CALCULATION
4. RESULTS
5. DISCUSSION
6. CONCLUSION
7. REFERENCES

A.OBJECTIVES

To introduce my reader with the application of content uniformity and also to share with them my experience on the post-manufacturing assessment on the content uniformity of the tablets prepared {the production of tablets had been described in the previous article under pretablet granulation( http://jiajuin0409.blogspot.com/2012/01/pre-tablet-granulation-by-law-jia-juin.html ) and also Tablet production and in process quality control 1, IPQC1 ( http://jiajuin0409.blogspot.com/2012/02/tablet-production-and-in-process.html ) } .

B.INTRODUCTION

In this practical we had learnt to check the variation of active ingredient contained within a batch using an evaluation method known as content uniformity test. It is important for the content uniformity test to be included into the monographs of all coated and uncoated tablets as well as the capsules intended for oral administration. Tablet monographs with a content uniformity requirement do not need to have weight variation requirements.

Content Uniformity Testing is useful for assessing the consistency of powder blends before filling or compressing .In addition to that, it also test the consistency of semi-solid and liquid bulk batches before filling . This test also help the workers to supervise for a proper filling during manufacturing (such as filling of powders into capsules or liquids into vials and bottles) . It also help us to do post manufacturing assessment on the amount of active ingredient contained within individual units for example: Amount of pure paracetamol contained wit.hin individual tablet after compression, is evaluated using this method. Content uniformity testing involves using a content/potency assay to determine the content of active material contained in multiple different samples collected throughout the batch. This test should be carried out along the process of manufacturing, so that any errors happening during the process of manufacturing can be detected early, and adjustment as well as changes can be done immediately to prevent the wastage of raw material and time.

C.CALCULATIONS

Ci)  Assay on 20 tablets

Total Weight of 20 tablets powder = 12.19 g

Weight of pure Paracetamol claimed in 1 tablet = 500 mg

Therefore weight of pure Paracetamol claimed in 20 tablets = 500mg X 20

                                                                                                               =10000 mg = 10 g

Amount of pure paracetamol to be taken is 0.15g (150mg)

10g pure paracetamol <------------------------------->12.19g raw tablet powder

0.15g of pure paracetamol  <-------------------------> B g of raw tablet powder

                                                         B = 0.15 X 12.19

                                                                    10

                                                               

                                                             = 0.183 g

(0.183g of raw tablet powder was needed to gained a 0.15g of pure paracetamol)

Average absorbance we got from the final diluted solution =  (0.367+0.375+0.369) /3 = 0.370 AU

A (1%, 1cm)

1% = 1 gram in 100 ml = 1000mg in 100ml = 10mg/ml of pure paracetamol

715 AU (UV spectroscopy) <--------->10mg/ml of pure paracetamol

The measured absorbance for our final diluted solution is 0.370AU

0.370AU <--------->D mg/ml of pure paracetamol in our sample

D(mg/ml) =   0.370 X 10

                          715

                =   0.00517 mg/ml

The concentration of pure paracetamol in our final diluted solution is 0.00517 mg/ml

Since the dilution factor = 10 X 10

                          = 100

Therefore the actual concentration of pure paracetamol

in our stock solution (before any dilution) is =0.00517X 100 = 0.517mg/ml

0.517mg of pure paracetamol <---------> 1ml of stock solution

Xmg of pure paracetamol <--------->200ml of stock solution

Total amount of pure paracetamol in our stock solution, X =0.517 x200= 103.4mg

Since we know that there is actually 0.183g(183mg) of raw tablet powder been dissolved to make up this 200ml of stock solution (undiluted), we can then deduced that 0.183g of raw tablet powder actually consisting of 103.4mg of pure paracetamol. [Not concise with what is claimed by the manufacturer. The manufacturer actually claimed that 1tablet (0.6g of raw tablet powder) contains 500mg of pure paracetamol and 0.183g of raw tablet powder should contain 0.150mg of pure paracetamol]

%drug variation = [(103.4mg- 150mg)/150mg]x100= -31.1%

C ii) Assay of 5 tablets Individually

Calculation on the % Drug Content Variation

1^st TABLET

Average absorbance recorded= 0.400AU

Concentration of pure paracetamol in final diluted solution

=[(0.400 X 10) / 715] =0.00559mg/ml

Actual concentration of pure paracetamol in stock solution

=0.00559x100(dilution factor)=0.559mg/ml

Pure paracetamol contained in 200ml of stock solution=0.559x200=111.89mg

%drug variation= [(111.89 – 103.4) / 103.4] X 100 = +8.21%

2^nd TABLET

Average absorbance recorded= 0.333AU

Concentration of pure paracetamol in final diluted solution

=[(0.307 X 10) / 715] =0.00466mg/ml

Actual concentration of pure paracetamol in stock solution

=0.00466x100(dilution factor)=0.466mg/ml

Pure paracetamol contained in 200ml of stock solution=0.466x200=93.2mg

%drug variation= [(93.2 – 103.4) / 103.4] X 100 = -9.86%

3^rd TABLET

Average absorbance recorded= 0.401AU

Concentration of pure paracetamol in final diluted solution

=[(0.401 X 10) / 715] =0.00561mg/ml

Actual concentration of pure paracetamol in stock solution

=0.00561x100(dilution factor)=0.561mg/ml

Pure paracetamol contained in 200ml of stock solution=0.561mg/ml x200=112.2mg

%drug variation= [(112.2 – 103.4) / 103.4] X 100 = +8.51%

4^th TABLET

Average Absorbance=0.347AU

[(0.347 X 10) / 715] X 100x200= 97.1mg of pure paracetamol ß---------- short cut

%drug variation =[(97.1 – 103.4) / 103.4] X 100 = -6.09

5^th TABLET

Average Absorbance=0.371AU

[(0.371 X 10) / 715] X 20000 = 103.78mg of pure paracetamol

%drug variation =[(103.78 – 103.4) / 103.4] X 100 =+ 0.36%

D) RESULTS

TAB NO.	WEIGHT	ABSORBANCE/AU (1)	ABSORBANCE /AU (2)	ABSORBANCE /AU (3)	ABSORBANCE /AU (AVERAGE)	% DRUG CONTENT VARIATION
20	12.19	0.367	0.375	0.369	0.370	-31.1%

TABLE 1

TABLET NUMBER	WEIGHT	Average ABSORBANCE/AU	% DRUG CONTENT VARIATION
1	0.61	0.400	+8.21%
2	0.62	0.307	-9.86
3	0.61	0.401	+8.51%
4	0.61	0.347	-6.09
5	0.61	0.371	+0.36%

TABLE 2                   

E) DISCUSSION

According to British Pharmacopoeia, in order to carry out a content uniformity test a representative samples of 30 tablets must be selected out from the batch and 10 out of this 30 tablets are assayed individually. In order for the test to be passed, at least 9 out of 10 tablets must have 85-115% of the labeled drug content (±15%variation only) . And the 10^th tablet should have a variation not more than ±25%.,with 75-125% of the labeled content. If these conditions are not met, the tablets remaining from 30 must be assayed individually & none of them should fall outside the range of 85-115% range, otherwise reject the whole batch.

Due to the time restriction we decided to evaluate only the first 5 tablets instead of doing all the ten tablets .So the result was extrapolated from the 5 tablets tested. Based on the results obtained, we predicted that there were at least 9 out of 10 tablets within the limits of 90-110% of labeled drug content (+/-10% variation) and the 10^th tablet is within the limit of 75-125% of labeled drug content (+/-25%variation ). Therefore, our batch of tablets had passed this content uniformity test successfully. The test was said to have passed (accepted)for the 20 tablets as well as the 5 tablets that were assayed individually. Thus, we can said that the manufacturing process of our tablets are good and well supervised .Each tablet produced contains similar amount of active ingredient with not acceptable variation  ,this can ensure a proper dosing to our patients in the future.

F) CONCLUSION

The Content Uniformity Test is said to have passed for the 20 tablets and also the 5 tablets that were assayed individually, this is because all the five tablets tested individually are within the limit of 85% - 115%.(with variation of +/- 15% ONLY)

G) REFERENCES

1)      www.pharmainfo.net/tablet-evaluation/content-uniformity

       2)   http://asi-rtp.com/content_uniformity_testing_.html

IRRITABLE BOWEL SYNDROME AND PROBIOTICS-by LAW JIA JUIN(WITH RELIABLE REFERENCES FROM REPUTABLE JOURNALS AND WEBSITE)



SOME PEOPLE DESCRIBED INTESTINAL BACTERIALS AS BUNCHES OF FLORAL SPECIES WHILE THE OTHERS DESCRIBED THEM AS BUGS

AS FOR ME I WILL DESCRIBED THEM AS MILLIONS OF SPECTATORS IN A SPORT STADIUM ,ALL WITH DIFFERENT IDENTITIES AND BACKGROUND. OR PERHAPS WE CAN DESCRIBE THEM AS THE MICROORGANISMS LIVING IN A DARK TUNNEL (INTESTINE) ,WHEN BALANCE IN POPULATIONS ,THEY GIVE BENEFICIAL EFFECT TO THE TUNNEL FUNCTION.

 WRITTEN BY LAW JIA JUIN               
             

In this portfolio I will be discussing on the evidences regarding the use of probiotics in irritable bowel syndrome.  In addition to that, I also included a brief explanation on the reply I will give to my patient LL, who had asked me on whether taking a probiotic would be helpful to her irritable bowel syndrome. World Health Organization (WHO) had defined probiotics as ‘live microorganisms which when administered in adequate amounts confer a health benefit on the host’^[1]. There are many probiotics marketed, including Activa yogurt, Vitagen, and Yakult cultured milk ^[2]. Probiotics had been proved in the treatment of bacterial vaginosis , diarrhea associated with acute infectious or antibiotic usage ,ventilator-associated pneumonia, necrotizing enterocolitis in neonates, and irritable bowel syndrome (IBS)^[3]. But our main concern here is on the usage of probiotics in IBS treatment. According to World Gastroenterology Organization  (WGO), IBS is defined as a functional bowel disorder in which abdominal pain or discomfort is associated with disordered defecation or a change in bowel habit. bloating and abdominal distension. ^[4]

In 2000 ,a study done by Nobaek Johansson (Nobaek,jahansson et al 2000) shown an obvious improvement of flatulence and bloating in patients treated with Lactobacillus plantarum.^[5] This study was incorporated with a 12 months follow up questionnaire ,and the results obtained shown that probiotic treated patients maintained a better gastrointestinal function than those who did not receive (control group). ^[5]The combination of these observations had proved to us that the probiotic is beneficial to IBS sufferer^[5]. But what is the mechanism behind? May be the next study can answer this question to us. Recent study suggested that peoples having abnormal changes in the indigenous flora is more prone to IBS^[6].  And scientists actually observed a correlation between small intestinal bacterial overgrowth (SIBO) and IBS syndrome^[6]. To prove this correlation, the scientists had administered a non -absorbable antibiotic rifaximin to a group of IBS patients with SIBO^[6]. As a result, breath hydrogen excretion fell significantly among those who received and responded to rifaximin ,and this fall is accomplished with improvements in bloating and overall symptom scores^[6]. This was indeed a great breakthrough because with this observation the scientists deduced that probiotic administration can actually relieve the symptoms of IBS by optimizing and balancing the flora population in the gut (prevent SIBO)^[6].

Another evidence proving to us that probiotic is beneficial to IBS patient is conducted by Camilleri’s group^[5] .They conducted two trials with VSL#3, which is a probiotic cocktail containing 8 strains of different bacterial species. Which involved Lactobacilli (L.acidophilus, L.casei, L. bulgaricus, L. plantarum) and Bifidobacteria (B. longum, B. infantis, B. breve) as well as Streptococcus salivarius subspecies termophilus^[5]. The first study (Kim, Camilleri et al. 2003) mainly focused on diarrhea predominant IBS patients and they observed a significant improvement of abdominal bloating, but no much effects on other IBS symptoms or gastrointestinal transit^[5]. Based on these results, a second study (Kim, Vazquez Roque et al. 2005) was also carried out ,and this second study involved mainly IBS patients with bloating^[5]. In this study they found out that there was a significant improvement of flatulence in the VSL#3-group, but the improvement in bloating, pain and urgency scores in the VSL#3 group are not obvious.^[5] The different observations in the two studies using VSL#3  may be due to the different sample groups used. (The first study used  diarrhea predominant IBS patient, the second study used bloating predominant IBS patient)^[5][6]. But overall ,the probiotics did bring beneficial effects to both groups of IBS patients (diarrhea and bloating). ^[5][6]

In 2005, O’Mahony et al. (O’Mahony, McCarthy et al. 2005) compared the effects of two different probiotics, Lactobacillus salivarius and Bifidobacterium infantis on the management of IBS^[5]. In this study the quality of patients’ life were assessed. In addition to that cytokine profile was also recorded^[5]. For example, the ratio between IL-10 and IL-12 in peripheral blood mononuclear cells (PBMC) before and after the administration of probiotic were evaluated. To their surprise, they observed an anti-inflammatory response in the guts of patients treated with  Bifidobacterium infantis probiotic , showing that this type of bacterial plays an important role in suppressing mucosal inflammation and restoring cytokine balance towards an anti-inflammatory state (Normalizing the ratio of IL-10 to IL-12 in peripheral blood mononuclear cells.).^[5][6] On the other hand ,study using Lactobacillus salivarius had showed a significant symptom improvement over placebo ,but this occured only in the second treatment-week, telling us that it is less effective than Bifidobacterium infantis in relieving IBS symptoms^[5].

In the same year, Niv et al. (Niv, Naftali et al. 2005) conducted a six months treatment trial with Lactobacillus reuteri ATCC 55730 in patients with IBS.^[5] The treated patients had shown an improvement in all symptoms, but there were no significant differences between the probiotic and the placebo group.^[5] However, a significant improvement in constipation and gas were observed in the probiotic-treated patients. ^[5]All these evidences and studies had proved to us that probiotics can be useful in the management and treatment of IBS syndrome, providing they are used wisely. Lactobacillus plantarum had been shown to be useful in maintaining the normal gut floral population in small intestine and also help in relieving abdominal pain. ^[5][6]VSL#3 had been proved to be useful in relieving bloating in diarrhea patient and relieving flatulence in bloating patients. ^[5][6] And Bifidobacterium infantis is now known to be useful in treating gut inflammation. ^[5][6]And lastly Lactobacillus reuteri is said to be useful in improving bowel movement thus treating constipation. ^[5][6]

I will advise my patient LL to take antibiotics as a non-pharmacological management of her IBS. I will also advise her to choose the appropriate probiotics which suited her situation the most, this is because different probiotics are having different effects to different patients.  For example Lactobacillus GG can help to relieve diarrhea but it is contraindicated to constipated patient.^[6] And on the other hand, Lactobacillus reuteri is used for constipated patient but it can worsen the situation of diarrhea patient. ^[6] For me I will suggest probiotics like Lactobacillus reuteri (Help in constipation) and  Lactobacillus plantarum (To relieve pain and bloating) to LL, as these 2 probiotics suit her situation the  most. I will also counsel LL on the appropriate way to take these probiotics as well as the effective amount to be taken. I will also educate LL on the way to live a healthy and happy lifestyle in order to improve her IBS syndrome, for example I will ask her to drink more water(address her dry skin), take high fiber diet (The amount of fiber intake should not be increased drastically but should be increased gradually), and went for meditation to distress herself. If she is going to start a probiotics course, then I will also asked LL to replace her naproxen with other NSAID drugs (Like: paracetamol), because I had found out that there might have some small interaction between probiotics and naproxen as said in a report published this year (I do not want my patient to be at risk).^[7]

            In conclusion, based on the evidences above probiotics are useful in the treatment of IBS patient provided the patients are properly educated and taught on the selection of suitable probiotics as well as the correct ways of using their probiotics. An individual who is about to consume a given probiotic preparation should know exactly what he or she is going to take and how to take them. The pharmacists should consider whether the organism taken by their patients will be able to survive when in contact with acid, bile and digestive enzymes, they should also know what will be the actual concentration of the organism at its desired site of action. A correct probiotics plus other symptomatic tretaments together with a balance diets and appropriate distressing channels will definitely improve the life of IBS patient.

or may be we can describe the intestinal microorganisms as molds lining on the surface of a dark tunnel (small intetsine)

RELIABLE REFERENCES

1.Probiotics-LoveThatBug. Probiotics Definition by the World Health Organization[internet].2007[updated on 2012.Cited on 2012 February28 ].Available from http://www.probiotics-lovethatbug.com/probiotics-definition.html.

2. Dr. Anil Minocha, a gastroenterologist and nutritionist. Probiotics on market[internet].2011[updated on 2012 January. Cited on 2012 February 28].Available from http://minochahealth.typepad.com/gut/probiotics.html

3.Drugs.com team. Probiotics[internet].2000[updated on 2012February17.Cited on 2012February29].Available from: http://www.drugs.com/npp/probiotics.html

4. Prof. Eamonn Quigley (Chairman, Ireland), Prof. Michael Fried (Switzerland), Prof. K.A. Gwee (Singapore), Prof. C. Olano (Uruguay), Prof. F. Guarner (Spain),

Prof. P. Hungin (United Kingdom).et.al. Introduction .Irritable bowel syndrome: a global perspective.[Guideline and Journal].2009.April.20.[cited on 2012 February 28].Page 2

5. Viola Andresen and Daniel C. Baumgart. ROLE OF PROBIOTICS IN THE TREATMENT OF IRRITABLE BOWEL SYNDROME: POTENTIAL MECHANISMS AND CURRENT CLINICAL EVIDENCE. International Journal of Probiotics and Prebiotics Vol. 1.[Journal].2006 January 17[cited on2012 February 28 ].Vol.1.pp11-18

6. E. M. M. QUIGLEY & B. FLOURIE. Probiotics and irritable bowel syndrome: a rationale for their use and an assessment of the evidence to date .Neurogastroenterol Motil .[Journal].2007[cited on on2012 February 28 ] (2007) 19, page166–172.

7. A real world approach to drugs. A study of drug interactions between Probiotic and Naproxen.[internet].2012[2012 April24.cited on 2012 February 28].Available from: http://www.ehealthme.com/drug-interactions/Probiotic-and-Naproxen