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mahonny
Junior

India,
2014-04-04 09:00

Posting: # 12764
Views: 6,020
 

 A fixed dose combination dissolution evaluation [Dissolution / BCS / IVIVC]

Dear Friends,

Many times i read topics in the forum and take advantage of your comments. Today i would like to ask a question for your evaluation.

We are working on a fixed dose combination product. Dissolution profiles of reference and test product are given below. API1 is BCS class I drug, whereas API2 is BCS class III.

Sampling points are 5-10-15-20-30-45 mins.

0.1 N HCl, 900 ml, 50 rpm, Pedal
API1
R

31.9
59.1
74.7
80.4
83.7
85.2

T
25.7
52.8
76.0
88.1
92.7
93.6

API2
R

42.2
77.1
91.6
95.2
95.7
94.8

T
30.5
60.3
84.2
95.3
97.2
97.7

pH 6.8, 900 ml, 50 rpm, Pedal
API1
R

21.1
48.5
72.1
83.2
88.9
92.3

T
23.0
45.2
72.1
92.3
102.8
102.4

API2
R

25.8
44.9
59.5
69.6
82.4
92.5

T
21.4
43.6
70.5
91.0
101.9
101.4

Do you think this formulation is eligible for BE study? For Class III drugs, drcampos has pointed that points earlier that 30 mins are negligible due to the fact that absorbtion is limiting step in BE study

http://forum.bebac.at/mix_entry.php?id=3314&page=0&category=0&

PS. API1 will be administed as one dose tablet whereas API2 will be of two doses in BE study. (Ref= A total of 3 tablets, Test= 1 tablet)

Looking for your kind comments.
Regards,
Mahonny
Dr_Dan
Senior

2014-04-04 10:43

@ mahonny
Posting: # 12766
Views: 5,222
 

 discriminatory methods?

Dear mahonny
Keeping in mind that both drugs are good soluble the results you present look rather strange and I would not draw any conclusion from these data. I suggest to evaluate if your method is discriminatory. In case of BCS class I and III substances you would expect dissolution profiles which show a rapid onset with more than 85% dissolution after 15 min. or at least after 30 min. and about 100% at the end for each pH level. If you show this for the reference product you can evaluate if your products is suitable.
I hope this helps
Dr_Dan

Kind regards and have a nice day
Dr_Dan
mahonny
Junior

India,
2014-04-04 11:12

@ Dr_Dan
Posting: # 12767
Views: 5,205
 

 discriminatory methods?

Dear Dr_Dan,

API3 is class III according to literature, however, API1 which is dexketoprofen trometamol, is expected to be class I (or class III). We could not find any knowledge in the literature survey. Below is given 75 rpm dissolution data of reference product of API1. If we study at 75 rpm, %85 dissolution in 15 minutes is achived, however, i do think that 75 rpm dissolution might not reflect biorelevant conditions. What do you think? To consider 75 rpm data or 50 rpm? In the case of considering 75 rpm data, any formulation possessing >%85 dissolution in 15 minutes will be suitable but i am very suspicious that it is biorelevant. Besides, i believe that main reason for relatively low solubility at 50 rpm is the particle size of the API1 in reference product.

0.1 N HCl, 900 ml, 75 rpm, Pedal
API1
R

43.0
79.9
90.7
93.3
94.7
95.2
95.0

API2
R

54.3
92.3
95.0
94.2
93.4
92.2


pH 6.8, 900 ml, 75 rpm, Pedal
API1
R

43.6
77.1
99.6
99.5
98.5
97.4
96.4

API2
R

32.1
57.7
74.0
83.9
91.4
93.5

Regards,

Mahonny


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Helmut]

Mahonny
Dr_Dan
Senior

2014-04-04 12:43

@ mahonny
Posting: # 12768
Views: 5,266
 

 discriminatory methods?

Dear mahonny,
I do not believe that main reason for relatively low solubility at 50 rpm is the particle size of the API1 in reference product since large particles dissolve more slowly indeed but at the end completely so that you will get 100% dissolution even if the profile is different. But you show differences in the proportion of dissolved API between your test and the reference formulation. I suggest to perform some more solubility and dissolution tests. On basis of the presented data I would not dare to give advice.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
mahonny
Junior

India,
2014-04-04 13:29

@ mahonny
Posting: # 12769
Views: 5,191
 

 A fixed dose combination dissolution evaluation

Any more comments from different point of views are highly appreciated...

Mahonny
luvblooms
Senior

India,
2014-04-07 08:28

@ mahonny
Posting: # 12778
Views: 5,199
 

 A fixed dose combination dissolution evaluation

Dear Mahonny

» Any more comments from different point of views are highly appreciated...

  1. Was there any heap formation at 50 rpm? The difference between 50 and 75 rpm points towards.
  2. Why not trying basket apparatus and check?
  3. Is there any impact of DT or any formulation excipients on solubility or release? As the end release is different in different media, this could be because of differential solubility of some excipient in different pH conditions. For class I and III drug, particle size will not have major effect but excipients will have.
Generally For class III product the main factor will be the gastric emptying and one should try to release >85% drug in 15-30 min time points and later body will take care of things (as my professor say)

As said, you should look for some more solubility and dissolution tests. With the current data I would be worried for my BE out come.

Regards

~A happy Soul~
mahonny
Junior

India,
2014-04-14 15:22

@ luvblooms
Posting: # 12836
Views: 5,035
 

 A fixed dose combination dissolution evaluation

@luvblooms

Thanks for your comments.

» a. Was there any heap formation at 50 rpm? The difference between 50 and 75 rpm points towards.

Heap is formed, that is right. But currently we have only reference tablets for BE study, therefore, we dont want to change the DT method :s

» b. Why not trying basket apparatus and check?

Basket method was tried as well, however heap still remains


Edit: Standard quotes restored. [Helmut]

Mahonny
susan dong
Junior

2018-11-26 08:35

@ mahonny
Posting: # 19650
Views: 300
 

 A fixed dose combination dissolution evaluation

I want to know when to use the dissolution sinker.
 
I see from this website(te(https://www.zhehanfilter.com/dissolution-accessories/dissolution-sinker.html) that the use of dissolution sinker may affect the test results, is that so?


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Ohlbe]
snow2020
Junior

2018-12-05 06:27

@ susan dong
Posting: # 19667
Views: 181
 

 A fixed dose combination dissolution evaluation

Thank you for your suggestion. I checked the website you gave.
would like to ask, does this dissolution sinker have an impact on the test results?
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