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I work in a Small pharmacetical Company . We produce Some Drugs for
human use.
But we face a Large problem in Dissolution of one product.the problem
is that
1-- This product is SR (Slow Release), so we make the Dissolutin and
take sample after ( 1 , 2 , 4 , 8 ) hours.
2-- each stage (ie time interval ) has its Requirement. ie Dissolved %
limits . ie after 1 hours :- 20- 40 %
after 2 hours :- 30-50 %
after 4 hours :- 50-80 %
after 8 hours :- not less that 65 %
The problem is that each time we produce a batch of this drug , we must
produce only 1 Kg of the whole batch , and then test its dissolutin
rate , if OK ,then make the whole batch under the same production
paramters (which is the particle size of the granules), if FAIL , then
the production department make some changes (by changing the particle
size of the granules used for compresion ) , and produce only 1 KG ,
and then we test it , if OK , make the whole batch under the same
conditions . if NOT , make more ADJUSTMENT (tuning of the particle size
of the granules) , then test it,...... do the same steps till get the
required dissolution rate that is OK with the limits stated above.
So, are there any method to predict WHICH PARTICLE SIZE OF THE GRANULES
THAT WILL PRODUCE 37 % DISSOLVED AFTER 1 HOUR .. NB.the 1st hour is
very critical to me , ie if we can make it 35 - 39 % , the remaining
times will be OK.
I am confused between 2 Choices :-
1- Use STATISTICS to find good CORRELATION between Granule Size and
the % quantity Dissolved.
2- Use Dissolution Equations to get a good estimation of the Dissolved
% after a the first hour .
I am confused , so can you help
Thanks for your help .
Best Regards,
Dr.Waleed Said Makarem
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The following message was posted to: PharmPK
There are many factors that could be responsible for your observation.
It is majorly a problem of scale-up. Parameters obtained with 1 kg
batch may not be extrapolated to large batch size, say 25 kg. You need
trials with a range of intermediate batch sizes i.e. scaling up
gradually, collecting data on repetitive batches of each size and
making appropriate adjustments.
On the other hand, your emphasis appears to be on granule size. Note
that many other variables could affect drug dissolution from a tablet.
Some of these are: Processing variable e.g. granulation technique,
efficiency of mixing and uniformity of binder distribution on
substrate; granule physical properties e.g. density, porosity,
deformation characteristics under compression, and factors controlling
release i.e. is it matrix controlled or surface coating-controlled, etc.
Your design and control of dissolution studies may also affect the
dissolution profiles e.g. control of temperature of dissolution medium,
sampling technique and timing and method of dilution of sample for
analysis, etc.
You need to consider all and many other factors critically using
stastistical procedures for making your judgement at every stage.
Dr. S. Adebayo
Lecturer
School of Pharmacy & Heakth Science
University of Technology, Jamaica.
237 old Hope Road, Kingston 6
Phone: 876-344-2367
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Dear Waleed,
In order to solve your problem I suggest that you use a method which is
called "multivariate calibration". As input you should use the particle
size distribution (and any other variables related to the dissolution
profile) of your product and as (multivariate) response the percentage
of dissolved compound at different times. Using the known input and
output for a series of formulations will allow you to build a model
which can then be used to predict dissolution profiles of new batches.
A group at the dept. of pharmacy at the university of Groningen
(Netherlands) has published in this area.
Best regards,
Martin
Martin M. Schumacher, Ph.D.
Principal Scientist
Novartis Pharma AG
BioMarker Development
WKL-136.1.19
CH-4002 Basel
Switzerland
Tel. +41 - 61 696 1030 (direct)
Fax +41 - 61 696 6212
Email martin.schumacher.aaa.pharma.novartis.com
[Is this something like a simplex optimization? - db]
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Read Remington Pharmaceutical sciences on factors that normally affect
drug dissolution.
Check the physiochemical properties of all the components of your
formula find out whether they are compartable or not.You may have to go
back to the drawing board if the drug cant meet the monographic
requirements of dissolution test
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The following message was posted to: PharmPK
Dear Dr Walleed,
Yes ! on the basis of particle size distribution you can forcast
the sucess of batch in your dissolution parameter. But first of
all you have to take at least 3-6 batches of different particle
size distribution and complete dissolution profiles of the same .
Method should be descriminatory.It is recommended you should
establish this particle size distribution by Malvern Particle Size
analyzer,if it is not available for your routine you can also use
suitable measuring microscope.
Also you have to develop accelerated dissolution method for your
inprocess control ( within 30 min),by incresing temp/pH of medium/
rpm etc and match trends with real time dissolution profiles,
I hope this will help you,
regards,
Dr Pradeep Sharma,
Wockhardt Research Center,Mumbai
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