Pharmacopeia method of extraction

[former_chemist]

Does anyone have the extraction method used by the US Pharmacopeia to determine bioavailability?

There are three major steps if I recall.

1) Acid soak - simulates stomach acid
2) Rising pH - simulates leaving the stomach
3) agitated water extraction - simulates the small intestine

I am unsure but for diffent formations these methods differ slightly.  for example quick dissolving formulations skip steps one and two.

There can also be a type of membrane used to separate the actives from the inactive (simulates intestinal wall).

The major drawback of this method (for our purpose) is the amount of water used.

Anyone who has access to this information, could you please post the exact procedures.  This may bee very helpful to fellow bees.

[former_chemist]

From a link in

Post 512150

(wareami: "Squidippy's Plug...", Stimulants)

Drug Content Analysis
     The drug content analysis was performed to ensure the drug concentration of the formulation before and after the supercritical processing. The drug (50mg) was incor-porated in 500 mg of the polymer. The solid dispersion was dissolved in 1000 ml of phosphate buffer pH 6.5 in a volumetric flask. Exactly 10 ml of the dispersion was filtered through a 45-micron filter, and the drug content was analyzed in a UV spectro-photometer at 227 nm. 97 % of the drug was present in the processed formulation after dissolving the sample.

So we can assume that a similar method will work for pseudo. This was the Eudragit class of polymers.
But it would require large amounts of distilled water and buffer as well as a molecular seive.  But using this method 97% of the drug can be recovered.

Just for kicks I figured the same process on 30 - 30mg pills would require 30L of water to recover 900mg of goodies.  But using the same process on 4-240mg pills would only require 4L to achieve the same effect assuming they also use 1L for the USP test and dissolve for 24 hours. This or a similar process is guaranteed to work on all pills.  After extracting of course the liquid is filtered then put through a molecular seive.  I don't know what additional cleanup might be needed but it seems doable.

[12cheman12]

okai... so now i gotta use my swimming pool for extractions, dam, im gonna need one hell of a big filter. Hang on, ill just modify my pools filter... hmmmmm.

[former_chemist]

Now that you mention it they make a pool filtering substance from diatomaceous earth.  That stuff might just do the trick for filtering jello.  A swimming pool might be overdoing it a bit but a hot tub might be handy (smallest model).  It has just about everything needed.  Large volume, pump, filter, and resistance to solvents.  Also has built in heaters.  So it can agitate heat and filter.  Why hadn't I thought of that before.  Now where can SWIM get enough pills.  say 200 gal(approx. 750L), that takes 750 240mg tablets.  That would produce 180g.

[methyl_ethyl]

I have access to the USP 27 however you will have to be more specific concerning the test you are inquiring about. 

I could be wrong, however I would assume there are more than one type of test concerning "bioavailability" of whatever substance you are looking for.  Provide as much information as possible and I more than likely can procure the information you seek.

much_love

methyl_ethyl

[former_chemist]

I think the people here are mainly concerned with the method used to determine the amount of pseudoephedrine released from the various formulations.

What methods do they use to dissolve the pills?
How do they make sure the inactives aren't retaining the medicine?
What does the apparatus look like?
How do they determine that the inactives aren't entering the blood stream and becoming reactive?

[Osmium]

> What methods do they use to dissolve the pills?

I assume pH resembling stomach pH, temperature around 37°C, agitation.

> How do they make sure the inactives aren't retaining the medicine?

pH and dilution.

> What does the apparatus look like?

Not sure, but it's pretty much a beaker on a hot plate with some means of stirring (a perforated plate moving up and down in the beaker?).

> How do they determine that the inactives aren't entering the blood
> stream and becoming reactive?

They are polymers. Polymers usually cannot cross into your blood stream.

[former_chemist]

I am looking for the specifics of the tests.

The pH for at least one test is 6.5,  my understanding is that there may be a 30 minute soak prior to this in a lower pH.  There are also buffers added, what are they?

The dilution is 1L/tablet (seems standard), but do they use different dilutions?

The test is specific to making sure the medicine crosses into the blood stream at the stated dosage.  There are detailed procedures in the USP.  That is really what I am looking for.

The apparatus includes some features that a hotplate and stirrer don't have.  What are those features?

They do have a test for inactives that might cross into the blood stream.  I am interested in exactly how that works, what do they test for?  Do they just filter with a molecular seive or is the test more complex?

[jsorex]

There is no pseudoephedrine specific pill extraction test in the pharmacopeia. Tere are several tests for durability of pills and the ones simulating the natural dissolving procedure of the pills in the human body.

They use machines that gently shake the pills in various media and write down the time and other parameters for each pill dissolution, and then calculate the averages and other numbers from the stastistical data.

Some of the tests do not even consider the release of the acticve ingredient, but rather that the formulation works like it should.

In other words the bioavailability is theoretical, and usually the only measurement for bioavailability that is considered reliable is a blood screen after administration.

[wareami]

F_C: Not sure how prominently this figures in to the broader scope, but it surely is playing a part in how testing is being introduced and accepted means of simulation in testing of coatings being introduced in pill manufacture.

[Materials and Methods
Drug Release Data

Dissolution data (125 profiles) obtained from SR minitablets, both coated and uncoated, were gathered for analysis. The original outputs for the neural network were the dissolution profiles for these SR tablets. A USP apparatus type 2 containing 900 mL of 0.015 M citrate/phosphate buffer, pH 6.8, was used for tablet dissolution testing. The complete dissolution of both enteric coatings (Eudragit L and S) required that the medium pH was greater than pH 6.5. Sodium lauryl sulphate (SLS), 0.5%, was introduced to achieve sink conditions for the CEL50.

The profiles were normalized between 0.0% and 100%. The times taken for 10% of the dosage form and 90% of the dosage form to be released were calculated from the profiles. These were converted to 2 outputs for use in the neural network:

   1. Time taken for 10% of the drug to be released (Tlag) was taken to be an indication of the lag time before release began (ie, the extent of the delaying effect of the enteric coating).
   2. Time taken for 90% of the drug to be released less the time taken for 10% of the drug to be released (T90-10) was taken to be an indication of the time taken for the drug to be released from the SR matrix once the outer coat had dissolved.

Similar simple dissolution parameters, such as the time to 50% drug dissolution have been used in other studies.2,4

The 2 separate phases in the dissolution profile (lag time followed by SR) are illustrated in Figure 1.
Software
The Trajan Neural Network Simulator, version 4, (Washington, Tyne and Wear, UK) was the software package used in this study. This is a Windows-based package, which supports numerous types of neural networks along with the fastest state-of-the-art training algorithms. The package includes other algorithms that carry out a variety of tasks such as pre- and post-processing of data, input feature selection, network design, and selection. The software also gives extensive statistical feedback on each network.15

Input variables
The number of inputs used for the network was 19 (see Tables 2, 3, and 4). The inputs included 11 variables related to the composition of the formulation and 8 variables related to the processing conditions: percentage Cel50 in the formulation, percentages of methocel K15M, methocel K100M, methocel K100LV, klucel, aerosil, magnesium stearate, avicel PH101, percentage weight gain after Eudragit L or Eudragit S coating, percentage weight gain after Opadry coating, spray rate of the coating solution (g/min), blend size of the original tablet batch (kg), batch size at that stage of processing (kg), time (minutes) the formulation was blended with the lubricant (magnesium stearate), press speed (revolutions per hour), Filomatic speed setting (setting on dial that governs how fast the blend was fed down from the hopper into the tablet press), tablet hardness (newtons), and tablet weight (mg).

http://www.aapspharmscitech.org/view.asp?art=pt040226&pdf=yes

[former_chemist]

Now can anyone describe a USP type 2 dissolution apparatus.
The clorpheneramine post had a similar description.  There was also a filteration through a seive and a GC/MS step as well.  This test was 900ml vs. 1000ml that I have seen for other tablets but they are in the same general area.

[java]

Many hits on Google found this one of interest.

http://www.indianpharma.org/pt/index.php/2004/2February/article6.htm

[former_chemist]

That article is most informative.

Summary:
   There are seven standard types of apparatus.  The temperature is set at 37C.  The pH and any associated buffers are specified in the USP monograph.  The solvent is water.  The volume may vary with equipment.

Equipment Types 4 and 7 listed below are probably most applicable to time release "goo".

Now someone mentioned they have the USP.  The pseudoephedrine monograph from the USP would be most helpful.

Apparatus types:

Apparatus 1 (basket) is generally preferred for capsules and operated at 100 rpm.

Apparatus 2 (paddle) is generally preferred for tablets and operated at 50 rpm.

Apparatus 3 (reciprocating cylinder) is useful for bead type modified-release dosage forms

Apparatus 4 (flow cell) is generally useful for modified release dosage forms that have limited solubility

Apparatus 5 (paddle over disc) and Apparatus 6(Cylinder) have been useful for evaluating transdermal dosage forms

Apparatus 7 (reciprocating disc) is useful for non-disintegrating type oral modified-release dosage forms.

[java]

Here are a couple of places you might look,

http://www.usp.org/

http://store.usp.org/OA_HTML/usp_ibeCSrdSrchResults.jsp?cg=-200&kw=pseudoephedrine&ds=0&dr=20&st=kw&cpg=0

I hope this helps...java

[methyl_ethyl]

I think you guys are barking up the wrong tree.  I do not see how the USP monograph is going to help you.  However I  will post the monographs if you like.  Pseudoephedrine has quite a few monographs.  Of the monographs in the pseudoephedrine folder which ones would you like to see?

Pseudoephedrine HCL
Pseudoephedrine Extended Release Capsules
Pseudoephedrine Hydrochloride Oral Solution
Pseudoephedrine HCL Syrup
Pseudoephedrine HCL Tablets
Pseudoephedrine HCL Extended Release Tablets
Pseudoephedrine Sulfate



Dissolution Apparatus:

I am unlcear on how this information will be of value to you either however someone asked for it.

Apparatus 1— The assembly consists of the following: a covered vessel made of glass or other inert, transparent material1 ; a motor; a metallic drive shaft; and a cylindrical basket. The vessel is partially immersed in a suitable water bath of any convenient size or placed in a heating jacket. The water bath or heating jacket permits holding the temperature inside the vessel at 37 ± 0.5 during the test and keeping the bath fluid in constant, smooth motion. No part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation, or vibration beyond that due to the smoothly rotating stirring element. Apparatus that permits observation of the specimen and stirring element during the test is preferable. The vessel is cylindrical, with a hemispherical bottom and with one of the following dimensions and capacities: for a nominal capacity of 1 liter, the height is 160 mm to 210 mm and its inside diameter is 98 mm to 106 mm; for a nominal capacity of 2 liters, the height is 280 mm to 300 mm and its inside diameter is 98 mm to 106 mm; and for a nominal capacity of 4 liters, the height is 280 mm to 300 mm and its inside diameter is 145 mm to 155 mm. Its sides are flanged at the top. A fitted cover may be used to retard evaporation2. The shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly and without significant wobble. A speed-regulating device is used that allows the shaft rotation speed to be selected and maintained at the rate specified in the individual monograph, within ±4%.



Apparatus 2— Use the assembly from Apparatus 1, except that a paddle formed from a blade and a shaft is used as the stirring element. The shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly without significant wobble. The vertical center line of the blade passes through the axis of the shaft so that the bottom of the blade is flush with the bottom of the shaft.




regards,

m_e