For a project I have to determine the drug concentration release profile of self-made methylphenidate HCl (MHCl) extended release tablets (hydrophilic matrix). We are thus doing a dissolution test as described conform the US/Eur. Pharmacopeia. However a problem we are facing is that we are not sure how to analyse the samples that we take from the dissolution test. This is because we are not sure what detection method to use. The problem is that we cannot directly get the right concentration for our primary detection method which is UV spectrophotometry. This is because MHCl has a very low extinction coefficient and thus a relatively higher concentration is needed to get the measurable absorption range of 0.2-0.8, but since the tablet dose is only 18 mg this is difficult to accomplish. We thought of doing two things: a solid phase extraction followed by UV or picric acid ionpairing followed by colorimetry. We asked our professor if the SPE followed by UV was possible, but he said that in this case it wasnt practical cause of the such low amount of drug in the tablets. So that leaves us with the picric acid analysis method. Problem is that we havent ever performed a colorimetric analysis before, though it looks pretty similar to spectrophotometric. From what we understand we need to measure the absorbance at a specific wavelength that the picric acid-MHCl complex is absorbing at. But how can we calculate the MHCl concentration from this? How much picric acid do we need to use to know for sure that all the MHCl has formed pairs with the picric acid? It's kind of confusing still and appreciate it if anyone could point us to some literature or give us insight on how to analyse these samples. Thanks in advance.

  • $\begingroup$ @xavier_fakerat I'm not quite following. What do you mean by taking the weight 10 or 20 tablets? What we have done so far is taken 3 tablets and performed a dissolution test with the paddle apparatus, taking around 8 samples per tablet over time period of 3 hours. $\endgroup$ – user21398 May 28 '17 at 14:27
  • $\begingroup$ Maybe I missed the question I will get back to you, I am thinking of another way.. $\endgroup$ – xavier_fakerat May 28 '17 at 14:53
  • $\begingroup$ @xavier_fakerat Isnt the method you're describing to test content uniformity instead of drug release profile over time? We want to individually analyse our 8 samples we took from each extended release tablet and eventually graph the concentration time profile. But the problem is that since the dose is really low, even if hypothetically everything got out of the matrix, only 18 mg would be dissolved in 500 ml water (our paddle setup). Since we only took samples of 5 ml we havent much to work with. Now that I think of it I think we couldve better done this in a smaller volume... $\endgroup$ – user21398 May 28 '17 at 14:56
  • $\begingroup$ Its somewhat similar though here is summary: USP II Apparatus was used to perform dissolution test. The speed for the paddle was set at 50rpm. 900ml of distilled water was placed in each of the vessels and maintained at a constant temp (37°C). Three tablets from each of the batches were added to each vessel (one tablet per vessel) at the same time and a timer started. The immediate release tablet was analysed every 5 minutes and the sustained release analysed every 10 minutes using UV-VIS Spectrophotometer at 271nm. The results were used to calculate conc and (%) released of the 3 batches. $\endgroup$ – xavier_fakerat May 28 '17 at 15:37
  • $\begingroup$ But I do get your point the dose is really low, you are very right, we did with 250mg so this range was more favourable, also we went on to do content uniformity as you noted $\endgroup$ – xavier_fakerat May 28 '17 at 15:39

If you are insistent on a picrate salt, I'd suggest first taking your methylphenidate and forming a known concentration of the picrate by adding a known amount of picric acid to a solution in which you know the base would be in excess. This ensures that all of the picric acids forms the picrate salt, and you would therefore know the picrate complex concentration (assuming there are no other compounds in solution that might react with the picrate). You could then measure the absorbances at a wavelength at which picric acid has only a negligible absorbance, provided one exists. Note that if no such wavelength exists, matters become rather more complex, and you will have to look for changes in absorbance on either side of an isosbestic point.

An alternative reaction to the use of picric acid is to instead use 1-fluoro-2,4-dinitrobenzene (FDNB), which reacts with primary and secondary amines at room temperature to form a highly-coloured 1-amino-2,4-dinitrobenzene (ADNB). The spectral overlap between FDNB and ADNB is typically pretty small, so using an excess of FDNB usually doesn't greatly change the absorbance at the maximal wavelength of ADNB. Again, to at least know the absorbance of the methylphenidate ADNB, you would have to first perform the reaction with an excess of methylphenidate, and assume a complete reaction to the ADNB.

  • $\begingroup$ Would it be possible to do a liquid liquid extraction to isolate the complex in an organic phase, since the unbound charged picrate should favor water more? And if this is possible which organic phase? $\endgroup$ – user21398 May 31 '17 at 14:22
  • $\begingroup$ @user21398 I think it would probably be decently difficult to separate by a normal extraction to a level acceptable for spectroscopy. The methylphenidate picrate salt is probably decently soluble in water (the HCl salt is has a solubility of about 18.6 mg/mL in water), but so is picric acid (about 12.7 mg/mL), resulting in a difficult separation. It may be worth seeing if there is a wavelength at which the complex absorbs a significant amount and at which picric acid does not. $\endgroup$ – JSK May 31 '17 at 16:19

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