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<ul><li>NAME: SHASHANK JAIN </li></ul><ul><li>INSTUCTOR: </li></ul><ul><li>DR. E.SQUILANTE </li></ul>Effect of hydrate for...
PRE-TEST <ul><li>Q.Do you know how hydrate formation effect the dissolution profile of a drug. </li></ul><ul><li>a] Yes </...
THESIS STATEMENT  <ul><li>To know the effect of hydrate formation on dissolution rate of theophylline and propose a best a...
Hydrates-A PIT <ul><li>Process-induced transformations (PIT) occur as a result of mechanical or thermal stress imposed upo...
 
Hydrate Formation in Theophylline
SEM ANALYSIS ( MORPHOLOGICAL CHANGE DURING  ANHYDRATE  MONOHYDRATE ) (Anhydrate theophylline) (Monohydrate theophylline)
“ EXPECTED ” DISSOLUTION PROFILE  OF THEOPHYLLINE <ul><li>Step1(stable anhydrate)  Step2(Hydrate)  Step3(metastable anhydr...
FIGURE 1. DISSOLUTION PROFILES OF UNPROCESSED AND PROCESSED ANHYDROUS THEOPHYLLINE SAMPLES: STEP 1 ( ● ), STEP 2 ( ♦ ), AN...
ACTUAL DISSOLUTION PROFILE <ul><li>Actual dissolution profile of theophylline follows:  </li></ul><ul><li>step 1(Stable) >...
CASE STUDY <ul><li>“ FDA issued a warning letter to XX company  due to failure of dissolution test in four batches of theo...
How we can determine the Hydrate formation in theophylline? <ul><li>Current approach- </li></ul><ul><li>NIR(Near Infra-Red...
NIR SPECTROSCOPY METHOD <ul><li>The absorption bands in NIR spectra are sensitive to changes in hydrogen bonding and packi...
<ul><li>NIR spectra of theophylline -microcrystalline cellulose (1:1, w/w) wet granules. Absorbance maxima are observed as...
CRITICAL ISSUES <ul><li>The NIR spectroscopy enables the determination of the state of water and has also been used for qu...
RAMAN SPECTROSCOPY <ul><li>Raman spectroscopy is based on measurement </li></ul><ul><li>of frequency shifts of scattered l...
Comparision of NIR and Raman spectra AT has distinct peaks at 1664 and 1707 cm -1  and MT has a distinct peak at 1686 cm -...
Waterfall Plot of NIR and Raman Effect
Summary :  Advantage of Raman Over NIR Spectroscopy <ul><li>In NIR, the free water absorbance may overlap the hydrate wate...
CONCLUSION <ul><li>NIR spectroscopy could not be used to monitor the phase transformation in this system because of the  l...
POST SEMINAR QUESTION <ul><li>Q. How hydrate formation may effect the End Point Determination in theophylline during  wet ...
 
THANK  YOU
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Effect Of Hydrate Formation (A Common Problem In Wet Granulation)

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Effect Of Hydrate Formation (A Common Problem In Wet Granulation)

  1. 1. <ul><li>NAME: SHASHANK JAIN </li></ul><ul><li>INSTUCTOR: </li></ul><ul><li>DR. E.SQUILANTE </li></ul>Effect of hydrate formation on dissolution profile of theophylline (A common problem in wet granulation) Theophylline (TP)
  2. 2. PRE-TEST <ul><li>Q.Do you know how hydrate formation effect the dissolution profile of a drug. </li></ul><ul><li>a] Yes </li></ul><ul><li>b] No </li></ul><ul><li>Response : 34 responses </li></ul><ul><li>Yes:3 </li></ul><ul><li>No :31 </li></ul>
  3. 3. THESIS STATEMENT <ul><li>To know the effect of hydrate formation on dissolution rate of theophylline and propose a best available method to detect these hydrate by analysing two current PAT techniques i.e NIR and Raman. </li></ul>
  4. 4. Hydrates-A PIT <ul><li>Process-induced transformations (PIT) occur as a result of mechanical or thermal stress imposed upon a system during processing or after exposure to solvent. </li></ul><ul><li>PIT’s are important because they may alter the properties of the final dosage form such as </li></ul><ul><li>Solubility </li></ul><ul><li>Dissolution rate </li></ul><ul><li>Hygroscopicity </li></ul><ul><li>Stability </li></ul><ul><li>Bioavailability. </li></ul>
  5. 6. Hydrate Formation in Theophylline
  6. 7. SEM ANALYSIS ( MORPHOLOGICAL CHANGE DURING ANHYDRATE MONOHYDRATE ) (Anhydrate theophylline) (Monohydrate theophylline)
  7. 8. “ EXPECTED ” DISSOLUTION PROFILE OF THEOPHYLLINE <ul><li>Step1(stable anhydrate) Step2(Hydrate) Step3(metastable anhydrate) </li></ul><ul><li>Least dissolution : Step 2( by affecting thermodynamic property of theophyllline) </li></ul><ul><li>Step3>Step1 </li></ul><ul><li>the expected rank order of dissolution rates was as follows: Step 3 > Step 1 > Step 2. </li></ul>
  8. 9. FIGURE 1. DISSOLUTION PROFILES OF UNPROCESSED AND PROCESSED ANHYDROUS THEOPHYLLINE SAMPLES: STEP 1 ( ● ), STEP 2 ( ♦ ), AND STEP 3 ( ■ ). THESE ARE DESCRIBED IN SCHEME 1. ( REF :DEBNATH S, SURYANARAYANAN R. INFLUENCE OF PROCESSING-INDUCED PHASE TRANSFORMATIONS ON THE DISSOLUTION OF THEOPHYLLINE TABLETS. AAPS PHARMSCITECH. 2004; 5(1) Step 1 Step 2 Step 3
  9. 10. ACTUAL DISSOLUTION PROFILE <ul><li>Actual dissolution profile of theophylline follows: </li></ul><ul><li>step 1(Stable) > Step 2(hydrate) ≈ Step 3(metastable) </li></ul><ul><li>Why ??? </li></ul><ul><li>Rapid metastable anhydrate(Step3) -> theophylline monohydrate during dissolution. </li></ul>
  10. 11. CASE STUDY <ul><li>“ FDA issued a warning letter to XX company due to failure of dissolution test in four batches of theophylline” </li></ul><ul><li>--Problem of hydrate formation was found to the major reason . </li></ul>
  11. 12. How we can determine the Hydrate formation in theophylline? <ul><li>Current approach- </li></ul><ul><li>NIR(Near Infra-Red) spectroscopy </li></ul><ul><li>Raman Spectroscopy </li></ul>
  12. 13. NIR SPECTROSCOPY METHOD <ul><li>The absorption bands in NIR spectra are sensitive to changes in hydrogen bonding and packing in the crystal lattice. </li></ul><ul><li>We can detect the hydrate formation by observing the energy distribution of OH vibration. </li></ul><ul><li>How ? </li></ul>
  13. 14. <ul><li>NIR spectra of theophylline -microcrystalline cellulose (1:1, w/w) wet granules. Absorbance maxima are observed as troughs. Free water: 1905 nm, hydrate water: 1970 nm. Arrows indicate changes taking place with increasing water content. </li></ul><ul><li>( Ref- Reseach based study of university of Helsinki ) </li></ul>
  14. 15. CRITICAL ISSUES <ul><li>The NIR spectroscopy enables the determination of the state of water and has also been used for quantitative determination of moisture (Osborne et al., 1993). </li></ul><ul><li>However the changes in other vibration originating from other constituents are obscured. </li></ul><ul><li>In addition, if the water content is high, the free water absorbance may overlap the hydrate water absorbance </li></ul><ul><li>This problem is not encountered using Raman spectroscopy, Why? </li></ul>
  15. 16. RAMAN SPECTROSCOPY <ul><li>Raman spectroscopy is based on measurement </li></ul><ul><li>of frequency shifts of scattered light. </li></ul><ul><li>Raman spectrometers can be coupled with fibre optic probing which enables on-line and </li></ul><ul><li>non-invasive measurements. </li></ul>
  16. 17. Comparision of NIR and Raman spectra AT has distinct peaks at 1664 and 1707 cm -1 and MT has a distinct peak at 1686 cm -1 , NIR spectra of AT and MT from 1100 to 1850 nm.
  17. 18. Waterfall Plot of NIR and Raman Effect
  18. 19. Summary : Advantage of Raman Over NIR Spectroscopy <ul><li>In NIR, the free water absorbance may overlap the hydrate water absorbance. Water is a weak Raman scatter </li></ul><ul><li>In contrast to NIR, the Raman bands are well resolved. </li></ul><ul><li>Raman instruments can also measure lattice vibrations (Bugay, 2001), so called phonons, which occur at low frequencies (400-50 cm -1 ). </li></ul>
  19. 20. CONCLUSION <ul><li>NIR spectroscopy could not be used to monitor the phase transformation in this system because of the large absorbance of bulk water . However In-line Raman spectroscopy was successfully interfaced to high-shear wet granulation for detection of hydrates in theophylline as water is the poor raman scatter. </li></ul>
  20. 21. POST SEMINAR QUESTION <ul><li>Q. How hydrate formation may effect the End Point Determination in theophylline during wet granulation process? </li></ul>
  21. 23. THANK YOU

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