NAME: SHASHANK JAIN

INSTUCTOR:DR. E.SQUILANTE

Effect of hydrate formation on dissolution profile of theophylline

(A common problem in wet granulation)

Theophylline (TP)

PRE-TEST

Q.Do you know how hydrate formation effect the dissolution profile of a drug.

a] Yesb] No

Response : 34 responsesYes:3No :31

THESIS STATEMENT

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.

Hydrates-A PIT

Process-induced transformations (PIT) occur as a result of mechanical or thermal stress imposed upon a system during processing or after exposure to solvent.

PIT’s are important because they may alter the properties of the final dosage form such as

Solubility Dissolution rate Hygroscopicity Stability Bioavailability.

Hydrate Formation in Theophylline

SEM ANALYSIS(MORPHOLOGICAL CHANGE DURING ANHYDRATE

MONOHYDRATE)

(Anhydrate theophylline)

(Monohydrate theophylline)

“EXPECTED” DISSOLUTION PROFILE OF THEOPHYLLINE

Step1(stable anhydrate) Step2(Hydrate) Step3(metastable anhydrate)

Least dissolution : Step 2( by affecting thermodynamic property of theophyllline)

Step3>Step1 the expected rank order of dissolution rates

was as follows: Step 3 > Step 1 > Step 2.

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

ACTUAL DISSOLUTION PROFILE

Actual dissolution profile of theophylline follows:

step 1(Stable) > Step 2(hydrate) ≈ Step 3(metastable)

Why ???Rapid metastable anhydrate(Step3) →

theophylline monohydrate during dissolution.

CASE STUDY

“FDA issued a warning letter to XX company due to failure of dissolution test in four batches of theophylline”

--Problem of hydrate formation was found to the major reason .

How we can determine the Hydrate formation in theophylline?

Current approach- NIR(Near Infra-Red) spectroscopy Raman Spectroscopy

NIR SPECTROSCOPY METHOD

The absorption bands in NIR spectra are sensitive to changes in hydrogen bonding and packing in the crystal lattice.

We can detect the hydrate formation by observing the energy distribution of OH vibration.

How ?

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.

( Ref- Reseach based study of university of Helsinki )

CRITICAL ISSUES

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).

However the changes in other vibration originating from other constituents are obscured.

In addition, if the water content is high, the free water absorbance may overlap the hydrate water absorbance

This problem is not encountered using Raman spectroscopy, Why?

RAMAN SPECTROSCOPY

Raman spectroscopy is based on measurement of frequency shifts of scattered light. Raman spectrometers can be coupled with

fibre optic probing which enables on-line and non-invasive measurements.

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 to1850 nm.

Waterfall Plot of NIR and Raman Effect

Summary: Advantage of Raman Over NIR Spectroscopy

In NIR, the free water absorbance may overlap the hydrate water absorbance. Water is a weak Raman scatter

In contrast to NIR, the Raman bands are well resolved.

Raman instruments can also measure lattice vibrations (Bugay, 2001), so called phonons, which occur at low frequencies (400-50 cm-1).

CONCLUSION

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.

POST SEMINAR QUESTION

Q. How hydrate formation may effect the End Point Determination in theophylline during wet granulation process?

THANK YOU