(233z) Wet Granulation-Induced Polymorphic Transitions in Piracetam: Raman Spectroscopy As a Potential in-Situ Process Analytical Tool | AIChE

(233z) Wet Granulation-Induced Polymorphic Transitions in Piracetam: Raman Spectroscopy As a Potential in-Situ Process Analytical Tool


Kollamaram, G. - Presenter, University of Limerick
Kelly, C., Bernal Institute, University of Limerick
Croker, D., University of Limerick
Walker, G., Bernal Institute, University of Limerick

Wet granulation induced
polymorphic transitions in Piracetam: Raman spectroscopy as a potential in-situ
process analytical tool


Gayathri Kollamaram, Catherine B. Kelly, Denise M. Croker, Gavin
M. Walker


University of Limerick,
Synthesis and Solid State Pharmaceutical Centre, Department of Chemical and
Environmental Sciences, Limerick, Ireland.



Wet granulation is one of the most popular techniques used during
the post processing of active pharmaceutical ingredients (APIs) due to its
ability to improve powder flow and compaction properties however the addition
of water can affect the crystal structure of certain APIs exhibiting
polymorphism. Piracetam is a highly aqueous-soluble drug which can exist in
many polymorphic forms including hydrates. The potential therefore exists for
process-induced transformations during wet granulation. Process-induced
polymorphic transitions in APIs are a major challenge in the pharmaceutical industry
as these unpredictable phase transitions can affect processability of the drugs
owing to altered physical properties such as compressibility and can result in
regulatory non-compliance due to altered bio-availability. Prior knowledge and
understanding of the mechanism of these process-induced polymorphic transitions
is therefore of the utmost importance. XRD and DSC techniques were used along
with Raman to examine the polymorphic transitions of Piracetam during wet
granulation so as to determine the effectiveness of Raman spectroscopy as a
process analytical technology (PAT) tool for this system.

Piracetam undergoes polymorphic transitions under the influence of
both solvent and temperature. FIII of Piracetam is
the most stable form at room temperature. FIII transforms to FI when heated to
140°C which transforms to metastable FII upon cooling to room temperature
following the Ostwald’s step rule of successive transformation. At ambient
conditions FII will eventually transform to the more stable FIII. It is known
that polymers can have a stabilizing and/or inhibitory effect on the
polymorphic transitions in APIs so different excipients with a range
of hydrophilicities, aqueous solubilities and molecular weights
were examined. Excipients used were Lactose monohydrate (LMH), microcrystalline
cellulose (MCC), Hydroxy propyl methyl cellulose (HPMC), Hydroxy
propyl cellulose (HPC) and Polyethylene glycol (PEG). LMH was chosen as the
excipient representing low molecular weight; MCC, HPMC and HPC represent the
excipients with varying degree of hydrophilicity while PEG is a water soluble

Piracetam was wet granulated with excipients with drug to
excipient ratio of 3:2 as Piracetam is a high dosage drug. The granules
produced were dried overnight at room temperature and the dried granules were
then analysed at pre-determined times points using XRD, Raman and
DSC. Raman was also employed to investigate the use of this technique as an
in-situ analysis method. Principle component analysis (PCA) and direct cluster
analysis (DCA) were used to process the Raman spectra as shown in (figure 1).
Prior to processing all spectra were normalised and the first
derivative was taken. XRD indicated that PIR granulated without any excipients
transformed from FIII to Piracetam monohydrate (PIR-MH) in the presence of
water and then recrystallized to FII upon drying. FII so obtained
gradually recrystallised to the stable FIII at room temperature
within two weeks. The Raman spectra gained from the granulation and drying of
PIR were analysed using PCA and DCA and showed clustering into three
distinct spectra which were confirmed to be those of FII, FIII and PIR-MH using
XRD. Raman was therefore used in conjunction with XRD to inspect the progress
of the transformation both from FIII to PIR-MH and from FII to FIII (Figure 2).

Granules of PIR containing LMH, MCC, HPMC and HPC exhibited
similar transformations as pure PIR during granulation, namely that FIII
transformed to monohydrate in the presence of water which recrystallized to FII
upon drying (Figure 3). The kinetics of solid state transformation of FII to
FIII at room temperature was retarded in the presence of excipients in
comparison to that of pure PIR and by different degrees depending on the
polymer. This was attributed to the interaction of excipients with the active functional
groups in the drug and by the hydrophilicity and molecular weight of the
excipients. However PEG had a different effect on these polymorphic
transitions. Piracetam remained in its stable FIII throughout the processes of
wetting and drying. Unlike the other excipients used in the study PEG is freely
soluble in water and therefore it is possible for PEG to competitively inhibit
the interaction between PIR and water. It is suggested that PEG inhibited the
solution-mediated polymorphic transition of FIII to FII through the
intermediate monohydrate.

Through the use of the complimentary techniques of XRD, DSC and
Raman spectroscopy the polymorphic transformations exhibited by Piracetam
during wet-granulation have been investigated. The importance of detecting the
monohydrate form of the API as a precursor to the production of the metastable
FII, the effectiveness of Raman spectroscopy in this detection, and the
importance of understanding the excipients typically used during wet
granulation have been demonstrated.


   Fig 1: Prinicpal component analysis of
the Raman spectra gained from the studies of Piracetam in water indicated
clustering of the spectra into three distinct forms.



   Fig 2: Raman spectra collected from an area on
the surface of the API on Day 3 and 30 after recrystallisation from
water illustrating the transformation of Piracetam FII to FIII during thirty
days at ambient temperature.


   Fig 3: Raman spectra showing transformation of
Piracetam from monohydrate to FII upon drying.