(83f) Turbidity and Endoscopy Assisted Monitoring of Solvent Mediated Polymorphic Transformation Processes

Polymorphism is a feature which characterizes most of the active
pharmaceutical ingredients and influences the solubility, shape and color of
crystals. The process of solvent mediated polymorphic transformation is a
series of events such as crystal dissolution, nucleation and growth and several
on-line PAT sensors have been evaluated to characterize the transformation
process by monitoring the solid or liquid phase properties. 

The focus of this work is to compare low-cost on-line PAT sensors with more
complex instruments such as the FBRM, FT-Raman, ATR-FTIR and FT-NIR
spectroscopy. The target of the investigation is to evaluate whether these
probes are able to detect changes in solid concentration due to
dissolution-nucleation-growth events and it is not expected that these give
information about the ratio of the polymorphic forms. In the family of low-cost
sensors are included the turbidity sensor and the bulk video imaging method
which can be implemented using an endoscope. Since the turbidity sensor is already
found in many industrial crystallizers and it is used to detect nucleation and
growth its evaluation for polymorphic transformation monitoring is obvious.
Moreover, note that no additional investment and installation costs occur.
Recently, GSK presented a case-study where turbidity and FT-Raman spectroscopy
was successfully used to follow the polymorphic transformation of an API [1].

 The endoscopy based process monitoring is a low-cost PAT tool in
evaluation phase [2]. It is based on imaging and recently it was proposed for
nucleation detection applications. Depending on the image analysis method used
it can detect the first formed crystals as objects; alternatively, when the
mean gray intensity of the images is calculated its operation is more similar
to that of the turbidity probes. Note that one image can provide the equivalent
information of several thousands of spatially distributed turbidity probes. In
this work the endoscopy images are analyzed using texture analysis based
methods. Simple image texture descriptors have been previously evaluated in the
form of mean, minimum and maximum intensities [3,4] for the purpose of
nucleation detection. Since the turbidity probe operates at 880 nm which is in
the NIR range FT-NIR spectroscopy was used to gain further information about
the operation of this probe. This work presents a quantitative evaluation of
the detection sensitivity of the dissolution and nucleation/steps of the
sensors mentioned above. Furthermore, parameters and sensor design issues which
influence the monitoring sensitivity are discussed in detail.

References:

[1] Barnes, S., Gillian, J., Diederich, A., Burton, D., Ertl, D., In Process
Monitoring of Polymorphic Form Conversion by Raman Spectroscopy and Turbidity
Measurements, American Pharmaceutical Review, http://americanpharmaceuticalreview.com/ViewArticle.aspx?ContentID=3386.

[2] Simon, L. L., Nagy, Z. K., Hungerbuhler, K., 2009b, Endoscopy-Based in
Situ Bulk Video Imaging of Batch Crystallization Processes, Organic Process
Research & Development, Special Issue on Polymorphism and Crystallization,
13: 1254-1261.

[3] Simon, L. L., Abbou Oucherif, K., Nagy, Z. K., Hungerbuhler, K., 2010,
Bulk Video Imaging Based Multivariate Image Analysis, Process Control Chart and
Acoustic Signal Assisted Nucleation Detection, Chem Eng Sci, 65: 4983-4995.

[4] Simon, L. L., Nagy, Z. K., Hungerbuhler, K., 2009a, Comparison of
External Bulk Video Imaging with Focused Beam Reflectance and Ultra
Violet-Visible Spectroscopy for Crystallization Nucleation Detection and
Metastable Zone Identification, Chem Eng Sci, 64: 3344-3351.