Manipulating Theophylline Monohydrate Formation During High-Shear Wet Granulation Through Improved Understanding of the Role of Pharmaceutical Excipients
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To investigate the effect of common pharmaceutical excipients on the kinetics of theophylline monohydrate formation during high-shear wet granulation.
Materials and methods
A mixture of anhydrous theophylline and the excipient was granulated in a high-shear granulator, using water as the granulation liquid. Non-contact Raman spectroscopy was used to monitor the rate of transformation of anhydrate to hydrate during the granulation process. The kinetics of conversion was also monitored in slurries of theophylline whereby the excipients were added to the aqueous phase. Optical microscopy was used to visualize the transformation and to measure the linear growth rates of hydrate crystals in the presence and absence of the excipients.
At pharmaceutically relevant amounts of excipient, the transformation kinetics of theophylline was unchanged for the majority of excipients tested. However, when granulating with low concentrations of some commonly used polymeric binders, the transformation kinetics could be significantly retarded. For example, methylcellulose polymers delayed both the onset of hydrate formation as well as retarding the transformation rate. When 0.3% (w/w) of hydroxypropyl methylcellulose was added to a model formulation containing 30% (w/w) theophylline anhydrous, the formation of the monohydrate could be completely prevented over the time period of the granulation experiment, without significantly affecting the granular properties. Microscopic observations of hydrate formation in the presence of the polymer revealed that the polymers that inhibited hydrate formation reduced the hydrate crystal growth rates and influenced hydrate morphology.
Raman spectroscopy is a useful technique to monitor hydrate formation during wet granulation. Some commonly used polymeric pharmaceutical excipients can be used to manipulate theophylline hydrate formation in aqueous pharmaceutical environments. These excipients may affect either the nucleation and/or the growth of the hydrate phase.
Key wordsadditive crystal growth excipients high-shear wet granulation hydrate formation Raman spectroscopy
high-performance liquid chromatography
hydroxypropyl methylcellulose acetate succinate
sodium carboxy methylcellulose
National Institute of Standards and Technology
cross-linked polyacrylic acid
sodium dodecyl sulfate
scanning electron microscopy
United States Pharmacopeia
powder X-ray diffractometry
Dr. Alan Gift, Daniel Sage and Margaret K. Kunkel (all Purdue University) are gratefully acknowledged for assistant with data analysis and experimental support. Jerry J. Sheppard (Purdue University) is acknowledged for his assistance with designing the small-scale granulator, and the general machine shop of Purdue University is thanked for building it. The authors are grateful to Mary A. Albrecht (SSCI, Inc.) for providing the SEM pictures. Sharon Deram (SBI Analytical, Inc.) and Kaiser Optical Systems, Inc., are acknowledged for their assistance with instrumentation. The Dow Chemical Company, BASF and ISP Technologies, Inc. are thanked for supplying the majority of the polymers used for this study. The Dane O. Kildsig Center for Pharmaceutical Processing Research and AstraZeneca R&D Mölndal are acknowledged for funding.
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