Manipulating Theophylline Monohydrate Formation During High-Shear Wet Granulation Through Improved Understanding of the Role of Pharmaceutical Excipients

• Published in: Pharmaceutical research Vol. 25; no. 4; pp. 923 - 935
• Main Authors: Wikström, Håkan, Carroll, William J., Taylor, Lynne S.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.04.2008; Springer; Springer Nature B.V
• Subjects: Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Chemistry, Pharmaceutical; Crystallization; Drug Compounding; Excipients - chemistry; General pharmacology; Hypromellose Derivatives; Kinetics; Medical Law; Medical sciences; Methylcellulose - analogs & derivatives; Methylcellulose - chemistry; Models, Chemical; Pharmaceutical technology. Pharmaceutical industry; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Polymers; Research Paper; Solubility; Spectrum analysis; Spectrum Analysis, Raman; Technology, Pharmaceutical - methods; Theophylline - chemistry; Water - chemistry; hydrate formation; high-shear wet granulation; crystal growth; excipients; Raman spectroscopy; additive; Shear; Pharmaceutical technology; Bronchodilator; Vehicle(excipient); Antiasthma agent; Phosphodiesterase inhibitor; Respiratory analeptic; Additive; Wet granulation; Phosphodiesterase 4 inhibitor; Xanthine derivatives; Raman spectrometry; Theophylline; Hydrates
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-007-9450-x

Purpose 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. Results 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. Conclusions 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.