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Crystal engineering of stable temozolomide cocrystals
N Jagadeesh Babu1, Palash Sanphui, Ashwini Nangia
1School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Central University P.O., Hyderabad 500 046, India.
Chemistry, an Asian Journal
|May 23, 2012
Summary
Temozolomide (TMZ) drug degradation is reduced by forming pharmaceutical cocrystals with organic acids. These cocrystals, particularly with succinic and oxalic acid, show enhanced stability and comparable dissolution rates to the original drug.
Area of Science:
- Pharmaceutical Science
- Materials Science
- Chemical Engineering
Background:
- Temozolomide (TMZ) is an important antitumor prodrug.
- TMZ exhibits poor stability in aqueous media at neutral to alkaline pH, undergoing rapid chemical degradation.
- This instability limits its therapeutic efficacy and formulation options.
Purpose of the Study:
- To enhance the stability of temozolomide (TMZ) through pharmaceutical cocrystal formation.
- To investigate the physicochemical properties and stability of TMZ cocrystals with various organic acids.
- To assess the potential of cocrystals to improve TMZ's pharmaceutical profile.
Main Methods:
- Cocrystal engineering of TMZ with safe organic acids (oxalic, succinic, salicylic, malic, tartaric acids).
- Characterization using powder X-ray diffraction (PXRD), single crystal X-ray diffraction, FT-IR, and FT-Raman spectroscopy.
- Stability studies under physiological conditions (pH 7 buffer) and accelerated ICH conditions (40°C, 75% RH).
- Dissolution rate assessment using UV/Vis spectroscopy and intrinsic dissolution rate (IDR) measurements.
Main Results:
- TMZ cocrystals with organic acids (pKa 2-6) demonstrated significantly improved stability compared to pure TMZ.
- Cocrystals with oxalic and salicylic acids showed a two-fold longer half-life in pH 7 buffer (3.5-3.6 h vs. 1.7 h for TMZ).
- Solid-state stability studies revealed that TMZ cocrystals with succinic and oxalic acid remained intact after 28 weeks under ICH conditions, while pure TMZ degraded within one week.
- The intrinsic dissolution rate of TMZ-oxalic acid and TMZ-succinic acid cocrystals was comparable to that of pure TMZ.
Conclusions:
- Pharmaceutical cocrystal formation is an effective strategy to stabilize temozolomide (TMZ).
- Cocrystals with succinic acid and oxalic acid offer a promising approach to improve TMZ stability without compromising its dissolution characteristics.
- These findings suggest that TMZ cocrystals could lead to more stable and potentially more effective pharmaceutical formulations.
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