Saccharin Salts of Active Pharmaceutical Ingredients, Their Crystal Structures, and Increased Water Solubilities

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• 作者：Rahul Banerjee ; Prashant M. Bhatt ; Nittala V. Ravindra ; and Gautam R. Desiraju
• 刊名：Crystal Growth & Design
• 出版年：2005
• 出版时间：November 2005
• 年：2005
• 卷：5
• 期：6
• 页码：2299 - 2309
• 全文大小：535K
• 年卷期：v.5,no.6(November 2005)
• ISSN：1528-7505

文摘

Salts of active pharmaceutical ingredients (APIs) have been traditionally used in drug formulationsbecause of improved properties with respect to solubility, stability, or bioavailability. Saccharin has been used asan acid for salt formation with APIs in a few cases hitherto. In this paper, we have explored the generality of thisproperty and have isolated saccharinates of quinine, haloperidol, mirtazapine, pseudoephedrine, lamivudine,risperidone, sertraline, venlafaxine, zolpidem, and amlodipine. These salts have been characterized with single-crystal X-ray methods. The structures contain many hydrogen bonds of the O-H···N^(-), N^(+)-H···N^(-), N⁽⁺⁾-H···O,N-H···O, O-H···O and N-H···N type, with auxiliary C-H···N^(-) and C-H···O interactions. These saccharinatesare mostly very soluble in water when compared to the free base. Additionally, aqueous solutions of these APIsaccharinates are of moderate pH. Both these properties may be advantageous in the pharmaceutical industry. Ingeneral, most saccharinates would appear to have high water solubility, and this follows from the molecular structureof the anion, which is donor-poor and acceptor-rich in terms of hydrogen-bonding functionalities. If an API ofinsufficient basicity is treated with saccharin, it may form a hydrogen-bonded cocrystal wherein proton transferfrom saccharin to the API does not take place. This phenomenon was found in the cocrystal saccharin-piroxicam.