Tailoring Chlorthalidone Aqueous Solubility by Cocrystallization: Stability and Dissolution Behavior of a Novel Chlorthalidone-Caffeine Cocrystal.

A cocrystal of the antihypertensive drug chlorthalidone (CTD) with caffeine (CAF) was obtained (CTD-CAF) by the slurry method, for which a 2:1 stoichiometric ratio was found by powder and single-crystal X-ray diffraction analysis. Cocrystal CTD-CAF showed a supramolecular organization in which CAF molecules are embedded in channels of a 3D network of CTD molecules. The advantage of the cocrystal in comparison to CTD is reflected in a threefold solubility increase and in the dose/solubility ratios, which diminished from near-unit values for D0D to 0.29 for D0CC. Furthermore, dissolution experiments under non-sink conditions showed improved performance of CTD-CAF compared with pure CTD. Subsequent studies showed that CTD-CAF cocrystals transform to CTD form I where CTD precipitation inhibition could be achieved in the presence of pre-dissolved polymer HPMC 80-120 cPs, maintaining supersaturation drug concentrations for at least 180 min. Finally, dissolution experiments under sink conditions unveiled that the CTD-CAF cocrystal induced, in pH-independent manner, faster and more complete CTD dissolution when compared to commercial tablets of CTD. Due to the stability and dissolution behavior of the novel CTD-CAF cocrystal, it could be used to develop solid dosage forms using a lower CTD dose to obtain the same therapeutic response and fewer adverse effects.

Molecular Cage Assembly by Sn-O-Sn Bridging of Di-, Tri- and Tetranuclear Organotin Tectons: Extending the Spacing in Double Ladder Structures.

Hydrolysis reactions of di- and trinuclear organotin halides yielded large novel cage compounds containing Sn-O-Sn bridges. The molecular structures of two octanuclear tetraorganodistannoxanes showing double-ladder motifs, viz., [{Me3 SiCH2 (Cl)SnCH2 YCH2 Sn(OH)CH2 SiMe3 }2 (µ-O)2 ]2 [1, Y=p-(Me)2 SiC6 H4 -C6 H4 Si(Me)2 ] and [{Me3 SiCH2 (I)SnCH2 YCH2 Sn(OH)CH2 SiMe3 }2 (µ-O)2 ]2 ⋅0.48 I2 [2⋅0.48 I2 , Y=p-(Me)2 SiC6 H4 -C6 H4 Si(Me)2 ], and the hexanuclear cage-compound 1,3,6-C6 H3 (p-C6 H4 Si(Me)2 CH2 Sn(R)2 OSn(R)2 CH2 Si(Me)2 C6 H4 -p)3 C6 H3 -1,3,6 (3, R=CH2 SiMe3 ) are reported. Of these, the co-crystal 2⋅0.48 I2 exhibits the largest spacing of 16.7 Šreported to date for distannoxane-based double ladders. DFT calculations for the hexanuclear cage and a related octanuclear congener accompany the experimental work.