Solubility

Title

Ketoconazole Salt and Co-crystals with Enhanced Aqueous Solubility

 

Authors

Flavia A. Martin, Mihaela M. Pop, Gheorghe Borodi, Xenia Filip, and Irina Kacso

 

Abstract

Crystal structures of ketoconazole oxalate salt (1) and three co-crystals with fumaric (2), succinic (3), and adipic (4) acids in 1:1 stoichiometry were determined by single-crystal X-ray diffraction in which 1 forms oxalate dimers involved in ionic interaction with the imidazole ring of ketoconazole molecules, while 2−4 display 4-member circuit networks between hydrogen-bonded ketoconazole and coformer molecules. The salt and co-crystal nature of 1−4 was confirmed by combining single-crystal X-ray diffraction, ss-NMR, and lattice energy calculations. Ketoconazole molecules show highly similar conformations and crystal packing in cocrystals 2 and 3, while different conformers are present in the 1, 2, and 4 structures. For all salt and co-crystals, powder dissolution measurements revealed a significant solubility improvement compared to ketoconazole, and the solubility of 1−4 is contrary to the solubility values of the corresponding acids. A 100-fold solubility increase in water was obtained by ketoconazole co-crystallization with fumaric and adipic acids. Additionally, 1−4 are stable in suspensions for at least 1 week and on storage at 40 °C/75% RH for at least 4 months. The melting points of 1, 3, and 4 are in line to their solubility, while the solubility difference between the highly similar co-crystals 2 and 3 is reflected in their different lattice energy. Our study emphasizes the benefit of crystal engineering in the landscape of the formulation techniques used to enhance the dissolution rate of poorly water-soluble drugs such as ketoconazole.

 

Publication

Crystal Growth & Design

 

Bibliography

Flavia A. Martin, Mihaela M. Pop, Gheorghe Borodi, Xenia Filip, and Irina Kacso. Ketoconazole Salt and Co-crystals with Enhanced Aqueous Solubility. Cryst Growth Des. 13(10):4295. August 2013.

 

Link

http://pubs.acs.org/doi/abs/10.1021/cg400638g

 

 

 

 

Title

Solubility–Excipient Classification Gradient Maps

 

Authors

A Avdeef, S Bendels, O Tsinman, M Kansy

 

Abstract

This study assessed the effect of excipients (sodium taurocholate, 2-hydroxypropyl-f-cyclodextrin, potassium chloride, propylene glycol, 1-methyl-2-pyrrolidone, and polyethylene glycol 400) on the apparent intrinsic solubility properties of eight sparingly soluble drugs (four bases, two neutrals, and two acids): astemizole, butacaine, clotrimazole, dipyridamole, griseofulvin, progesterone, glibenclamide, and mefenemic acid. Over 1,200 UV-based solubility measurements (pH 3-10) were made with a high-throughput instrument. New equations, based on the "shift-in-pKa" method, were derived to interpret the complicated solubility-pH dependence observed, and poorly predicted by the Henderson-Hasselbalch equation. An intrinsic solubility-excipient classification gradient map visualization tool was developed to rank order the compounds and the excipients. In excipient-free solutions, all of the ionizable compounds formed either uncharged or mixed-charge aggregates. Mefenamic acid formed anionic dimers and trimers. Glibenclamide displayed a tendency to form monoanionic dimers. Dipyridamole and butacaine tended to form uncharged aggregates. With strong excipients, the tendency to form aggregates diminished, except in the case of glibenclamide. We conclude that a low-cost, compound-sparing, and reasonably accurate high-throughput assay which can be used in early screening to prioritize candidate molecules by their eventual developability via the excipient route is possible with the aid of the "self-organized" intrinsic solubility-excipient classification gradient maps.

 

Publication

Pharmaceutical Research

 

Bibliography

Avdeef, A.; Bendels, S.; Tsinman, O.; Kansy, M. Solubility–Excipient Classification Gradient Maps. Pharm Res. 2007 Mar;24(3):530-45. (Part 22 PAMPA Series)

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/17245653

 

 

 

 

Title

Solubility of sparingly-soluble drugs

 

Authors

A Avdeef

 

Abstract

The experimental and computational basis of the pH-dependent measurement of solubility of sparingly-soluble ionizable drugs is reviewed. Recently described compound-sparing (but still accurate) approaches, suitable for application in preclinical development, and appropriate for the analysis of solubility of “problematic” molecules, are critically examined. A number of useful experimental methods are reviewed, including the miniaturized shake-flask microtitre plate, the micro solubility self-calibrating direct UV, potentiometric, and the micro dissolution methods. Several molecules were selected as case studies to illustrate important concepts, with re-analysis of literature data using recently established computational tools.

 

Publication

Advanced Drug Delivery Reviews

 

Bibliography

Avdeef, A. Solubility of sparingly-soluble drugs. Dressman, J.; Reppas, C. (Eds., special issue: The Importance of Drug Solubility). Adv Drug Deliv Rev. 2007 Jul 30;59(7):568-90. (Part 2 in μDISS series)

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/17644216

 

 

 

 

Title

A measured solution.

 

Authors

J Ruell, A Avdeef

 

Abstract

Researchers are using different techniques to address drug solubility issues.

 

Publication

Modern Drug Discovery

 

Bibliography

Ruell, J.; Avdeef, A. A measured solution. Modern Drug Disc. 2003, June issue, 47-49.

 

Link

http://pubs.acs.org/subscribe/archive/mdd/v06/i06/pdf/603toolbox.pdf

 

 

 

 

Title

Factors influencing the water solubility of crystalline drugs. (in Drug Bioavailability. Estimation of Solubility, Permeability, Absorption and Bioavailability)

 

Authors

JW McFarland, CM Du, A Avdeef

 

Publication

Drug Bioavailability. Estimation of Solubility, Permeability, Absorption and Bioavailability

 

Bibliography

McFarland, J.W.; Du, C.M.; Avdeef, A. Factors influencing the water solubility of crystalline drugs. In: van de Waterbeemd, H.; Lennernäs, H.; Artursson, P. (Eds.). Drug Bioavailability. Estimation of Solubility, Permeability, Absorption and Bioavailability. Wiley -VCH: Weinheim, 2003, pp. 232-242. . (Part 6 in pSOL series)

 

Link

http://onlinelibrary.wiley.com/doi/10.1002/3527601473.ch10/summary