Graduation Year

2011

Document Type

Thesis

Degree

M.S.

Degree Granting Department

Chemistry

Major Professor

Michael J. Zaworotko

Keywords

BCS, Caffeine, Hydrogen Bond, Pentoxifylline, Solubility

Abstract

Pharmaceutical cocrystals use principles of crystal engineering for the design of crystalline forms of drugs and can improve their solubility, bioavailability, stability and other important properties without changing the efficacy of the drug. Herein reported are pharmaceutical cocrystals of two API's, caffeine and Pentoxifylline.

Research has indicated that caffeine has the ability to reverse AB; plaque deposition in the brain (believed to be the primary cause of Alzheimer's pathogenesis) and thus revert memory and improve cognitive impairment. But owing to the fast absorption rate and short half life, a controlled release formulation of caffeine would be clinically beneficial. Thus, novel cocrystals of caffeine are presented with varying solubilities with respect to caffeine. The pharmaceutical cocrystals of caffeine used herein include: caffeine.cyanuric acid monohydrate, caffeine.syringic acid tetrahydrate, caffeine.chlorogenic acid and caffeine.catechin hydrate. Three caffeine cocrystals were prepared in our lab previously which include caffeine.ferulic acid, caffeine.ethyl gallate dihydrate and caffeine.caffeic acid. In addition, six caffeine cocrystal forms were reproduced from the literature and included in the solubility study: caffeine.quercetin, caffeine.salicylic acid, caffeine.1-hydroxy-2-napthoic acid, caffeine.gallic acid hemihydrate, caffeine.ellagic acid monohydrate and caffeine.coumaric acid. Dissolution studies were performed in aqueous media at room temperature. All of the cocrystals decreased the solubility of caffeine with the highest being a 278 fold decrease in the solubility of caffeine. Analysis of melting point, crystal packing efficiency and solubility of cocrystal former with solubility was also done to determine if they influenced the solubility. Presented herein are the results of the analyses. It was seen that solubility of the cocrystal former had no effect on the decrease in cocrystal solubility. Moreover melting point and solubility of the cocrystal could not be correlated probably due to the variability in the cocrystal formers. Crystal packing efficiency though did not show a high correlation with solubility but it was seen that highest solubility achieved by pure caffeine achieved the lowest crystal packing efficiency and vice versa suggesting its role in cocrystal solubility.

Pentoxifylline is contraindicated for its use in autism. But owing to high solubility of the drug, a less soluble form of the drug would help in decreasing the half life and thereby help in forming a sustained form of the drug by modifying the inherent solubility of the API. Here, novel cocrystals of Pentoxifylline are presented with varying solubilities with respect to the API. The pharmaceutical cocrystals used herein include: pentoxifylline.benzoic acid, pentoxifylline.1-hydroxy-2-napthoic acid, pentoxifylline.salicylic acid, pentoxifylline.gallic acid, pentoxifylline. salicylamide, pentoxifylline.coumaric acid, pentoxifylline.caffeic acid and pentoxifylline.catechin hydrate. Dissolution studies were also performed in aqueous media at room temperature. All of the cocrystals decreased the solubility of Pentoxifylline with the highest being a 99 fold decrease in the solubility with pentoxifylline.coumaric acid. On analyzing melting point, crystal packing efficiency and relation of solubility of cocrystal former with solubility of cocrystal, as was done in the case of caffeine, the parameters showed no effect on solubility of the cocrystal.