Indeed, melting point was shown to decrease with increased chain length, and the reduction was 80 вЊ for the derivative with the most flexible substituent ( 5f) compared to the parent compound. For the ciprofloxacin derivatives herein melting point was used to investigate how the crystal lattice was affected by the alkyl chains. (8) The authors speculated that the higher solubility of the derivatives was an effect of a less ordered crystal lattice however, the solid state was not characterized to prove this. (7) A similar approach in which the flat, planar molecular structure of phosphodiesterase-4 inhibitors was disrupted through introduction of bulky substituents based on cyclohexyl was recently published. The long, flexible alkyl chains will perturb the crystal lattice, and the reduced hydrogen bond capacity, as a result of esterification of the carboxylic acid function, will result in less ordered intermolecular hydrogen bond patterns.

Intermolecular interactions can be lowered by this approach.

(2a)Д¬iprofloxacin is a compound with solid-state limited solubility, and hence, we decided to improve the aqueous solubility by introducing bulky, flexible side chains and reducing the hydrogen bond capacity of the molecule to disrupt the crystal lattice. This is in agreement with our previous finding that for compounds with a log P of 3 or more, significantly increased apparent solubility can be expected in intestinal fluids compared to pure water or buffers. A significant solubilization in lipid aggregates naturally available in the intestine, as simulated with FaSSIF, was only seen for the most lipophilic compound ( 5f), i.e., the hexyl derivative with a log P of 3.3 (log D pH6.5 of 1.1 see Figure 2). For the more lipophilic derivatives ( 5f and 5g) the solubility was significantly reduced compared to ciprofloxacin, with the compounds having 10- to 30-fold lower solubility in all media (Figure 3). Compounds 5c and 5d displayed solubilities of 0.5вЂ“1 of that of ciprofloxacin. 5b showed 2- to 3-fold higher solubility in the three media, whereas 5e had 4-, 27-, and 10-fold higher solubility compared to ciprofloxacin in PhB 7.4, PhB 6.5, and FaSSIF, respectively. Derivative 5a showed 48-, 66-, and 111-fold higher solubility at pH 7.4 (PhB 7.4), at pH 6.5 (PhB 6.5), and in the fasted state simulated intestinal fluid (FaSSIF, pH 6.5). The chemical modifications led to higher solubility for three of the derivatives of ciprofloxacin (Figure 3). (3) The underlying molecular reason(s) for poor solubility can hence inform the medicinal chemists upon strategies to improve the aqueous solubility. Typically these are highly lipophilic, small, and rigid molecules with a strong hydrogen bond capacity within the crystal lattice. (2a) In addition there are intermediate compounds that have both a strong crystal lattice and a poor solvation. In comparison, the solvation limited compounds are larger, flexible, and lipophilic. (2c) These structural features allow the molecules to pack densely in the crystal and provide strong intermolecular bonds through van der Waals interaction, ПЂвЂ“ПЂ stacking, and hydrogen bond formation. The molecules that are solid state limited in their solubility, are smaller, rigid, and often flat molecules. (1) We have investigated molecular features of importance for poor solubility (2) and identified structural differences between compounds that are poorly soluble because of strong crystal lattice and those that are poorly hydrated in the aqueous environment. Poor aqueous solubility is a main hurdle to overcome in current discovery programs with 40вЂ“70% of all new hits estimated to have too low solubility to allow complete absorption from the GI tract.

Bcs class 1 drugs