Bcs Class 4
Esterification was used to simultaneously increase solubility and permeability of ciprofloxacin, a biopharmaceutics classification system (BCS) class 4 drug (low solubility/low permeability) with solid-state limited solubility. Molecular flexibility was increased to disturb the crystal lattice, lower the melting point, and thereby improve the solubility, whereas lipophilicity was increased to enhance the intestinal permeability.
Bcs Classification System
These structural changes resulted in BCS class 1 analogues (high solubility/high permeability) emphasizing that simple medicinal chemistry may improve both these properties. Poor aqueous solubility is a main hurdle to overcome in current discovery programs with 40–70% of all new hits estimated to have too low solubility to allow complete absorption from the GI tract.
Bcs Class 4 Drugs
The solubility issues complicating the delivery of many existing drugs. The various tradition and novel technique that can be used for bioavability enhancement of BCS class 4 drugs are discussed in this article. Hydrophobic drugs that are P-gp substrates (BCS Class IV) such as paclitaxel, CUDC-101 etc. Pose a serious challenge for oral drug delivery.
Bcs Class 2 Drug
We have investigated molecular features of importance for poor solubility 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. The molecules that are solid state limited in their solubility, are smaller, rigid, and often flat molecules. These structural features allow the molecules to pack densely in the crystal and provide strong intermolecular bonds through van der Waals interaction, π–π stacking, and hydrogen bond formation. In comparison, the solvation limited compounds are larger, flexible, and lipophilic.
In addition there are intermediate compounds that have both a strong crystal lattice and a poor solvation. Typically these are highly lipophilic, small, and rigid molecules with a strong hydrogen bond capacity within the crystal lattice. The underlying molecular reason(s) for poor solubility can hence inform the medicinal chemists upon strategies to improve the aqueous solubility. Solubility together with permeability form the basis for the biopharmaceutics classification system (BCS). The BCS sorts compounds into four classes based on high/low permeability and solubility, in which BCS class 1 represents highly permeable and highly soluble compounds that will be well-absorbed after oral administration.
In contrast, class 4 compounds have both low solubility and low permeability. In this study we investigated whether classical medicinal chemistry using esterification could be used to simultaneously improve solubility and permeability for ciprofloxacin, a rare model compound reflecting BCS class 4 drugs with solid-state limited solubility.
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Our hypothesis was that the solubility and permeability of this compound could be improved through esterification producing derivatives with less strong crystal lattice and improved lipophilicity and that these structural features possibly position the ester derivatives in BCS class 1. Seven ciprofloxacin analogues (Figure, 5a– g) were synthesized by esterification of ciprofloxacin. By elongation of the alkyl chains in a stepwise manner (Me, Et, iPr, Pr, Bu, Hex, and Bn as an example of a more rigid ester; see Figure ), a systematic study of the effect of esterification and molecular flexibility on the lipophilicity, melting point, solubility, and permeability could be undertaken. These structural modifications of ciprofloxacin produced derivatives with increased flexibility and a lipophilicity range of almost 100 000-fold (). Further, the esterification eliminated the zwitterionic nature of ciprofloxacin, resulting in basic derivatives with a single p K a of ∼8.6 and reduced hydrogen bond capacity. Differential scanning calorimetry (DSC) thermograms showed that only one polymorph was obtained of each of the derivatives synthesized. No indications of salt formations or solvent residues were obtained, and the final product obtained was the free base.