*1.7.1 Permeability enhancement*

Drug absorption and distribution of drugs mainly depend upon the permeability of drugs across the biological membrane. The permeability of the drug is generally expected to depend upon hydrophobic interactions on the crystal surface that may interact with nonpolar cell membranes during diffusion, hydrophobic (π⋯π/H⋯π) and hydrophilic (N/O⋯H) interactions may play an improving role in the permeability. Co-crystals improve the penetration of drugs inside the biological membrane by changing their crystalline structure [104]. Hydrochlorothiazide is a diuretic and BCS class IV drug with low solubility and low permeability, exhibiting poor oral absorption solubility and permeability [68].

Another example, 5-fluorouracil (5FU) a BCS class III drug with good solubility and poor permeability was subjected to co-crystallization with the use of coformers such as 3-hydroxybenzoic acid, 4-aminobenzoic acid and cinnamic acid. 5FU has dense packing in the crystal lattice, which may cause its poor permeability. The 5FU have disrupted and loose molecular packing during the co-crystallization process. When 5FU is co-crystallized with carboxylic acid, the hydrogen bonding sites of two components would adjust to achieve a balance, whereas new drug-coformer heterosynthons and packing generated. This modification may change 5FU's activity and subsequently improve its permeability when across a membrane [105].
