*1.7.11 pH-independent solubility*

In pharmaceutical co-crystal design and screening in most cases the API is uncharged. There are very few reports on the co-crystallization of charged APIs. Co-crystals constitute an important class of pharmaceutical solids for their ability to modulate solubility and pH dependence of water-insoluble drugs [131]. Co-crystals with acidic coformers, indomethacin−saccharin (IND − SAC) carbamazepine−saccharin (CBZ − SAC), not only enhance aqueous solubility but also impart a pH sensitivity than the drugs. IND − SAC exhibited solubilities 13 to 65 times higher than IND at pH values of 1 to 3, whereas CBZ − SAC exhibited a 2 to 10 times higher solubility than CBZ dihydrate in acidic pH values of 1 to 3 [132]. Gabapentin is shown to form co-crystal with 3-hydroxy benzoic acid and salts with salicylic acid, 1-hydroxy-2-napthoic acid and RS-mandelic acid. There is partial proton transfer from 4-hydroxy benzoic acid to gabapentin. Multicomponent crystals gabapentin-3-hydroxybenzoic acid (1:1), gabapentin-4-hydroxybenzoic acid (1:1), gabapentin-salicylic acid (1:1), gabapentin-1-hydroxy-2-napthoic acid (1:1) and gabapentin-RS-mandelic acid (1:1) are thermodynamically more stable and equal or less soluble than gabapentin hydrate and carboxylic acid coformers in pure water. Gabapentin-3-hydroxy benzoic acid co-crystal is stable at pH 4.0 and 5.7. This indicates that gabapentin3HBA co-crystal is less soluble at pH 4.0 and 5.7, while co-crystal is more soluble at pH 2.6 [133].

#### *1.7.12 Hygroscopicity reduction*

The ability of a solid substance that absorbs moisture from its surroundings is known as hygroscopic material. Hygroscopicity is a term that refers to materials that easily absorb water in a non-structured way. Thus, the adsorbed water is reversible and not structured inside a crystal lattice. The categorization of hygroscopic

and non-hygroscopic materials in pharmaceuticals are regarded as hygroscopic if they absorb more than 5% of their mass in RH between 40 and 90% at 25°C. Nonhygroscopic materials are those that absorb less than 1% moisture under the same conditions. If the critical RH of a hygroscopic material is lower than that of the surrounding atmosphere, it may deliquesce (where adsorbed water starts to solvate molecules of the solid) [134]. Co-crystals of levofloxacin (LVFX) and N-acetylmeta-aminophenol (AMAP) using a grinding and heating approach crystallized from a eutectic melting of the 2 drugs after water desorption from an LVFX hydrate. Levofloxacin monohydrate contains one ½ H2O, while co-crystal formation coformer metacetamol contains OH group at meta position, which binds with LVFX through hydrogen bonds leaving no binding site for H2O to make compound hygroscopic. This co-crystal exhibited dramatic improvements in physicochemical properties of LVFX, including hygroscopicity, physical stability and photostability, while retaining its good dissolution characteristics and chemical stability under various temperature and humidity conditions [133]. Co-crystal of metoclopramide HCl (MCPHCl), with oxalic acid (OXA), is acting as the coformer. The crystal structure of metoclopramide HCl-oxalic acid (MCPHCl–OXA) co-crystal was determined by single-crystal X-ray crystallography. The salt co-crystal has higher stability than its parent drug against high humidity and dissociation in an aqueous environment. These properties are attributed to the utilization of all hydrogen bond donors and acceptors of MCP, suggesting the OXA acts as a substitute for a water molecule in the structure, which makes it less hygroscopic. In addition, the salt co-crystal is promising for extendedrelease drug formulation by exhibiting a lower dissolution rate compared to the parent drug. These findings demonstrate the utility of salt [134]. The amide groups of individual nicotinamide molecules are all involved in intermolecular hydrogen bonding in co-crystals of ibuprofen-nicotinamide and flurbiprofen-nicotinamide, leaving the pyridine nitrogen free to interact with the environmental water vapour molecules, contributing to its hygroscopic nature. However, in co-crystal form with IBU or FLU, all of nicotinamide's pyridine nitrogen forms hydrogen bonds with the profens' carboxylic hydrogens and is thus unavailable for bonding with water, resulting in a decrease in moisture sorption at relatively low RHs [135–140].
