The solid form landscape of 5-HT2a antagonist 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid hydrochloride (B5HCl) proved difficult to establish. Many crystalline materials were produced by solid form screening, but few forms readily grew high quality crystals to afford a clear picture or understanding of the solid form landscape. Careful control of crystallization conditions, a range of experimental methods, computational modeling of solvate structures, and crystal structure prediction were required to see potential arrangements of the salt in its crystal forms. Structural diversity in the solid form landscape of B5HCl was apparent in the layer structures for the anhydrate polymorphs (Forms I and II), dihydrate and a family of solvates with alcohols. The alcohol solvates, which provided a distinct packing from the neat forms and the dihydrate, form layers with conserved hydrogen bonding between B5HCl and the solvent, as well as stacking of the aromatic rings. The ability of the alcohol hydrocarbon moieties to efficiently pack between the layers accounted for the difficulty in growing some solvate crystals and the inability of other solvates to crystallize altogether. Through a combination of experiment and computation, the crystallization problems, form stability, and desolvation pathways of B5HCl have been rationalized at a molecular level.