The objective of this study was to find optimal freeze-drying process parameters to design porous and friable freeze-dried bismuth-potassium-ammonium citrate (FD BPAC) with improved dissolution behavior. The nucleation and melting temperatures of frozen BPAC solution in water and tert-butanol/water co-solvent system were studied with use of thermal analysis. The phases that resulted on cooling were studied by low-temperature powder x-ray diffraction. BPAC formed an amorphous freeze concentrate on cooling and remained amorphous during freeze-drying and subsequent storage. The nucleation of colloidal bismuth subcitrate (CBS) in the FD BPAC and starting BPAC systems in 0.1 M and 0.01 M HCl was studied by dynamic light scattering (DLS) method. The proposed preparation method of FD BPAC can be the basis for design of formulations with enhanced dissolution rate for bismuth-based triple/quadruple therapy, where FD BPAC simultaneously act as a carrier and an active ingredient.