Table 1.

Overview of Bottom-Up Techniques to Prepare Drug Nanocrystals

Preparation technique	Abbreviation	Inventors	Year	Description	Composition	Major disadvantage	Reference
Hot melt method	–	K. Sekiguchi and N. Obi	1961	Rapidly cooling of a eutectic melt of drug and matrix	Drug composite	Possible decomposition of the drug	(3)
Solvent evaporation method	–	T. Tachibana and A. Nakamura	1965	Evaporation of the solvent in which the drug and matrix are dissolved	Drug composite	Contamination from toxic organic solvents	(4)
Hydrosol	–	M. List and H. Sucker	1988	Precipitation from an organic solvent by addition of water	Pure drug or drug composite	Difficult to control the size	(6)
Gas anti-solvent recrystallization	GAS	V.J. Krukonis et al.	1991	Saturation of a drug solution with a supercritical fluid	Pure drug or drug composite	Difficult to remove organic solvent	(7)
Rapid expansion of supercritical solutions	RESS	G.W. Pace et al.	1999	Rapid decrease of the pressure of a supercritical fluid in which the lipophilic drug is dissolved.	Pure drug or drug composite	Solubility of the drug in the solvent	(8)
Controlled crystallization during freeze-drying	CCDF	H. de Waard, et al.	2008	Freeze-drying at a relatively high temperature of a mixture of drug, matrix, organic solvent, and water.	Drug composite	Long processing times	(9)