Recent advances in freeze-drying: variables, cycle optimization, and innovative techniques.

Freeze-drying (FD) is the most substantial drying technique utilized in the pharmaceutical and biopharmaceutical industries. It is a drying process where the solvent is crystallized at low temperatures and then sublimed from the solid-state directly into the vapor phase. Although FD possesses several merits as its suitability for thermolabile materials and its ability to produce dry products with high-quality attributes, it is a complex and prolonged process that requires optimization of both; process and formulation variables. This review attains to disassemble FD complications through a detailed explanation of the lyophilization concept, stages, the factors influencing the process including controlled ice nucleation, and the modified and innovative FD technologies proposed in recent years to overcome the shortage of traditional FD. In addition, this work points out the quality by design (QbD), critical quality of attributes (CQAs), limitations, and drawbacks of lyophilization.HIGHLIGHTSLyophilization is a propitious drying technique for thermolabile materials.Optimizing the lyophilization cycle requires controlling the process parameters.The formulation excipients and the dispersion medium play crucial roles in designing a successful process.Numerous approaches were developed to ameliorate the lyophilization performance.