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Table 1 Traditional method conditions

From: Enhancing chemical and physical stability of pharmaceuticals using freeze-thaw method: challenges and opportunities for process optimization through quality by design approach

Factor

Effect

Specification

Reference

Freezing rate and temperature

It influences mechanical stress, pores size, and sharp edges

12 h, room temperature until -80° C

[11, 12]

Cycles (time and length)

It affects thermal stability and crystallinity degree

Between 3 and 10

[34,35,36]

Thawing rate and temperature

It impacts three-dimensional network stability

-80 °C to 4 °C, in 20 min

[31]

Medium

It determines suitable physicochemical properties

Water, ethanol, methanol, DMSO, acetone

[10, 37]

Solute concentration

It exerts a direct influence on the rate of transition phases

Saturated solution

[25, 38]

Additives

They provide structure stabilization

Polysaccharides, polyols, and proteins

[39, 40]

Solute nature

It influences mechanical properties and chemical functionality

Polymers, oils, proteins, and nanoparticles

[16, 22]

pH changes

It affects swelling and mechanical properties

non-ionic

[30, 38, 41]