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

Abstract

The freeze-thaw (F/T) method is commonly employed during the processing and handling of drug substances to enhance their chemical and physical stability and obtain pharmaceutical applications such as hydrogels, emulsions, and nanosystems (e.g., supramolecular complexes of cyclodextrins and liposomes). Using F/T in manufacturing hydrogels successfully prevents the need for toxic cross-linking agents; moreover, their use promotes a concentrated product and better stability in emulsions. However, the use of F/T in these applications is limited by their characteristics (e.g., porosity, flexibility, swelling capacity, drug loading, and drug release capacity), which depend on the optimization of process conditions and the kind and ratio of polymers, temperature, time, and the number of cycles that involve high physical stress that could change properties associated to quality attributes. Therefore, is necessary the optimization of F/T conditions and variables. The current research regarding F/T is focused on enhancing the formulations, the process, and the use of this method in pharmaceutical, clinical, and biological areas. The present review aims to discuss different studies related to the impact and effects of the F/T process on the physical, mechanical, and chemical properties (porosity, swelling capacity) of diverse pharmaceutical applications with an emphasis on their formulation properties, the method and variables used, as well as challenges and opportunities in developing. Finally, we review the experimental approach for choosing the standard variables studied in the F/T method applying the systematic methodology of quality by design.

Dynamically Cross-Linked Double-Network Hydrogels with Matched Mechanical Properties and Ideal Biocompatibility for Artificial Blood Vessels

“…In addition, cylindrical samples with a thickness of ≈4 mm and a diameter of ≈25 mm were used to perform the compression test at a speed of 10 mm min –1 , with single-side compression to 80% deformation end. For each group, three parallel samples were measured. , …”

“…For each group, three parallel samples were measured. 29,30 The mechanical properties of artificial blood vessels were further tested. Samples were cut with a length of 60 mm.…”

Development and Evaluation of Phycocyanin-Infused Hydrogel Topical Formulations for Wound Healing

“…A product is considered thermally stable and suitable for transportation if it undergoes three consecutive freezethaw cycles without significant changes, thus ensuring its reliability under various environmental conditions. [11,18] Determination of drug content A sample of hydrogel was weighed accurately to determine the drug content. The hydrogel sample was diluted with phosphate buffer saline (PBS) of pH 7.4 and then subjected to vortexing for 10 minutes.…”

Kasturi Orange Peel (Citrus Microcarpa Bunge) Essential Oil: Chemical Profile, Formulation as Roll-on Aromatherapy and Its Evaluation

“…The freezethaw cycle for roll-on aromatherapy preparations was stored at 5 ˚C for the first 12 h and 35 ˚C for the next 12 h, carried out in 6 cycles. The aromatherapy roll-on control preparation was stored at 25 ˚C [21].…”

“…After the preparations had been stored for six cycles, no organoleptic changes occurred in the four formulas and comparison preparations. If the preparation does not change before and after the stability test, the preparation is stable at any temperature [21].…”