Abstract
Objective: The aim of this study was to obtain recommendations about critical process parameters (CPP) and optimal ratio of trehalose and inulin as critical material attribute (CMA) on insulin dry powder formulation with spray-freeze-drying (SFD) method.
 Methods: Inulin dry powder was formulated with the SFD method, which consisted of an atomization process and freeze-drying (FD). SFD processes were optimized in order to obtain dry powder and CPP was analyzed. All seven variations of formulas proceeded with physicochemical characterization to obtain the optimal formula.
 Results: In the early optimization, there was a slight time lag between the atomization process and FD; as a result, some of the powder coagulated and crystallized. Another critical parameter was that the FD process should not be interrupted for at least 50 h of FD. Dry powder proceeded with physicochemical characterization, a formula without inulin showed semicrystalline properties, while six formulas had amorphous properties due to its combination. All formulas had a spherulite shape and rough surface. Five formulas with the combination of trehalose and inulin obtained dry powders with a diameter range of 30-43 μm, moisture content below 3.5% and high encapsulation efficiency (EE). Formula with the ratio of 1:1 (F4) showed optimal properties with moisture content and EE of 2.62% and 99.68%, respectively.
 Conclusion: This study concluded that there were two critical process parameters in the SFD method. There should be no time lag in SFD process and FD time which should not be interrupted. The optimal ratio for trehalose and inulin was shown by F4 with ratio of 1:1.
Highlights
Insulin is formulated as a solution in water which has a limited shelf life and often requires keeping refrigerated (2-8 οC) during storage and transportation [1]
The optimal formulation is achieved with a FD process of at least 50 hours without any delay
Based on the results obtained, F1, F2, F3, F4, F5, F6, F7 dry powder were found to have moisture content percentages of 3.44%, 3.35%, 3.02%, 2.64%, 2.41%, 2.20%, and 2.19%, respectively. These results showed a decrease of moisture with an increase of the inulin ratio
Summary
Insulin is formulated as a solution in water which has a limited shelf life and often requires keeping refrigerated (2-8 οC) during storage and transportation [1]. Insulin can be formulated in dry form. Storing insulin in dry form may drastically reduce the degradation rates due to limited molecular mobility [2]. During the drying process and storage, insulin can be exposed to stress, including freezing and drying with high pressure and low temperature, which causes damage to its integrity. Protection against exposure to stress during manufacturing and storage is needed. One strategy in the aspect of insulin stabilization is to form dry proteins with additional stabilizers such as sugar [3,4,5]. Adding sugar into an existing protein usually means immobilizing protein molecules in sugar glass matrices
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