Abstract
Introduction . In the lyophilization technology, the freezing stage plays a key role in determining the time of primary sublimation, secondary desorption, and often the appearance of the lyophilisate. The duration of lyophilization is related to the composition and freezing conditions through the parameter resistance to mass transfer, which depends on the size of ice crystals.Objective: to select temperature regimes of thermal cycling (“annealing”) to obtain the most vapor-permeable sublimation layer, calculate the value of resistance to mass transfer of water and select the most optimal lyophilization mode for preparing lyophilisate GK-2 for preparing solutions for injections.Materials and methods . Substance: GK-2 (hexamethyleneamide bis-(N-monosuccinyl-L-glutamyl-L-lysine)) (V.V. Zakusov Research Institute of Pharmacology, Russia); excipients intended for parenteral use: lyoprotector – sucrose (CompriSugar®) (CristalUnion, France), cryoprotector – polyethylene glycol 4000 (PEG, macrogol) (Polyglykol® 4000, Panreac, Spain). Edwards EF-6 Lyophilic Dryer (Italy); microscope Nikon Eclipse E200; digital camera Nikon DS-Ri2; confocal microscope LEXT OLS 4100. Various freezing, lyophilization, direct optical microscopy in a cold chamber, laser microscopy and mathematical formulas were used to determine the values of resistance to mass transfer of water vapor from model lyophilisates.Results . This article discusses the possibilities of optimizing the freezing stage and, accordingly, the entire lyophilization cycle by introducing an intermediate thermal cycling stage, provides calculations of the mass transfer coefficient of the composition under different freezing conditions and ice crystal sizes.Conclusion . A simplified equation for calculating the coefficient of resistance to mass transfer for model solutions of GK-2 based on the correlation dependence was determined. The selection of freezing and “annealing” modes was carried out on the basis of the most important indicators, such as productivity and time of lyophilization.
Highlights
The freezing stage plays a key role in determining the time of primary sublimation, secondary desorption, and often the appearance of the lyophilisate
The duration of lyophilization is related to the composition and freezing conditions through the parameter resistance to mass transfer, which depends on the size of ice crystals
Lyophilization, direct optical microscopy in a cold chamber, laser microscopy and mathematical formulas were used to determine the values of resistance to mass transfer of water vapor from model lyophilisates
Summary
Длительность лиофилизации связана с составом и условиями замораживания через параметр сопротивления массопереноса, который зависит от размера кристаллов льда. Цель исследования – осуществить подбор температурных режимов термоциклирования («отжига») для получения наиболее паропроницаемого сублимационного слоя, рассчитать значение сопротивления массопереносу воды и выбрать оптимальный режим лиофилизации для приготовления лиофилизата ГК-2 для приготовления растворов для инъекций. В работе использованы различные режимы замораживания, лиофилизации, прямая оптическая микроскопия в холодной камере, лазерная микроскопия и математические формулы для определения значений сопротивления массопереносу водяного пара модельных лиофилизатов. Рассмотрены возможности оптимизации этапа замораживания и соответственно всего цикла лиофилизации путем введения промежуточной стадии термоциклирования, приведены расчеты коэффициента сопротивления массопереносу состава при различных условиях замораживания и размерах кристаллов льда. Осуществлен подбор режимов замораживания и «отжига» исходя из наиболее важных показателей, таких как производительность и время лиофилизации.
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