药学学报

Material	Method	Change of glass transition temperature (T_g)	Application	Reference
Mulberry juice	Added 35% maltodextrin (MD)	↑(13.03℃→67.88℃)	The yield of spray drying products: ↑ (0→43%)	[13]
Shuang-huang-lian	Added 5% leucine	↑(58.3℃→68.6℃)	Avoid sticking to the wall during spray drying; yield: ↑(39%→73%); powder flowability: ↑	[14]
Schisandrae Chinensis Fructus	Added 40% MD	↑(30.67℃→66.32℃)	Avoid spray drying to stick to the wall; yield: ↑(35.09%→60.85%)	[15]
Bovine plasma protein	Added 5% inulin	↑(16.31℃→48.35℃)	Processing freezing temperature: ↑; costs: ↓	[16]
Qiju Dihuang pills	Chose the drying temperature point by T_g	/	Avoid crusts and cracks during the drying process of pills; times: ↓	[17]
Ju'anshen preparation	Added 50% MD	↑(22.07℃→58.88℃)	Avoid the sticky roller phenomenon of dry granulation; yield: ↑(30%→71.1%)	[18]
MD	Added 20% moisture content	↓(110℃→70℃)	The process of fluidized bed granulation was improved	[19]
MD	Tableting temperature exceeds 10℃ of the material T_g	/	Tensile strength and delay dissolution of tablet: ↑	[20]
Poly (DL-lactic acid)	Added 1.3% moisture content	↓(49℃→37.8℃)	Release of tablet: ↓	[21]
Ethylcellulose	Adjusted the coating temperature by T_g	/	Efficiency and effectiveness of coating: ↑; the phenomenon of cracks during curing of coating film: ↓	[22]
Diclofenac sodium	Added coating materials of different T_g(30℃-80℃)	↑(22.07℃→58.91℃)	Chose the best coating material by T_g	[23]
Eudragit® RS/RL	Added different proportions of triethyl citrate (0→15%→30%→45%)	↓(63℃→46℃→38℃→29℃)	Chose the proportion of addition; the effectiveness of coating: ↑	[24]
Acrylic resin II	Added polyethylene glycol (PEG)6000	↓, to below coating temperature	The tableting properties of the coating layer and the tensile strength of the tablet: ↑	[25]
Maleic rosin	Added 20% dibutyl sebacate	↓(91.4℃→72.8℃)	The elastic modulus of the material: ↓; avoid material fracture	[26]
Posaconazole	Added carriers of different T_g	↑(60℃→170℃)	Chose hot melt extruded carrier materials by T_g	[27]
Indomethacin	Added 15% PEG8000	↓(47℃→12℃)	The influence of hot melt extrusion on drug stability: ↓	[28]
Posaconazole solid dispersion (SD)	Added 10% triethyl citrate	↓(168℃→125℃)	The operability of preparation and the dissolution of extrudates: ↑	[27]
Poly-oxyethylene with polyoxypropylene copolymer	Compression temperature around T_g	/	Yield pressure: ↓; compressibility: ↑	[29]
Black garlic powder	Crushing below T_g	/	Powder yield: ↑ (32.5%→95.5%); flowability: ↑(angle of repose, 56°→49°); solubility: ↑(96.7%→98.4%)	[30]
Toad venom in Xinbao pills	Crushing below T_g	/	Yield of fine powder: ↑(90%→95.7%)	[31]

Material	Method	Change of glass transition temperature (T_g)	Application	Reference
Mulberry juice	Added 35% maltodextrin (MD)	↑(13.03℃→67.88℃)	The yield of spray drying products: ↑ (0→43%)	[13]
Shuang-huang-lian	Added 5% leucine	↑(58.3℃→68.6℃)	Avoid sticking to the wall during spray drying; yield: ↑(39%→73%); powder flowability: ↑	[14]
Schisandrae Chinensis Fructus	Added 40% MD	↑(30.67℃→66.32℃)	Avoid spray drying to stick to the wall; yield: ↑(35.09%→60.85%)	[15]
Bovine plasma protein	Added 5% inulin	↑(16.31℃→48.35℃)	Processing freezing temperature: ↑; costs: ↓	[16]
Qiju Dihuang pills	Chose the drying temperature point by T_g	/	Avoid crusts and cracks during the drying process of pills; times: ↓	[17]
Ju'anshen preparation	Added 50% MD	↑(22.07℃→58.88℃)	Avoid the sticky roller phenomenon of dry granulation; yield: ↑(30%→71.1%)	[18]
MD	Added 20% moisture content	↓(110℃→70℃)	The process of fluidized bed granulation was improved	[19]
MD	Tableting temperature exceeds 10℃ of the material T_g	/	Tensile strength and delay dissolution of tablet: ↑	[20]
Poly (DL-lactic acid)	Added 1.3% moisture content	↓(49℃→37.8℃)	Release of tablet: ↓	[21]
Ethylcellulose	Adjusted the coating temperature by T_g	/	Efficiency and effectiveness of coating: ↑; the phenomenon of cracks during curing of coating film: ↓	[22]
Diclofenac sodium	Added coating materials of different T_g(30℃-80℃)	↑(22.07℃→58.91℃)	Chose the best coating material by T_g	[23]
Eudragit® RS/RL	Added different proportions of triethyl citrate (0→15%→30%→45%)	↓(63℃→46℃→38℃→29℃)	Chose the proportion of addition; the effectiveness of coating: ↑	[24]
Acrylic resin II	Added polyethylene glycol (PEG)6000	↓, to below coating temperature	The tableting properties of the coating layer and the tensile strength of the tablet: ↑	[25]
Maleic rosin	Added 20% dibutyl sebacate	↓(91.4℃→72.8℃)	The elastic modulus of the material: ↓; avoid material fracture	[26]
Posaconazole	Added carriers of different T_g	↑(60℃→170℃)	Chose hot melt extruded carrier materials by T_g	[27]
Indomethacin	Added 15% PEG8000	↓(47℃→12℃)	The influence of hot melt extrusion on drug stability: ↓	[28]
Posaconazole solid dispersion (SD)	Added 10% triethyl citrate	↓(168℃→125℃)	The operability of preparation and the dissolution of extrudates: ↑	[27]
Poly-oxyethylene with polyoxypropylene copolymer	Compression temperature around T_g	/	Yield pressure: ↓; compressibility: ↑	[29]
Black garlic powder	Crushing below T_g	/	Powder yield: ↑ (32.5%→95.5%); flowability: ↑(angle of repose, 56°→49°); solubility: ↑(96.7%→98.4%)	[30]
Toad venom in Xinbao pills	Crushing below T_g	/	Yield of fine powder: ↑(90%→95.7%)	[31]

Material	Application	Method	Reference
Nabumetone SD	Characterization of thermal stability	The higher the T_g value of SD, the better the thermal stability	[50]
Lopinavir SD	Judgment of drug compatibility	That the mixture of drug and carrier material has two or more T_g indicates poor compatibility, and only a T_g indicates good compatibility	[51]
Bicalutamide SD	Judgment of drug compatibility	All SDs with different ratios of drug-polymer have only one single T_g, which indicates that the drug and polymer are compatible	[52]
Carbamazepine SD	Prediction of the force between drug molecules	The measured value of T_g is less than or equal to the predicted value (GT equation), there is no interaction between the drug and the carrier, and the stability is poor; while when the measured value of T_g is greater than the predicted value, there is an interaction between the drug and the carrier, and the stability is excellent	[53]
Limulus peptide microcapsules	Affecting microcapsule embedding rate	The embedding rate of the microcapsules can be improved by adjusting the value of their T_g, which is controlled by the water content	[49]
Grape seed microcapsules	Preparation of microcapsules	The microcapsule is protected from oxidation, browning and flavor when microcapsule wall is in a glass state	[54]
Hawthorn fruit microcapsule	Preparation of microcapsules	Compared to the extract powder, the stability under light, heat and oxygen conditions 5 weeks of microcapsules in the glass state is improved, and the preservation rate is still over 90%	[55]
Risperidone microspheres	Drug release prediction	Compared with crystalline drugs, amorphous drugs are easy to dissolve, and release speed: ↑(over 42 d→37 d), delay time: ↓(21 d→8-18 d)	[56]
Algae oil microcapsules	Affecting microcapsule embedding rate	The embedding rate first increases and then decreases with the decrease of T_g(water content: ↑)	[57]
Fish oil microcapsules	Affecting microcapsule embedding rate	The embedding rate first increases and then decreases with the decrease of T_g(inlet air temperature: ↓)	[58]
Polylactic acid-glycolic acid (PLGA) microcapsules	Affecting microcapsule embedding rate	The best embedding rate is obtained by adjusting the preparation temperature above T_g	[59]
PLGA microspheres	Prediction of drug release	The prepared particles below T_g show open pore structure and promote drug release, and particles above T_g with a dense matrix and smooth surface, which hinder drug release	[60]
L-α-Dipalmitoylphosphatidylcholine liposomes	Preparation of liposomes	The ratio of polylactic acid (PLA, T_g is 45℃)/polycaprolactone (PCL, T_g is-60℃): ↑, the release of calcein: ↓, the degree of encapsulation: ↑	[61]
Quercetin multilamellar liposome	Characterization of thermal stability	After being coated with polyelectrolyte, the T_g value of liposome is increased from127.2℃→141.5℃, and the thermal stability is also improved	[62]
Resveratrol, blank liposomes and resveratrol liposomes	Characterization of thermal stability	Compared with blank liposomes (T_g: 174℃) and resveratrol liposomes (T_g: 241.5℃), resveratrol (T_g: 271.8℃) exhibits better thermal stability and worse lipid bilayer structure according their T_g values	[63]
Seabuckthorn leaf extract and its liposome	Characterization of thermal stability	The value of T_g: ↑(227.99℃→271.05℃), the thermal stability: ↑	[64]
Pravastatin lyophilized liposome	Preparation of liposomes	Trehalose with high T_g is chosen as freeze-dried protective agent, T_g and the protective effect are improved	[65]
Trehalose and hydroxyethyl starch	Preparation of liposomes	Sugars in glassy state can protect lipids and cell membranes, prevent phase change or crystallization, and reduce the possibility of membrane fusion during drying	[66]
Sucrose and lecithin	Preparation of liposomes	Controlling the operating temperature lower than the T_g of sugars can prevent solute leakage	[67]
MD particles	Controllingthe particle surface morphology	MD particles with high T_g has voids and smooth surface; MD particles with low T_g appears wrinkling and folding phenomenon	[19]
Polystyrene (PS) microspheres	Controllingthe particle surface morphology	T_g is chosen as the end point of the copolymerization reaction, the PS powder with irregular shape and rough surface is copolymerized with styrene through ethyl acrylate, thus, the smooth microsphere with controllable T_g is obtained.	[68]
PLGA drug-loaded nanoparticles	Prediction of drug release	When T > T_g, the sample shows burst release (93%); when T < T_g, the drug release of sample decreases (40%)	[69]
Risperidone Microspheres	Prediction of drug release	With the water content of the drug increasing, T_g: ↓(below body temperature), the flexibility and diffusion coefficient of the drug: ↑(3-4 orders of magnitude)	[70]
PLGA	Prediction of drug release	The drug releases rapidly after 30 days in the release medium (37℃) with the T_g decreasing to below 37℃	[71]

Material	Application	Method	Reference
Nabumetone SD	Characterization of thermal stability	The higher the T_g value of SD, the better the thermal stability	[50]
Lopinavir SD	Judgment of drug compatibility	That the mixture of drug and carrier material has two or more T_g indicates poor compatibility, and only a T_g indicates good compatibility	[51]
Bicalutamide SD	Judgment of drug compatibility	All SDs with different ratios of drug-polymer have only one single T_g, which indicates that the drug and polymer are compatible	[52]
Carbamazepine SD	Prediction of the force between drug molecules	The measured value of T_g is less than or equal to the predicted value (GT equation), there is no interaction between the drug and the carrier, and the stability is poor; while when the measured value of T_g is greater than the predicted value, there is an interaction between the drug and the carrier, and the stability is excellent	[53]
Limulus peptide microcapsules	Affecting microcapsule embedding rate	The embedding rate of the microcapsules can be improved by adjusting the value of their T_g, which is controlled by the water content	[49]
Grape seed microcapsules	Preparation of microcapsules	The microcapsule is protected from oxidation, browning and flavor when microcapsule wall is in a glass state	[54]
Hawthorn fruit microcapsule	Preparation of microcapsules	Compared to the extract powder, the stability under light, heat and oxygen conditions 5 weeks of microcapsules in the glass state is improved, and the preservation rate is still over 90%	[55]
Risperidone microspheres	Drug release prediction	Compared with crystalline drugs, amorphous drugs are easy to dissolve, and release speed: ↑(over 42 d→37 d), delay time: ↓(21 d→8-18 d)	[56]
Algae oil microcapsules	Affecting microcapsule embedding rate	The embedding rate first increases and then decreases with the decrease of T_g(water content: ↑)	[57]
Fish oil microcapsules	Affecting microcapsule embedding rate	The embedding rate first increases and then decreases with the decrease of T_g(inlet air temperature: ↓)	[58]
Polylactic acid-glycolic acid (PLGA) microcapsules	Affecting microcapsule embedding rate	The best embedding rate is obtained by adjusting the preparation temperature above T_g	[59]
PLGA microspheres	Prediction of drug release	The prepared particles below T_g show open pore structure and promote drug release, and particles above T_g with a dense matrix and smooth surface, which hinder drug release	[60]
L-α-Dipalmitoylphosphatidylcholine liposomes	Preparation of liposomes	The ratio of polylactic acid (PLA, T_g is 45℃)/polycaprolactone (PCL, T_g is-60℃): ↑, the release of calcein: ↓, the degree of encapsulation: ↑	[61]
Quercetin multilamellar liposome	Characterization of thermal stability	After being coated with polyelectrolyte, the T_g value of liposome is increased from127.2℃→141.5℃, and the thermal stability is also improved	[62]
Resveratrol, blank liposomes and resveratrol liposomes	Characterization of thermal stability	Compared with blank liposomes (T_g: 174℃) and resveratrol liposomes (T_g: 241.5℃), resveratrol (T_g: 271.8℃) exhibits better thermal stability and worse lipid bilayer structure according their T_g values	[63]
Seabuckthorn leaf extract and its liposome	Characterization of thermal stability	The value of T_g: ↑(227.99℃→271.05℃), the thermal stability: ↑	[64]
Pravastatin lyophilized liposome	Preparation of liposomes	Trehalose with high T_g is chosen as freeze-dried protective agent, T_g and the protective effect are improved	[65]
Trehalose and hydroxyethyl starch	Preparation of liposomes	Sugars in glassy state can protect lipids and cell membranes, prevent phase change or crystallization, and reduce the possibility of membrane fusion during drying	[66]
Sucrose and lecithin	Preparation of liposomes	Controlling the operating temperature lower than the T_g of sugars can prevent solute leakage	[67]
MD particles	Controllingthe particle surface morphology	MD particles with high T_g has voids and smooth surface; MD particles with low T_g appears wrinkling and folding phenomenon	[19]
Polystyrene (PS) microspheres	Controllingthe particle surface morphology	T_g is chosen as the end point of the copolymerization reaction, the PS powder with irregular shape and rough surface is copolymerized with styrene through ethyl acrylate, thus, the smooth microsphere with controllable T_g is obtained.	[68]
PLGA drug-loaded nanoparticles	Prediction of drug release	When T > T_g, the sample shows burst release (93%); when T < T_g, the drug release of sample decreases (40%)	[69]
Risperidone Microspheres	Prediction of drug release	With the water content of the drug increasing, T_g: ↓(below body temperature), the flexibility and diffusion coefficient of the drug: ↑(3-4 orders of magnitude)	[70]
PLGA	Prediction of drug release	The drug releases rapidly after 30 days in the release medium (37℃) with the T_g decreasing to below 37℃	[71]

Material	Method	Change of T_g	Application	Reference
Mango powder	Added 80% MD	↑(48.9℃→108.5℃)	The degree of caking: ↓(86%→17%); storage stability: ↑	[4]
Pluripotent stem cells	Added 25% Ficoll 70	↑(-118.2℃→-67.0℃)	The recrystallization rate during storage: ↑, and it can be stored at-80℃ for up to one year	[79]
Liposomes encapsulated with carboxyfluorescein	Added 50% sucrose	↑(-101℃→77℃)	Retention rate: ↑(30%→98%, the first day), and it is still 90% after three months	[80]
Nimodipine SD	Added 30% hypromellose methylcellulose acetate succinate	↑(15℃→57℃)	Storage stability: ↑	[83]
Fish oil microcapsules	Added chitosan and soy protein isolate	↑(13.05℃→71℃)	The degree of oxidation: ↓(66%→39%); storage stability: ↑	[84]
Wolfberry powder	Added moisture content (13.3%→53.0%)	↓(10.8℃→-59.7℃)	The critical storage conditions are determined according to the correlation between T_g and a_w	[90]
Schisandrae Chinensis Fructus	/	/	The storage condition (a_w is 0.392 at 25℃) of Schisandrae are determined according to water activity-equilibrium moisture content-T_g(a_w- EMC-T_g) state diagram	[15]
Paprika oleoresin microcapsules	/	/	The critical storage conditions of carotene microcapsules at 35℃ are determined according to correlation between T_g and a_w	[87]
Ascorbic acid microcapsules	/	/	The best storage condition (a_w is 0.328 at 25℃) is determined by T_g	[88]
Kouyanqing extract	/	/	The storage conditions (EMC ≤ 3.42% and a_w ≤ 0.188 at 25℃) of Kouyanqing are determined according to the a_w-EMC-T_g state diagram	[89]

Material	Method	Change of T_g	Application	Reference
Mango powder	Added 80% MD	↑(48.9℃→108.5℃)	The degree of caking: ↓(86%→17%); storage stability: ↑	[4]
Pluripotent stem cells	Added 25% Ficoll 70	↑(-118.2℃→-67.0℃)	The recrystallization rate during storage: ↑, and it can be stored at-80℃ for up to one year	[79]
Liposomes encapsulated with carboxyfluorescein	Added 50% sucrose	↑(-101℃→77℃)	Retention rate: ↑(30%→98%, the first day), and it is still 90% after three months	[80]
Nimodipine SD	Added 30% hypromellose methylcellulose acetate succinate	↑(15℃→57℃)	Storage stability: ↑	[83]
Fish oil microcapsules	Added chitosan and soy protein isolate	↑(13.05℃→71℃)	The degree of oxidation: ↓(66%→39%); storage stability: ↑	[84]
Wolfberry powder	Added moisture content (13.3%→53.0%)	↓(10.8℃→-59.7℃)	The critical storage conditions are determined according to the correlation between T_g and a_w	[90]
Schisandrae Chinensis Fructus	/	/	The storage condition (a_w is 0.392 at 25℃) of Schisandrae are determined according to water activity-equilibrium moisture content-T_g(a_w- EMC-T_g) state diagram	[15]
Paprika oleoresin microcapsules	/	/	The critical storage conditions of carotene microcapsules at 35℃ are determined according to correlation between T_g and a_w	[87]
Ascorbic acid microcapsules	/	/	The best storage condition (a_w is 0.328 at 25℃) is determined by T_g	[88]
Kouyanqing extract	/	/	The storage conditions (EMC ≤ 3.42% and a_w ≤ 0.188 at 25℃) of Kouyanqing are determined according to the a_w-EMC-T_g state diagram	[89]

玻璃化转变现象在药剂学中的应用研究进展

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曹秋芳 ¹ , 饶小勇 ¹ , 张尧 ¹ , 张爱玲 ¹ , 李敏 ² , 李哲 ¹^,^* , 罗晓健 ¹^,^*

药学学报 | 综述 2021,56(5): 1301-1313

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药学学报 | 综述 2021, 56(5): 1301-1313

玻璃化转变现象在药剂学中的应用研究进展

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曹秋芳¹, 饶小勇¹, 张尧¹, 张爱玲¹, 李敏², 李哲¹^,^*, 罗晓健¹^,^*

作者信息

1.江西中医药大学, 中药固体制剂制造技术国家工程中心, 现代中药制剂教育部重点实验室, 江西南昌 330004

2.扬子江药业集团有限公司, 江苏泰州 225300

通讯作者:

*李哲, Tel: 86-791-87119027, E-mail: lizhezd@163.com;

罗晓健, Tel: 86-791-87119619, E-mail: luoxj98@126.com

Research progress in the application of glass transition phenomenon in pharmaceutics

Qiu-fang CAO¹, Xiao-yong RAO¹, Yao ZHANG¹, Ai-ling ZHANG¹, Min LI², Zhe LI¹^,^*, Xiao-jian LUO¹^,^*

Affiliations

1. National Pharmaceutical Engineering Research Center for Solid Preparation in Chinese Herbal Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, China

2. Yangzijiang Pharmaceutical Group Co., LTD., Taizhou 225300, China

出版时间: 2021-05-12 doi: 10.16438/j.0513-4870.2020-1755

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摘要

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近年来，玻璃化转变现象逐渐应用到药剂学领域，对药物制剂的多个操作单元、制剂中间体与产品的性质及贮存有重要影响。目前已在干燥、制粒和包衣等制剂制备环节中广泛应用，同时对固体分散体、微囊、脂质体、微粒和片剂等制剂中间体及其产品的制备具有指导意义。因此，本文对玻璃化转变现象在制剂过程中的应用及其对制剂中间体和制剂产品的影响，进行详细分析和系统总结，为制剂生产和产品贮存提供理论指导。

关键词

玻璃化转变 / 无定形 / 温度 / 含水量 / 药剂 / 稳定性

Abstract

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In recent years, the phenomenon of glass transition has been gradually applied to the field of pharmaceutics. And it exhibits important influences on multiple operating units of pharmaceutical preparations, and the properties and storage of pharmaceutical intermediates and products. At present, it has been widely used in the process of preparations such as drying, granulation, coating, tableting, holt-melt extrusion, cryogenic comminution, and so on. Meanwhile, it showed guiding significance for the process of preparation intermediates and their products, such as solid dispersion, microcapsule, liposome, particle, tablet, and other preparation intermediates and their products. Therefore, this article conducts a detailed analysis and systematic summary of the application guidance of the phenomenon of glass transition in the preparation process, and its influence on the preparation intermediates and products, so as to provide theoretical guidance for preparation production and product storage.

Key words

glass transition / amorphous / temperature / moisture content / pharmaceutics / stability

引用本文

曹秋芳, 饶小勇, 张尧, 张爱玲, 李敏, 李哲, 罗晓健. 玻璃化转变现象在药剂学中的应用研究进展. 药学学报, 2021 , 56 (5) : 1301 -1313 . DOI: 10.16438/j.0513-4870.2020-1755

Qiu-fang CAO, Xiao-yong RAO, Yao ZHANG, Ai-ling ZHANG, Min LI, Zhe LI, Xiao-jian LUO. Research progress in the application of glass transition phenomenon in pharmaceutics[J]. Acta Pharmaceutica Sinica, 2021 , 56 (5) : 1301 -1313 . DOI: 10.16438/j.0513-4870.2020-1755

正文

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玻璃化转变是指无定形物质玻璃态与橡胶态(高弹态) 之间的转变, 对应的转变温度称为玻璃化转变温度(glass transition temperature, T_g)。T_g为玻璃化转变现象中的关键参数, 影响产品的加工及贮存性能^[1]。当物质处于玻璃态时, 体系黏度大而自由体积小, 运动阻力大, 分子处于被冻结状态, 松弛时间几乎无穷大, 使玻璃态物质的分子扩散速率和化学反应速率极低, 具有很高的物理和化学稳定性; 而玻璃化转变后, 分子链段运动解冻、体系黏度迅速下降、扩散系数迅速上升, 从而导致各种反应速率加快, 体系稳定性下降^[2]。

由于药物制剂原料及其辅料中常含有无定形成分, 如无定形糖类、脂类和蛋白质等^[3], 因此当其达到一定的温度或含水量时, 具有玻璃化转变现象, 即无定形成分由玻璃态转变成橡胶态而具有黏性并结块的现象, 不利于制剂中间体及产品的生产及贮存^[4]。研究发现, 利用玻璃化转变现象指导制剂的制备过程, 避免物料发生玻璃化转变, 可显著改善产品质量和贮存稳定性, 目前已在固体分散体(solid dispersion, SD)^[5]、微囊^[6]、脂质体^[7]和微粒^[8]等制剂中间品及其产品中广泛应用。因此, 玻璃化转变现象在药剂学中具有重要研究意义和应用前景。

目前, 研究者围绕T_g进行了广泛研究, 主要集中在解释理论、测量方法及其对制剂过程及产品稳定性的影响, 已有学者针对玻璃化转变的解释理论^[9]、测定方法^[10]、影响因素以及食品应用^{[11, 12]}方面进行了总结与分析, 但未涉及玻璃化转变在药剂学中的应用。本课题组前期初步分析讨论了中药浸膏粉的玻璃化转变^[3], 在此基础上, 本文对玻璃化转变现象在制剂过程中的应用, 及其对制剂中间体和制剂产品的影响进行详细分析和系统总结归纳。

1 玻璃化转变现象在制剂过程中的应用

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玻璃化转变在多个制剂操作单元均有广泛应用, 如干燥、制粒、压片、包衣、热熔挤出和低温粉碎工艺等(表 1)^[13-31]。

1.1 干燥

目前, 常见的干燥工艺有鼓风干燥、减压干燥、喷雾干燥和流化床干燥等^[32]。在干燥过程中常会出现各种问题, 如含糖量较高的中药提取液在喷雾干燥时易出现黏壁现象^[33]、冷冻干燥过程的结构崩塌^[34]、浓缩液在减压干燥时易表面结壳而出现“假干”现象、丸剂在干燥过程中出现裂纹^[35]等现象。研究发现, 上述现象均与T_g有关。

干燥过程可分为3个阶段(预热、恒速干燥和降速干燥), 其中降速干燥阶段直接影响产品的质量。在喷雾干燥过程中, 若微粒表面温度远高于其T_g, 将会使颗粒表面软化变为黏流态, 在塔壁出现黏壁现象; 但表面温度仅高于T_g 20℃以下时仍呈玻璃态, 不会出现黏壁现象。因此, 研究者常通过添加辅料提高物料T_g值, 以避免喷雾干燥过程中黏壁现象的发生。如Shi等^[13]发现, 与桑葚汁直接喷雾干燥相比, 在桑葚汁中加入麦芽糊精(maltodextrin, MD) (以干燥物计, 65/35, w/w) 可显著改善喷雾干燥产物的收率(0→43%), 这主要是由于桑葚汁含有大量低分子质量糖类, T_g值较低, 在干燥后呈橡胶态, 导致喷雾干燥过程中黏壁严重, 粉末收率为零; 而加入MD后, T_g值显著增加(13.03 ℃→67.88 ℃), 从而收率提高。Chang和Liu等^{[14, 15]}关于T_g对干燥过程影响的研究也获得了相似结果, 均证实加辅料提高物料T_g后, 不仅减少了喷雾干燥过程中的黏连现象, 同时增加了收率, 且显著改善了粉末的物理化学性质, 如流动性、抗黏性和整体抗潮解能力等。

冻干产物一般呈多孔结构, 但若干燥温度高于样品的T_g, 药品黏度迅速降低, 物质流动性增强并在毛细作用下浓缩而团聚, 导致表面萎缩, 多孔结构被破坏, 不能支持自身重量而发生结构塌陷现象。因此, T_g常被作为干燥温度的参考标准。如Hancock等^[36]认为药品的干燥温度必须低于T_g, Bosca等^[37]也认为在冷冻干燥过程中药品的温度必须低于塌陷温度或冷冻溶液的T_g。但若样品T_g太低, 会导致干燥时间长且能源浪费等问题。有文献^[38]报道, 样品T_g每升高1 ℃, 冷冻干燥时间将缩短13%。因此, 研究者通常加入一些高T_g辅料来提高样品整体T_g, 如海藻糖和蔗糖等。此外, 随着干燥时间增加, 含水量减少, 样品T_g逐渐升高, 因此可以适当提高温度以缩短干燥时间。如Furlan等^[16]在牛血浆蛋白中添加菊粉(以干燥物计, 95/5, w/w) 以提高T_g (16.31 ℃→48.35 ℃), 从而允许加工过程中更高的冷冻温度, 降低生产成本。

丸剂干燥过程中易出现表面结壳或裂纹等现象, 严重影响制剂的药效发挥。Yue等^[39]应用玻璃化转变现象发现, 在干燥过程中, 随着丸剂表面快速脱水, 物料内部水分来不及扩散到表面以补充失去的水分, 其表面T_g快速升高, 迅速由高弹态转变为玻璃态而结壳, 且在收缩时表面产生拉应力, 当拉应力超过丸剂本身的极限强度时表面将产生裂纹。此外, 减压干燥过程中, 药液处于负压状态下, 水分较易蒸发, 更易出现上述现象。研究表明, 及时调整干燥温度, 避免玻璃化转变, 可有效改善表面结壳和裂纹现象。如Hou等^[17]采用60 ℃和80 ℃作为杞菊地黄丸的干燥变温点, 很好地防止了丸剂表面玻璃态的形成, 利于中药丸剂内部水分的充分扩散, 最大程度地保证丸剂的干燥品质, 未出现结壳或裂纹等现象。

1.2 制粒

黏轮与颗粒得率低是干法制粒最常见的问题, 均与物料T_g有关。干法制粒时需要控制环境湿度, 导致室内温度较高, 而且干压过程中机械能会转化为热能使压轮表面温度升高, 且在压制条带物时的高压促进大分子链段运动, 显著降低物料的T_g, 使物料由玻璃态快速转变为橡胶态, 从而导致黏轮和颗粒得率低^[3]。研究者和生产工作者常通过添加高T_g的辅料或调整工艺参数解决该难题。如Liu等^[18]研究发现, 巨安神制剂干法制粒时易出现黏轮现象, 颗粒得率 < 30%, 而添加MD后物料的T_g由22.07℃提高到58.88 ℃, 高于滚轮温度(42 ℃), 显著减少黏轮现象的发生, 并增加颗粒得率(65.3%~71.1%)。连续双螺杆干法制粒能够通过调节工艺参数而不损害压缩性能, 且让加工条件低于制剂成分的T_g, 改善黏轮现象及提高颗粒得率, 为常规干法制粒技术(如辊压) 提供了潜在的替代方法^[40]。

而对于流化床制粒, 研究者一般选择高于物料T_g值20 ℃~30 ℃作为制粒的操作温度, 以制备形貌较好的颗粒。这是由于流化床制粒是通过热空气将药液雾化, 在颗粒表面形成黏性区域, 制备颗粒。研究发现, 颗粒表面黏性与其非晶态组分的T_g有关, 当含水量增加或温度高于T_g时, 发生玻璃化转变, 橡胶态时颗粒表面黏性增加^[41]。如Avilés-Avilés等^[19]发现葡萄糖当量(glucose equivalent, DE) 12的MD在流化床制粒温度不变的条件下, 含水量增加使MD的T_g降低, 发生玻璃化转变从而促进制粒过程, 粒径与其增长率均随含水量增加而增加。

1.3 压片

研究表明, 材料特性会影响片剂质量。片剂中所用的辅料大多是无定形聚合物, 在压制过程中自发地从周围环境中吸收水分, 导致其T_g降低。若压制过程中物料温度大于T_g, 则会引起粉末内部发生玻璃化转变, 使粒子形变和微烧结作用增强, 导致粒子间固体桥和抗张强度增加。如Patel等^[42]研究发现压片过程中发生可逆的玻璃化转变(压片时转变为橡胶态, 压完后回到玻璃态), 可形成具有较高抗张强度的稳定片剂。

同时研究发现, 玻璃化转变会减慢片剂的溶出行为。如Mitchell等^[20]发现MD在压片过程中, 粒子间及其与模壁间的摩擦使温度升高, 当超过物料的T_g 10 ℃时, 会发生玻璃化转变, 产生更强的形变和粒子间作用力及接触面积, 从而导致片剂孔隙率降低、拉伸强度增加和溶出变慢等。Steendam等^[21]研究了玻璃化转变对聚右旋乳酸片剂的药物释放机制的影响, 发现在相对湿度为95%条件下, 片剂的T_g降低了11 ℃, 平均弛豫时间随着T_g-T的差值降低呈指数增长, 药物的释放度降低。因此, 研究者可通过选用高T_g的辅料, 以避免物料发生玻璃化转变, 获得机械稳定的片剂。

1.4 包衣

研究发现, 在包衣过程中, 可根据T_g选择最佳包衣温度, 避免出现黏片、橘皮膜、架桥和裂膜等问题。薄膜是包衣材料在高于其T_g的温度下发生变形和黏性流动形成的, 最低成膜温度(minimum molding temperature, MFT) 通常比其T_g高5 ℃~10 ℃^{[43, 44]}, 因此, 为形成连续衣膜, 包衣温度应高于聚合物T_g。如Kondo等^[22]使用乙基纤维素(ethyecellulose, EC) 纳米粒对茶碱颗粒进行干法包衣, 发现当包衣温度(80 ℃) 高于EC的T_g (73.7 ℃) 时, EC转变为橡胶态, 包衣量显著增加, 从而包衣层变厚, 茶碱颗粒得到有效包覆。同时, 包衣材料颗粒聚结, 包衣层致密化和孔隙率降低, 防止了固化期间包衣膜出现裂纹现象。

但包衣温度过高, 也会对包衣过程产生不利影响。如薄膜包衣时包衣温度过高, 雾滴尚未到达片芯表面就被干燥成粉状, 造成部分包衣材料损失, 且由于过早干燥, 阻碍了胶粒变形所需的毛细管压的产生, 使胶粒间的结合力变弱, 从而使胶粒在片芯表面伸展程度降低, 薄膜衣层表面粗糙, 严重时出现皱皮和衣膜开裂等现象^[45]。干法包衣时, 温度过高则会使包衣颗粒发生玻璃化转变, 附着力和变形性提高, 在颗粒上形成不均匀的涂层, 甚至出现黏片。然而, 在实际操作过程中, 控制工艺温度条件的成本相对较高, 因此研究者通常在包衣处方中加入增塑剂, 如硬脂酸、聚乙二醇(polyethylene glycol, PEG) 6000/8000等。增塑剂分子嵌入到成膜剂聚合物的分子链间, 在很大程度上阻断了聚合物分子间的相互作用, 并与成膜剂中的特殊分子形成氢键, 使膜弹性和柔韧性增强, 降低T_g和MFT, 从而解决包衣过程中的问题^[46]。

Yasunaga等^[23]考察了包衣温度(80 ℃) 恒定时, 不同T_g值(30 ℃~80 ℃) 的包衣材料对氯芬酸钠颗粒包衣性能的影响, 发现包衣材料的T_g值越高, 黏性低, 不易在氯芬酸钠颗粒表面形成包衣层。反之, 包衣材料的T_g值越低, 包衣越均匀, 但当T_g低于一定范围时, 包衣材料易相互作用形成团聚体, 反而包衣越不均匀, 导致包衣效果下降, 综合考虑T_g为60 ℃时成膜效果最好, 证实包衣材料的T_g是影响包衣过程的关键因素。Qiao等^[24]使用增塑剂(柠檬酸三乙酯)降低丙烯酸树脂的T_g, 使其在布洛芬片上包衣均匀。但需控制增塑剂加入量, 当包衣材料T_g降低到室温以下时, 可能会出现黏片和老化现象。Liu等^[25]在阿莫西林缓释微丸包衣过程中, 选用肠溶丙烯酸树脂II包衣材料, 并加入一定量的PEG6000作为增塑剂调节T_g, 可有效改善包衣层的成膜性能与薄膜的拉伸强度。同样, Fulzele等^[26]将癸二酸二丁酯作为增塑剂, 降低了材料的T_g和弹性模量, 发现材料即使在干燥状态下弯曲也不会断裂。此外, 包衣过程完成后, 包衣产物需立即放置于高于聚合物T_g的环境下, 进一步促进薄膜的聚结, 并确保增塑剂的均匀分散^[47]。

1.5 热熔挤出

与传统的固体分散技术相比, 热熔挤出(hot melt extrusion, HME) 具有可连续化操作、无需有机溶剂和稳定性更高等优点^[48]。HME技术制备SD过程中, 虽然高黏度的聚合物会影响SD的相容性, 但熔体的高黏度及在挤出过程中保持较高的T_g, 在热力学上能有效防止SD的重结晶^[49]。因此, 需关注物料的加工性能和热稳定性(如T_g), 从而解决SD稳定性不高等难题。

当载体的T_g较低时, SD的稳定性差; 而T_g过高时, 则需在较高的挤出温度下操作, 易引起药物降解。因此, 研究者采用T_g初步筛选载体。如Zhu等^[27]利用T_g对聚维酮KollidonVA64、丙烯酸树脂L100、羟丙甲纤维素、PEG6000和聚乙烯己内酰胺-聚乙酸乙烯酯-PEG接枝共聚物Soluplus (其T_g分别为101 ℃、130 ℃、170 ℃、-60 ℃和70℃) 进行泊沙康唑SD的载体初筛, 其中PEG6000的T_g较低, 不利于SD的稳定。

一般情况下, 挤出温度越高, 药物熔融越完全, 且黏度随温度的增加而降低, 流动性得到改善, 在载体中的分散程度越好, 但药物受热降解的可能性亦随之增加。目前, 研究者多通过添加增塑剂降低体系T_g解决这一难题。Desai等^[28]通过添加增塑剂(PEG8000) 以降低吲哚美辛的T_g和加工温度, 从而减少热熔挤出对药物稳定性的影响。Zhu等^[27]在制备泊沙康唑SD时, 从热稳定性和能源消耗角度出发, 加入增塑剂(10%柠檬酸三乙酯) 以降低挤出温度(170 ℃→150 ℃), 观察到熔融物黏度降低、操作性高, 且挤出物的溶出度略微提高。虽然热机械效应会对样品的弹塑性造成不利影响, 但影响较弱, 且可通过一定的方法弥补。如Partheniadis等^[29]发现热熔挤出粉末(聚乙烯醇基和聚甲基丙烯酸甲酯) 的T_g及其制备的片剂的抗张强度较低, 且压缩过程中弹性复原率和屈服压力较高; 于是通过“热”压缩改善样品的压缩性, 当压缩温度接近T_g时, 可减少在压缩过程中的能量储存, 显著降低屈服压力, 得到以塑性形变为主的片剂。

1.6 低温粉碎

药用高分子材料、含有大量糖类成分的中药浸膏及含挥发油的中药等低T_g制剂原料, 在常温条件下粉碎困难, 且易造成有效成分的损失。研究者通常采用低温粉碎法, 将其冷却至T_g以下, 其强韧性转变为高脆性, 易于粉碎, 且粉碎产物的粒度较细、形貌更接近球形, 其理化性质也不易被破坏, 同时能耗低、污染少。Yu等^[30]研究发现, 与普通超微粉碎技术相比, 低温超微粉碎制备的黑蒜粉出粉率(32.5%→95.5%)、流动性(休止角: 56°→49°) 和溶解性(96.7%→98.4%) 更优, 且其1, 1-二苯基-2-三硝基苯肼(DPPH) 自由基清除能力(66.1%→76.8%) 和超氧阴离子自由基清除能力(42.1%→45.6%) 均得到显著提高, 体外抗氧化能力更高; 此外, 其颜色呈浅棕色, 更易被服用者接受。Wu等^[31]对心宝丸中蟾酥的粉碎工艺进行相关研究, 也获得了相似结果。

2 玻璃化转变现象在制剂中间体和产品中的应用

收起

玻璃化转变能指导多种制剂中间体和产品的合成, 如制备SD、微囊、脂质体和微球等(表 2)^[50-71]。

2.1 SD

将难溶性药物制成SD, 可在一定程度上抑制药物结晶, 解决其生物利用度难题。但由于无定形药物处于热力学高能态, 体系不稳定, 易在生产和贮存过程中出现重结晶和相分离等现象, 从而影响药物疗效^[72]。研究发现, T_g可作为SD制备过程及贮存过程的重要参数, 预测分子流动性、药物载体相容性以及分子作用力等, 为制定适合的工艺及贮存条件提供指导。

当环境温度高于T_g时, 无定形物质的分子链段自由运动能急剧增加, 导致SD处于不稳定状态; 而当环境温度在T_g以下时, 可减慢无定形药物分子迁移速率, 延缓药物分子重结晶。根据经验法则, 对大多数物质而言, T₀值(分子迁移速率为零时的温度) 约在T_g值的50 K以下^{[73, 74]}, 因此, (T_g-50) K是SD的最佳贮存温度。但对于低T_g值的SD, 此规则操作困难, 且温度过低易引起SD脆性增加, 形成新表面而诱发重结晶^[75]。因此, 研究者可通过筛选合适的载体材料, 提高SD的T_g值, 降低分子流动性, 从而提高热稳定性。Frank等^[50]将6种具有不同T_g值的载体材料与奈丁美酮制备SD, 进行比较发现, 载体材料T_g值越高, 则SD的T_g值越高, 稳定性越好。

研究发现, 药物与载体相容性也会影响SD稳定性^[76], 若药物和载体完全互容, 形成同质单相的稳定混合体系, 否则形成多相体系, 药物易聚集, 导致重结晶和相分离。T_g可用来表征SD中药物与载体的相容性, 若存在多个T_g, 表明药物与载体的相容性差; 若存在1个T_g, 则表明两者具有良好的相容性。如Li等^[51]在制备洛匹那韦SD时发现, 洛匹那韦与载体材料丙烯酸树脂在不同比例下的物理混合物可检测出两个T_g值, 而洛匹那韦与EC在不同比例下的物理混合物只能检测出1个T_g值。结晶实验证明, 检测出两个T_g值的体系, 均在16 h内发生结晶现象, 说明洛匹那韦与丙烯酸树脂相容性较差。同样, Tho等^[52]以比卡鲁胺和聚乙烯吡咯烷酮为载体制备SD时, 发现当药物-聚合物比例为1∶10、2∶10和3∶10 (w/w) 时, 所有的SD均具有单一的T_g, 表明药物和聚合物的相容性好。

当药物和载体处于理想混合状态时, SD的T_g预测值可通过Gordon-Taylor (GT) 公式计算^[77] ( ${T_g} = \frac{{{X_1} \cdot {T_{g1}} + {\rm{k}} \cdot {X_2} \cdot {T_{g2}}}}{{{X_1} + {\rm{k}} \cdot {X_2}}}$, 其中T_g1和T_g2分别为药物和载体的T_g, X₁和X₂分别为药物和载体的质量分数, k为常数), 但SD中的各组分间很难达到理想的混合状态, 其T_g实测值与预测值存在偏差, 该偏差可判断药物和载体间相互作用的强弱。当实测值小于或等于预测值时, 自身结合的趋势大于彼此相互结合的趋势, 表明该体系的稳定性较差, 在贮存过程中易出现相分离和重结晶现象; 当T_g的实测值大于预测值时, 说明药物和载体间相容性好, 稳定性高^[78]。如Ueda等^[53]在制备卡马西平SD时发现, 载体材料柠檬酸、L-精氨酸分别与药物二元混合时, T_g实测值等于预测值, 无相互作用, 在40 ℃发生转晶现象, 体系均不稳定; 当三元混合时, T_g实测值大于预测值(80.8 ℃的正偏差), 在40 ℃条件下2个月未发生转晶现象, 稳定性得到显著提高。

2.2 微囊

针对受光、热、氧、水分等影响极大或有异味、易挥发、风化的药物, 一般将其作为包埋芯材, 制成微囊, 降低芯材(药物) 对光、热、氧及水分的影响, 增强其稳定性, 并掩盖不良气味等。玻璃化转变现象在微囊的制备过程、包埋率的预测和药物释放等方面均有广泛应用^[54-56], 具有重要的指导意义。

2.2.1 微囊的制备

当微囊壁处于玻璃态时, 自由体积极小, 大约仅占总容积的2%~13%, 体系黏度高达10¹²~10¹⁴ Pa·s, 分子流动阻力较大, 体系中分子扩散速率较小, 分子间相互接触及反应速率亦很慢, 在一定程度上阻止了氧化、褐变和气味散失等现象, 从而起到对芯材的有效保护。但是, 当温度大于T_g时, 分子链段运动解冻、体系黏度迅速下降和扩散系数迅速上升, 从而导致各种反应速率加快, 不利于对芯材的保护^[79]。因此, 微囊壁材包埋芯材后, 需及时将体系温度降至T_g以下, 使微囊壁处于玻璃态, 从而减少加工过程中环境的影响与破坏。如Zhang等^[54]以阿拉伯胶或MD为复合壁材, 将在40 ℃条件下不稳定的葡萄籽提取物制成微囊, 得到了T_g为141.4 ℃的葡萄籽微囊, 稳定性显著提高。Gao等^[55]采用喷雾干燥法制备山楂果微囊, 发现玻璃态的微囊在光、热和氧条件下贮存5周后的稳定性显著高于提取物粉末, 且保存率达90%以上。

2.2.2 包埋率

微囊的包埋率受乳状液含水量和干燥温度等因素影响, 均与T_g有关。乳状液是壁材、芯材和水的混合物, 其T_g介于各组分T_g之间。当乳状液含水量过低时, 体系T_g增加, 乳状液黏度增大、自由体积和分子流动性降低, 其包埋率偏低; 含水量过高时, T_g随之减小, 稳定性与包埋率下降。Xie等^[48]研究了复合壁材浓度(0.5%→1.0%→1.5%→2.0%→2.5%) 对微囊的包埋率的影响, 发现其呈先增加后下降的变化趋势(67%→75%→83%→81%→72%)。Zhang等^[56]研究亦发现藻油微囊的包埋率随含水量(50%→60%→70%→80%→90%) 增加呈先增加后下降趋势(66%→74%→93%→87%→75%)。因此, 在制备微囊时需合理控制其含水量。

此外, 研究表明包埋率会随温度的升高呈先升高后降低的变化趋势。在一定温度范围内, 较高的进风温度会加快干燥速率, 缩短恒速干燥阶段, 促进玻璃体形成, 提升包埋率; 但过高的进风温度会对芯材造成不利影响。因此, 需将进风温度控制在适当范围内。如Zhang等^[57]研究了进风温度(160 ℃、170 ℃、180 ℃、190 ℃和200 ℃) 对鱼油微囊包埋率的影响, 发现包埋率随进风温度升高逐渐增加而后逐渐减小(56%→79%→80%→85%→76%)。而Nomura等^[58]将包埋温度提高到T_g以上, 聚乳酸-羟基乙酸共聚物(polylactic acid-glycolic acid copolymer, PLGA) 微囊达到最佳包埋率, 且微囊表面光滑。

2.2.3 释药

与晶型药物相比, T_g是无定形药物的特有性质, 因此可通过判断药物是否存在玻璃化转变, 从而预测药物释放。如Luan等^[59]研究利培酮微球中结晶型药物对药物释放的影响。结果表明, 相比于结晶型药物, 无定形药物易溶解, 从而释放较快(42 d以上→37 d), 时滞期较短(21 d→8~18 d)。同时, 制备温度也会影响药物释放, 如Vay等^[60]分析了制备温度对PLGA微球特性的影响, 在10 ℃下制备的颗粒显示出开孔结构, 有利于药物释放; 而当温度高于T_g时, 则会导致形成致密基质和光滑表面, 阻碍药物释放。

2.3 脂质体

近年来, 玻璃化转变现象在脂质体的研究中也发挥着越来越重要的作用, 如脂质体制备过程中条件的选择^[61]、热稳定性的表征^[62]及贮存^[79]等。

首先, T_g可作为脂质体制备材料的选择依据。在制备脂质体时, 共聚物疏水性嵌段的刚性或柔韧性改变会影响脂质双层膜的性质。而刚性和柔韧性均与T_g有关, 刚性越大, 柔韧性越小, T_g越高。Flandez等^[61]研究了两亲性二嵌段共聚物聚乳酸(polylactic acid, PLA) 和聚己内酯(polycaprolactone, PCL) 的比例对L-α-二棕榈酰磷脂酰胆碱脂质体双层脂质体理化性质的影响, 发现随PLA (T_g 45℃)/PCL (T_g -60 ℃) 升高, 疏水嵌段的刚性增强, 双分子层内极性降低, 酰基链的有序度增加, 最终脂质体的水和钙黄体释放量减少、包封程度增加。

其次, T_g值可以判断脂质体热稳定性的优劣, T_g值越大, 热稳定性越好。如Jeon等^[62]研究发现, 相比未被涂覆的槲皮素脂质体, 被涂覆聚电解质(壳聚糖与透明质酸钠) 的多层脂质体热稳定性更高(T_g: 127.2 ℃→141.5 ℃)。Balanč等^[63]将T_g作为白藜芦醇、空白脂质体及白藜芦醇脂质体热稳定性的判断依据, 发现其T_g值分别为271.8 ℃、174 ℃和241.5 ℃。结果表明, 白藜芦醇有良好的热稳定性, 但与脂质双分子层结合不稳定。Ghatnur等^[64]运用T_g对沙棘叶提取物及其脂质体的热稳定性进行了相关研究, 获得了类似结果。

再次, T_g亦可作为脂质体冻干保护剂的选择依据。当样品T_g较低时, 脂质体冻干品常出现明显的囊泡融合现象, 导致有效成分渗漏, 研究者通常选用高T_g材料作为保护剂以避免此现象。如Sylvester等^[65]将T_g作为普伐他汀冻干脂质体的关键质量属性, 并选择T_g较高的海藻糖作为首选冻干保护剂。此外, 降低冻结速率, 减少玻璃基质中的含水量, 可获得更高的T_g (85.91 ℃→132.18 ℃), 从而产生更好的保护效果, 得到的脂质体光滑紧密、无渗漏现象。

研究者使用低温保护剂[如二甲基亚砜(dimethyl sulfoxide, DMSO)], 使脂质体在解冻后保存活性, 但需在液氮中长期保存, 成本高。目前通常使用DMSO与高T_g材料结合提高T_g, 如双糖(蔗糖、海藻糖) 和聚合物(聚蔗糖、羟乙基淀粉、聚乙烯吡咯烷酮) 等, 增强分子间相互作用、延长弛豫时间和降低分子迁移率, 防止重结晶, 使其在-80 ℃的冷冻柜中也能稳定贮存。如Yuan等^[79]在DMSO配方中添加25%聚蔗糖70, 提高多能干细胞T_g (-118.2 ℃→-67.0 ℃), 从而降低储存过程中重结晶率, 在-80 ˚C下保存可长达1年。Sydykov等^[80]发现添加了5% DMSO的羧荧光素脂质体T_g为-101 ℃时, 在-80 ℃条件下贮存1天后保留率仅为30%, 后期加入蔗糖将样品的T_g提高到-77 ℃, 第1天保留率提高到98%, 3个月后保留率仍达90%。

此外, 糖类的玻璃化转变对脂质体的制备过程及性质有显著影响。Chen等^[66]认为糖类的玻璃化可以阻止脂质体膜在干燥过程中融化导致溶质泄漏。这是由于脂质体膜细胞内玻璃态的糖类可保护脂类和细胞膜, 防止发生相变或结晶; 同时, 糖类玻璃化后, 还可以防止糖键合在细胞膜的极性基团上, 从而降低了膜在干燥过程中融合的可能性。Sun等^[67]也研究发现, 当温度低于糖类T_g时, 溶质从脂质体中泄漏非常慢; 当温度升至接近或高于T_g时, 泄漏率以指数形式增长。同时还发现溶质泄漏的活化能在温度低于T_g时更高, 初步分析是由于玻璃态糖类提高了脂质体融化的活化能, 从而防止溶质泄漏。

2.4 微粒

研究者常通过提高微粒T_g以改善其热稳定性, 如①引入共聚单体(马来酸酐、丙烯腈、α-甲基苯乙烯、4-金刚烷基苯乙烯和甲基丙烯酸异冰片酯等); ②在分子链上引入极性、刚性或大体积的取代基团, 增加聚合物分子链相互作用力或内旋转阻力; ③对交联微球的尺寸和结构进行调控, 提高交联密度等。Yao等^[81]将苯乙烯和二乙烯基苯自由基共聚, 并对其产物采用热交联方法进行高温热处理, 在热能作用下苯环上残留的-CH=CH₂生成大分子自由基, 进一步聚合交联, 提高交联密度, 从而阻碍链段运动, 制备了耐热型聚苯乙烯(PS) 微球(T_g: 94.5 ℃→116 ℃)。

研究发现, 可通过T_g控制微粒表面形态。如Avilés-Avilés等^[19]发现高T_g (低DE) MD的液滴表面表现出显著的弹性, 能够承受表面压缩, 形成具有空穴但表面光滑的颗粒; 而低T_g (高DE) MD液滴表面没有弹性, 由于表面压缩而发生变形, 引起折叠或起皱现象。此外, Zhang等^[68]将T_g作为判断共聚反应的终点, 以外形不规则、表面粗糙的PS粉末为原料, 通过丙烯酸乙酯与微球中残存的苯乙烯共聚, 得到T_g可控的光滑PS微球。

此外, 聚合物微球的释放也与T_g有关。当温度在T_g以上时, 聚合物微球的分子迁移率和自由体积增加, 促进聚合物的降解与药物通过聚合物基质的扩散, 加快微球释药速度, 且随水分渗入微球T_g下降, 进一步促进药物释放。如Lappe等^[69]考察了PLGA载药纳米粒在不同温度下的释放行为, 在高于T_g的温度下, 观察到纳米粒药物的突释, 而在较低温度下, 药物释放量较少(93%→40%)。同时, Rawat等^[70]发现利培酮微球的释放度主要由T_g触发, 最初利培酮的T_g (50 ℃) 大于体温(37 ℃), 随着水分渗透, 含水量增加, T_g下降到体温以下, 聚合物柔韧性增加, 扩散系数随之增加3~4个数量级。Santoveña等^[71]对人体生长激素-PLGA可降解植入式片剂的释放研究也获得类似结果。

3 玻璃化转变现象在制剂贮存中的应用

收起

在贮存过程中, 制剂原料、中间体与产品常会出现结晶、黏连、结块、坍塌、氧化及非酶褐变等现象, 严重影响其品质, 如感官性能下降, 货架寿命缩短等。研究发现, 上述现象均与T_g有关。玻璃态物质处于亚稳态, 当贮存温度(temperature, T) > T_g时可能发生结晶, 结晶速率随△T (△T= T- T_g) 的增大而升高; 而结晶导致物料吸湿性增强, 吸入的水分引起T_g降低, 再次促进结晶, 且结晶过程释放的水被邻近的粒子吸收形成液体桥, 引起结块。当贮存湿度和T较高时(即T > T_g), 体系黏度降至10⁶~10⁸ Pa·s内, 无定形物质发生结构塌陷和黏连现象, 随着在高湿、高温环境中接触时间的延长, 黏连和结块的程度逐渐加剧^{[82, 83]}。

Liu等^[84]发现, 当T高于T_g时, 鱼油微囊壁材的褐变反应和重结晶加剧, 壁材从玻璃态转变为高弹态, 进而出现结晶、结构塌陷、芯材加速扩散而损失等现象, 且温度差越大, 结晶和结块速度越快; 进一步研究证实, 使用壳聚糖和大豆分离蛋白制备T_g为71 ℃的鱼油微囊, 在4 ℃和37 ℃贮存条件下, 氧化程度比前者分别降低了24%和27%, 提高了稳定性。Wang等^[85]对洋葱精油微囊进行了类似研究, 制备了T_g为46 ℃的微囊, 使其在常温下具有良好的贮存稳定性。Lu等^[86]用扫描电子显微镜观察喷雾干燥微囊形态时, 发现环境相对湿度在43%~64%时, 微囊未发生深度变化; 从64%上升到75%后, 水分开始吸收, 壁材溶胀, 微囊间开始出现搭桥现象, 芯材损失严重; 在75%~92%时, 壁材开始溶解; 到97%时壁材已完全形成浆糊状、完全损失。Bley等^[44]研究亦证实包衣片的吸湿率随着贮藏温度、湿度的增加而增加, 其本质原因为样品发生了玻璃化转变。

因此, 制剂原料、中间体及产品贮存时, 需保证有利的贮存条件(表 3)^{[4, 15, 79, 80, 83, 84, 87-90]}。研究发现, 临界贮存条件对制剂的品质具有重要意义, 当贮存温度、含水量与湿度低于其对应临界值, 稳定性显著提高。如微囊在T_g以下存放, 以维持其玻璃态, 囊壁才能对芯材起到有效的保护, 从而延长货架期。同时, 基于水分活度(water activity, a_w)、平衡吸湿量(equilibrium moisture content, EMC) 与T_g绘制a_w-EMC-T_g状态图, 能有效预测其稳定性及最佳贮存条件, 假设制剂的T_g为25℃ (室温) 时, 预测出相应的临界相对湿度和临界含水量, 在此临界条件下, 各成分处于性质稳定的玻璃态, 各种变化反应均被抑制, 有利于制剂中间体及其制剂的储存。Rascón等^[87]采用T_g与a_w的相关性确定了胡萝卜素微囊贮存的临界条件, 即在35 ℃时, a_w为0.241时, 系统处于玻璃态, 胡萝卜素降解最低; 在a_w ≤ 0.627条件下贮存的微囊都能够保持其结构完整性而不会发生黏结和结块现象。Palma-Rodriguez等^[88]使用改性淀粉作为基质制备抗坏血酸微囊时, 发现在25 ℃条件下, a_w为0.328时淀粉基质的结构随贮存时间的变化最小, 表明在此条件下抗坏血酸微囊的贮存稳定性最好。Liu等^[15]利用a_w-EMC-T_g状态图预测五味子储存在39.2%以上的临界湿度(25 ℃时) 或更高的温度下会吸湿结块。He等^[89]为提高贮存稳定性, 利用a_w-EMC-T_g状态图预测了口炎清在25 ℃时的贮存条件: 水分含量≤3.42%, 且贮藏的环境相对湿度≤18.8%。Song等^[90]在制剂贮存方面也获得了类似的结果。

4 总结与展望

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综上所述, 药物制剂原料、中间体及其产品基本上都存在玻璃化转变现象, 且与环境的温度和水分的变化密切相关。因此, 玻璃化转变现象在药物制剂的研发与生产过程中具有重要的意义和应用前景, 如指导制剂工艺于处方的选择与优化、预测中间产物及产品的贮存条件、提升制剂产品质量等。

但目前还存在一些难点: ①玻璃化转变的内在机制尚不明晰, 现有理论主要从自由体积、动力学及热力学等角度解释, 且其应用有限; ② T_g的测定与结果受测试条件、仪器设备和计算方法等影响, 测定结果的准确性有待进一步提高; ③目前关于物质构成与其T_g的关联性规律研究主要集中在宏观层面, 如低分子糖类、水分和小分子酸等低T_g物质引起混合体系T_g的降低; MD、海藻糖等高T_g物质引起混合体系T_g的升高, 通过单一物质的T_g对多元混合物的T_g进行预测等。而对于物质结构如何影响T_g的内在机制的微观研究较少, 且现有研究主要集中在材料学领域, 即分析单一成分的化学结构对T_g的内在影响, 如链的长短、取代基的大小等, 而对于成分复杂的中药研究尚未开展。因此, 在未来的研究中, 研究者可进一步完善并阐明玻璃化转变的内在机制, 促进玻璃化转变理论的发展, 并对物质结构对T_g的内在影响及其关联性规律进行深层次的探究, 同时探索并建立统一的、准确性更高的T_g测定与计算方法, 为其在药剂学中的应用提供更坚实的理论基础, 并进一步拓展其在药物制剂方面的应用。

作者贡献: 曹秋芳负责全文的撰写及图表等的制作; 饶小勇和张尧参与文章相关资料的调研; 张爱玲和李敏参与文章的校正与修改; 李哲和罗晓健提供文章的撰写思路, 负责文章的审阅与修改。

利益冲突: 所有作者声明无利益冲突。

基金

收起

国家重点研发计划“中医药现代化研究”重点专项(2018YFC1706901)
国家自然科学基金资助项目(82003953)
中国博士后科学基金面上资助项目(2019M662278)
江西省青年科学基金资助项目(20202BAB216039)
江西省教育厅科学技术研究项目(GJJ190688)

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2021年第56卷第5期

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doi: 10.16438/j.0513-4870.2020-1755

接收时间：2020-11-17
首发时间：2025-12-18
出版时间：2021-05-12

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收稿日期：2020-11-17
修回日期：2021-01-15

基金

国家重点研发计划“中医药现代化研究”重点专项(2018YFC1706901)

国家自然科学基金资助项目(82003953)

中国博士后科学基金面上资助项目(2019M662278)

江西省青年科学基金资助项目(20202BAB216039)

江西省教育厅科学技术研究项目(GJJ190688)

作者信息

1.江西中医药大学, 中药固体制剂制造技术国家工程中心, 现代中药制剂教育部重点实验室, 江西南昌 330004

2.扬子江药业集团有限公司, 江苏泰州 225300

通讯作者:

*李哲, Tel: 86-791-87119027, E-mail: lizhezd@163.com;

罗晓健, Tel: 86-791-87119619, E-mail: luoxj98@126.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Material	Method	Change of glass transition temperature (T_g)	Application	Reference
Mulberry juice	Added 35% maltodextrin (MD)	↑(13.03℃→67.88℃)	The yield of spray drying products: ↑ (0→43%)	[13]
Shuang-huang-lian	Added 5% leucine	↑(58.3℃→68.6℃)	Avoid sticking to the wall during spray drying; yield: ↑(39%→73%); powder flowability: ↑	[14]
Schisandrae Chinensis Fructus	Added 40% MD	↑(30.67℃→66.32℃)	Avoid spray drying to stick to the wall; yield: ↑(35.09%→60.85%)	[15]
Bovine plasma protein	Added 5% inulin	↑(16.31℃→48.35℃)	Processing freezing temperature: ↑; costs: ↓	[16]
Qiju Dihuang pills	Chose the drying temperature point by T_g	/	Avoid crusts and cracks during the drying process of pills; times: ↓	[17]
Ju'anshen preparation	Added 50% MD	↑(22.07℃→58.88℃)	Avoid the sticky roller phenomenon of dry granulation; yield: ↑(30%→71.1%)	[18]
MD	Added 20% moisture content	↓(110℃→70℃)	The process of fluidized bed granulation was improved	[19]
MD	Tableting temperature exceeds 10℃ of the material T_g	/	Tensile strength and delay dissolution of tablet: ↑	[20]
Poly (DL-lactic acid)	Added 1.3% moisture content	↓(49℃→37.8℃)	Release of tablet: ↓	[21]
Ethylcellulose	Adjusted the coating temperature by T_g	/	Efficiency and effectiveness of coating: ↑; the phenomenon of cracks during curing of coating film: ↓	[22]
Diclofenac sodium	Added coating materials of different T_g(30℃-80℃)	↑(22.07℃→58.91℃)	Chose the best coating material by T_g	[23]
Eudragit® RS/RL	Added different proportions of triethyl citrate (0→15%→30%→45%)	↓(63℃→46℃→38℃→29℃)	Chose the proportion of addition; the effectiveness of coating: ↑	[24]
Acrylic resin II	Added polyethylene glycol (PEG)6000	↓, to below coating temperature	The tableting properties of the coating layer and the tensile strength of the tablet: ↑	[25]
Maleic rosin	Added 20% dibutyl sebacate	↓(91.4℃→72.8℃)	The elastic modulus of the material: ↓; avoid material fracture	[26]
Posaconazole	Added carriers of different T_g	↑(60℃→170℃)	Chose hot melt extruded carrier materials by T_g	[27]
Indomethacin	Added 15% PEG8000	↓(47℃→12℃)	The influence of hot melt extrusion on drug stability: ↓	[28]
Posaconazole solid dispersion (SD)	Added 10% triethyl citrate	↓(168℃→125℃)	The operability of preparation and the dissolution of extrudates: ↑	[27]
Poly-oxyethylene with polyoxypropylene copolymer	Compression temperature around T_g	/	Yield pressure: ↓; compressibility: ↑	[29]
Black garlic powder	Crushing below T_g	/	Powder yield: ↑ (32.5%→95.5%); flowability: ↑(angle of repose, 56°→49°); solubility: ↑(96.7%→98.4%)	[30]
Toad venom in Xinbao pills	Crushing below T_g	/	Yield of fine powder: ↑(90%→95.7%)	[31]

Material

Method

Change of glass transition temperature (T_g)

Application

Reference

Mulberry juice

Added 35% maltodextrin (MD)

↑(13.03℃→67.88℃)

The yield of spray drying products: ↑ (0→43%)

[13]

Shuang-huang-lian

Added 5% leucine

↑(58.3℃→68.6℃)

Avoid sticking to the wall during spray drying; yield: ↑(39%→73%); powder flowability: ↑

[14]

Schisandrae Chinensis Fructus

Added 40% MD

↑(30.67℃→66.32℃)

Avoid spray drying to stick to the wall; yield: ↑(35.09%→60.85%)

[15]

Bovine plasma protein

Added 5% inulin

↑(16.31℃→48.35℃)

Processing freezing temperature: ↑; costs: ↓

[16]

Qiju Dihuang pills

Chose the drying temperature point by T_g

Avoid crusts and cracks during the drying process of pills; times: ↓

[17]

Ju'anshen preparation

Added 50% MD

↑(22.07℃→58.88℃)

Avoid the sticky roller phenomenon of dry granulation; yield: ↑(30%→71.1%)

[18]

Added 20% moisture content

↓(110℃→70℃)

The process of fluidized bed granulation was improved

[19]

Tableting temperature exceeds 10℃ of the material T_g

Tensile strength and delay dissolution of tablet: ↑

[20]

Poly (DL-lactic acid)

Added 1.3% moisture content

↓(49℃→37.8℃)

Release of tablet: ↓

[21]

Ethylcellulose

Adjusted the coating temperature by T_g

Efficiency and effectiveness of coating: ↑; the phenomenon of cracks during curing of coating film: ↓

[22]

Diclofenac sodium

Added coating materials of different T_g(30℃-80℃)

↑(22.07℃→58.91℃)

Chose the best coating material by T_g

[23]

Eudragit® RS/RL

Added different proportions of triethyl citrate (0→15%→30%→45%)

↓(63℃→46℃→38℃→29℃)

Chose the proportion of addition; the effectiveness of coating: ↑

[24]

Acrylic resin II

Added polyethylene glycol (PEG)6000

↓, to below coating temperature

The tableting properties of the coating layer and the tensile strength of the tablet: ↑

[25]

Maleic rosin

Added 20% dibutyl sebacate

↓(91.4℃→72.8℃)

The elastic modulus of the material: ↓; avoid material fracture

[26]

Posaconazole

Added carriers of different T_g

↑(60℃→170℃)

Chose hot melt extruded carrier materials by T_g

[27]

Indomethacin

Added 15% PEG8000

↓(47℃→12℃)

The influence of hot melt extrusion on drug stability: ↓

[28]

Posaconazole solid dispersion (SD)

Added 10% triethyl citrate

↓(168℃→125℃)

The operability of preparation and the dissolution of extrudates: ↑

[27]

Poly-oxyethylene with polyoxypropylene copolymer

Compression temperature around T_g

Yield pressure: ↓; compressibility: ↑

[29]

Black garlic powder

Crushing below T_g

Powder yield: ↑ (32.5%→95.5%); flowability: ↑(angle of repose, 56°→49°); solubility: ↑(96.7%→98.4%)

[30]

Toad venom in Xinbao pills

Crushing below T_g

Yield of fine powder: ↑(90%→95.7%)

[31]

Material	Application	Method	Reference
Nabumetone SD	Characterization of thermal stability	The higher the T_g value of SD, the better the thermal stability	[50]
Lopinavir SD	Judgment of drug compatibility	That the mixture of drug and carrier material has two or more T_g indicates poor compatibility, and only a T_g indicates good compatibility	[51]
Bicalutamide SD	Judgment of drug compatibility	All SDs with different ratios of drug-polymer have only one single T_g, which indicates that the drug and polymer are compatible	[52]
Carbamazepine SD	Prediction of the force between drug molecules	The measured value of T_g is less than or equal to the predicted value (GT equation), there is no interaction between the drug and the carrier, and the stability is poor; while when the measured value of T_g is greater than the predicted value, there is an interaction between the drug and the carrier, and the stability is excellent	[53]
Limulus peptide microcapsules	Affecting microcapsule embedding rate	The embedding rate of the microcapsules can be improved by adjusting the value of their T_g, which is controlled by the water content	[49]
Grape seed microcapsules	Preparation of microcapsules	The microcapsule is protected from oxidation, browning and flavor when microcapsule wall is in a glass state	[54]
Hawthorn fruit microcapsule	Preparation of microcapsules	Compared to the extract powder, the stability under light, heat and oxygen conditions 5 weeks of microcapsules in the glass state is improved, and the preservation rate is still over 90%	[55]
Risperidone microspheres	Drug release prediction	Compared with crystalline drugs, amorphous drugs are easy to dissolve, and release speed: ↑(over 42 d→37 d), delay time: ↓(21 d→8-18 d)	[56]
Algae oil microcapsules	Affecting microcapsule embedding rate	The embedding rate first increases and then decreases with the decrease of T_g(water content: ↑)	[57]
Fish oil microcapsules	Affecting microcapsule embedding rate	The embedding rate first increases and then decreases with the decrease of T_g(inlet air temperature: ↓)	[58]
Polylactic acid-glycolic acid (PLGA) microcapsules	Affecting microcapsule embedding rate	The best embedding rate is obtained by adjusting the preparation temperature above T_g	[59]
PLGA microspheres	Prediction of drug release	The prepared particles below T_g show open pore structure and promote drug release, and particles above T_g with a dense matrix and smooth surface, which hinder drug release	[60]
L-α-Dipalmitoylphosphatidylcholine liposomes	Preparation of liposomes	The ratio of polylactic acid (PLA, T_g is 45℃)/polycaprolactone (PCL, T_g is-60℃): ↑, the release of calcein: ↓, the degree of encapsulation: ↑	[61]
Quercetin multilamellar liposome	Characterization of thermal stability	After being coated with polyelectrolyte, the T_g value of liposome is increased from127.2℃→141.5℃, and the thermal stability is also improved	[62]
Resveratrol, blank liposomes and resveratrol liposomes	Characterization of thermal stability	Compared with blank liposomes (T_g: 174℃) and resveratrol liposomes (T_g: 241.5℃), resveratrol (T_g: 271.8℃) exhibits better thermal stability and worse lipid bilayer structure according their T_g values	[63]
Seabuckthorn leaf extract and its liposome	Characterization of thermal stability	The value of T_g: ↑(227.99℃→271.05℃), the thermal stability: ↑	[64]
Pravastatin lyophilized liposome	Preparation of liposomes	Trehalose with high T_g is chosen as freeze-dried protective agent, T_g and the protective effect are improved	[65]
Trehalose and hydroxyethyl starch	Preparation of liposomes	Sugars in glassy state can protect lipids and cell membranes, prevent phase change or crystallization, and reduce the possibility of membrane fusion during drying	[66]
Sucrose and lecithin	Preparation of liposomes	Controlling the operating temperature lower than the T_g of sugars can prevent solute leakage	[67]
MD particles	Controllingthe particle surface morphology	MD particles with high T_g has voids and smooth surface; MD particles with low T_g appears wrinkling and folding phenomenon	[19]
Polystyrene (PS) microspheres	Controllingthe particle surface morphology	T_g is chosen as the end point of the copolymerization reaction, the PS powder with irregular shape and rough surface is copolymerized with styrene through ethyl acrylate, thus, the smooth microsphere with controllable T_g is obtained.	[68]
PLGA drug-loaded nanoparticles	Prediction of drug release	When T > T_g, the sample shows burst release (93%); when T < T_g, the drug release of sample decreases (40%)	[69]
Risperidone Microspheres	Prediction of drug release	With the water content of the drug increasing, T_g: ↓(below body temperature), the flexibility and diffusion coefficient of the drug: ↑(3-4 orders of magnitude)	[70]
PLGA	Prediction of drug release	The drug releases rapidly after 30 days in the release medium (37℃) with the T_g decreasing to below 37℃	[71]

Material

Application

Method

Reference

Nabumetone SD

Characterization of thermal stability

The higher the T_g value of SD, the better the thermal stability

[50]

Lopinavir SD

Judgment of drug compatibility

That the mixture of drug and carrier material has two or more T_g indicates poor compatibility, and only a T_g indicates good compatibility

[51]

Bicalutamide SD

Judgment of drug compatibility

All SDs with different ratios of drug-polymer have only one single T_g, which indicates that the drug and polymer are compatible

[52]

Carbamazepine SD

Prediction of the force between drug molecules

The measured value of T_g is less than or equal to the predicted value (GT equation), there is no interaction between the drug and the carrier, and the stability is poor; while when the measured value of T_g is greater than the predicted value, there is an interaction between the drug and the carrier, and the stability is excellent

[53]

Limulus peptide microcapsules

Affecting microcapsule embedding rate

The embedding rate of the microcapsules can be improved by adjusting the value of their T_g, which is controlled by the water content

[49]

Grape seed microcapsules

Preparation of microcapsules

The microcapsule is protected from oxidation, browning and flavor when microcapsule wall is in a glass state

[54]

Hawthorn fruit microcapsule

Preparation of microcapsules

Compared to the extract powder, the stability under light, heat and oxygen conditions 5 weeks of microcapsules in the glass state is improved, and the preservation rate is still over 90%

[55]

Risperidone microspheres

Drug release prediction

Compared with crystalline drugs, amorphous drugs are easy to dissolve, and release speed: ↑(over 42 d→37 d), delay time: ↓(21 d→8-18 d)

[56]

Algae oil microcapsules

Affecting microcapsule embedding rate

The embedding rate first increases and then decreases with the decrease of T_g(water content: ↑)

[57]

Fish oil microcapsules

Affecting microcapsule embedding rate

The embedding rate first increases and then decreases with the decrease of T_g(inlet air temperature: ↓)

[58]

Polylactic acid-glycolic acid (PLGA) microcapsules

Affecting microcapsule embedding rate

The best embedding rate is obtained by adjusting the preparation temperature above T_g

[59]

PLGA microspheres

Prediction of drug release

The prepared particles below T_g show open pore structure and promote drug release, and particles above T_g with a dense matrix and smooth surface, which hinder drug release

[60]

L-α-Dipalmitoylphosphatidylcholine liposomes

Preparation of liposomes

The ratio of polylactic acid (PLA, T_g is 45℃)/polycaprolactone (PCL, T_g is-60℃): ↑, the release of calcein: ↓, the degree of encapsulation: ↑

[61]

Quercetin multilamellar liposome

Characterization of thermal stability

After being coated with polyelectrolyte, the T_g value of liposome is increased from127.2℃→141.5℃, and the thermal stability is also improved

[62]

Resveratrol, blank liposomes and resveratrol liposomes

Characterization of thermal stability

Compared with blank liposomes (T_g: 174℃) and resveratrol liposomes (T_g: 241.5℃), resveratrol (T_g: 271.8℃) exhibits better thermal stability and worse lipid bilayer structure according their T_g values

[63]

Seabuckthorn leaf extract and its liposome

Characterization of thermal stability

The value of T_g: ↑(227.99℃→271.05℃), the thermal stability: ↑

[64]

Pravastatin lyophilized liposome

Preparation of liposomes

Trehalose with high T_g is chosen as freeze-dried protective agent, T_g and the protective effect are improved

[65]

Trehalose and hydroxyethyl starch

Preparation of liposomes

Sugars in glassy state can protect lipids and cell membranes, prevent phase change or crystallization, and reduce the possibility of membrane fusion during drying

[66]

Sucrose and lecithin

Preparation of liposomes

Controlling the operating temperature lower than the T_g of sugars can prevent solute leakage

[67]

MD particles

Controllingthe particle surface morphology

MD particles with high T_g has voids and smooth surface; MD particles with low T_g appears wrinkling and folding phenomenon

[19]

Polystyrene (PS) microspheres

Controllingthe particle surface morphology

T_g is chosen as the end point of the copolymerization reaction, the PS powder with irregular shape and rough surface is copolymerized with styrene through ethyl acrylate, thus, the smooth microsphere with controllable T_g is obtained.

[68]

PLGA drug-loaded nanoparticles

Prediction of drug release

When T > T_g, the sample shows burst release (93%); when T < T_g, the drug release of sample decreases (40%)

[69]

Risperidone Microspheres

Prediction of drug release

With the water content of the drug increasing, T_g: ↓(below body temperature), the flexibility and diffusion coefficient of the drug: ↑(3-4 orders of magnitude)

[70]

PLGA

Prediction of drug release

The drug releases rapidly after 30 days in the release medium (37℃) with the T_g decreasing to below 37℃

[71]

Material	Method	Change of T_g	Application	Reference
Mango powder	Added 80% MD	↑(48.9℃→108.5℃)	The degree of caking: ↓(86%→17%); storage stability: ↑	[4]
Pluripotent stem cells	Added 25% Ficoll 70	↑(-118.2℃→-67.0℃)	The recrystallization rate during storage: ↑, and it can be stored at-80℃ for up to one year	[79]
Liposomes encapsulated with carboxyfluorescein	Added 50% sucrose	↑(-101℃→77℃)	Retention rate: ↑(30%→98%, the first day), and it is still 90% after three months	[80]
Nimodipine SD	Added 30% hypromellose methylcellulose acetate succinate	↑(15℃→57℃)	Storage stability: ↑	[83]
Fish oil microcapsules	Added chitosan and soy protein isolate	↑(13.05℃→71℃)	The degree of oxidation: ↓(66%→39%); storage stability: ↑	[84]
Wolfberry powder	Added moisture content (13.3%→53.0%)	↓(10.8℃→-59.7℃)	The critical storage conditions are determined according to the correlation between T_g and a_w	[90]
Schisandrae Chinensis Fructus	/	/	The storage condition (a_w is 0.392 at 25℃) of Schisandrae are determined according to water activity-equilibrium moisture content-T_g(a_w- EMC-T_g) state diagram	[15]
Paprika oleoresin microcapsules	/	/	The critical storage conditions of carotene microcapsules at 35℃ are determined according to correlation between T_g and a_w	[87]
Ascorbic acid microcapsules	/	/	The best storage condition (a_w is 0.328 at 25℃) is determined by T_g	[88]
Kouyanqing extract	/	/	The storage conditions (EMC ≤ 3.42% and a_w ≤ 0.188 at 25℃) of Kouyanqing are determined according to the a_w-EMC-T_g state diagram	[89]

Material

Method

Change of T_g

Application

Reference

Mango powder

Added 80% MD

↑(48.9℃→108.5℃)

The degree of caking: ↓(86%→17%); storage stability: ↑

[4]

Pluripotent stem cells

Added 25% Ficoll 70

↑(-118.2℃→-67.0℃)

The recrystallization rate during storage: ↑, and it can be stored at-80℃ for up to one year

[79]

Liposomes encapsulated with carboxyfluorescein

Added 50% sucrose

↑(-101℃→77℃)

Retention rate: ↑(30%→98%, the first day), and it is still 90% after three months

[80]

Nimodipine SD

Added 30% hypromellose methylcellulose acetate succinate

↑(15℃→57℃)

Storage stability: ↑

[83]

Fish oil microcapsules

Added chitosan and soy protein isolate

↑(13.05℃→71℃)

The degree of oxidation: ↓(66%→39%); storage stability: ↑

[84]

Wolfberry powder

Added moisture content (13.3%→53.0%)

↓(10.8℃→-59.7℃)

The critical storage conditions are determined according to the correlation between T_g and a_w

[90]

Schisandrae Chinensis Fructus

The storage condition (a_w is 0.392 at 25℃) of Schisandrae are determined according to water activity-equilibrium moisture content-T_g(a_w- EMC-T_g) state diagram

[15]

Paprika oleoresin microcapsules

The critical storage conditions of carotene microcapsules at 35℃ are determined according to correlation between T_g and a_w

[87]

Ascorbic acid microcapsules

The best storage condition (a_w is 0.328 at 25℃) is determined by T_g

[88]

Kouyanqing extract

The storage conditions (EMC ≤ 3.42% and a_w ≤ 0.188 at 25℃) of Kouyanqing are determined according to the a_w-EMC-T_g state diagram

[89]