Progress of research on quantitative techniques for trace amount of crystals in solid state drugs
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摘要:
晶型是影响药物理化性质的关键因素，进而影响药物的体内药效、安全性及稳定性。固态药物的晶型研究对于药物的生产工艺开发、质量控制、临床疗效评价等至关重要。化学计量学方法与分析检测技术的联合应用，表现出对大量多维数据极强的分析能力，为痕量晶体（< 1%）的定量检测提供了可能。同时，利用过程分析技术（process analytical technology，PAT）对制剂制备过程中的晶体含量进行实时监测，可进一步实现对制剂质量的控制，并作为支撑晶型专利保护的核心技术。本文概述了晶体定性定量分析技术和化学计量学方法联合应用于痕量晶体的定量测定，以期为药品的生产和质量控制提供指导。
Abstract:It is well-known that crystal form of a drug is a key factor impacting the physicochemical properties of the drug, which in turn affects its in vivo efficacy, safety and stability. The study on crystal forms of solid-state drugs is crucial for drug quality control, selection of production process and evaluation of clinical efficacy. The combination of chemometric and analytical techniques exhibited its great ability to analyze a large amount of multidimensional data, providing the possibility for quantification of trace amount of crystals (< 1%). Meanwhile, using the process analytical technology (PAT) to monitor the crystal content real-time during prescription preparation process can further realize the control on formulation quality and serve as a core technology to support the patent protection of crystalline forms. In this review, the combined application of crystal analytical techniques and chemometric methods for the quantitative analysis of trace crystals were summarized, aiming to provide guidance for the manufacturing of pharmaceutical preparations and their quality control.
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非甾体抗炎药（non-steroidal anti-inflammatory drugs, NSAIDs）是一类不含甾体结构的抗炎药物，通过靶向环氧化酶COX发挥作用，临床上广泛用于骨关节炎、类风湿性关节炎、多种发热和各种疼痛症状的缓解[1]。NSAIDs按化学结构分为水杨酸类、苯胺类、芳基甲酸类、芳基乙酸类和芳基丙酸类，代表性药物有阿司匹林、对乙酰氨基酚、双氯芬酸、萘普生、酮洛芬和托芬那酸等[2]。根据2023年国家卫生健康委的数据，我国关节炎患者已超过1亿，且随着老龄化加剧，患者人数将持续增加，这为NSAIDs市场带来了巨大的增长潜力。然而，由于NSAIDs价格低廉、易购且部分人群对其滥用风险认识不足，导致滥用现象严重[3]。
庞大的市场促进了NSAIDs产业的成熟，伴随而来的是生产过程中大量中间体与原形药物的产生。由于污水处理效率的局限性，这些化合物经由出水排放进入河流或渗透至地下水，构成了NSAIDs进入水环境的主要路径[4−5]。同时人类与动物医疗及日常生活产生的废弃物通过垃圾填埋方式处理，也导致NSAIDs以原形的形式随粪便、尿液和填埋场渗滤液进入水体[6]。进入水体的NSAIDs难以降解，且常规污水处理流程无法有效去除，导致其作为新兴污染物以痕量长期存在水中，这可能对人体健康构成潜在危害。因此，从公共卫生的角度出发，监测环境水中的NSAIDs至关重要[7]。
水体中复杂的成分和大量干扰物常影响NSAIDs的检测，并且NSAIDs通常以痕量的形式存在，为了获得更为精准的测定结果，在进行仪器分析前需要经过纯化、富集和浓缩等前处理过程。对于该类药物目前常使用的前处理方法包括固相萃取（SPE）[8]、固相微萃取（SPME）[9]、搅拌棒吸附萃取（SBSE）[10]、液相微萃取法[11]等。相较于传统前处理方法，磁性固相萃取（MSPE）采用具有超顺磁或铁磁特性的磁性材料，免去了离心、沉淀、过滤等烦琐步骤，有效降低了人力和物力的消耗，具有快速、简便、经济、低溶剂消耗和高重现性等优点，更适用于大体积样品的处理[12]。
MSPE中的吸附材料起着至关重要的作用。聚乙烯亚胺（PEI）是一种深入研究的高分子药物载体材料，具有线性和支化结构，表面氨基丰富，且易功能化。在吸附应用中，PEI能够通过氢键、静电作用及共价结合等多重机制实现对目标物的高效和选择性吸附[13]。PEI对于去除水中阴离子态的NSAIDs（pKa 3.7～4.9）表现出高适配性。本研究首先采用溶剂热法制备了氨基功能化Fe3O4纳米粒子（Fe3O4-NH2）。随后，通过室温下水溶液中的席夫碱反应，以戊二醛为交联剂，将具有支链结构的聚乙烯亚胺（PEI）成功地接枝到Fe3O4纳米粒子上，合成了一种可回收的PEI接枝磁性纳米吸附剂（Fe3O4@PEI）并将其应用于环境水中NSAIDs的检测。
1. 实验部分
1.1 药品及试剂
酮洛芬对照品（KPF，CAS：
22071 -15-4，纯度99.0%），萘普生对照品（NPX，CAS：22004 -53-1，纯度99.6%），双氯芬酸（DCF，CAS：15307 -86-5，纯度98.0%）和托芬那酸（TOL，CAS：13710 -19-5，纯度100%）均购自中国食品药品检定研究院。乙二醇、1,6-己二胺、磷酸氢二钠（Na2HPO4·12H2O）、磷酸二氢钠（NaH2PO4·2H2O）、盐酸（HCl）和氢氧化钠（NaOH）均购自国药控股化学试剂有限公司。三氯化铁（Ⅲ）六水合物（FeCl3·6H2O）和戊二醛由中国Aladdin公司提供。无水乙酸钠（批号150721452E）购自南京化学试剂有限公司。甲醇（MeOH）、乙腈（ACN）为色谱纯，其他试剂均为市售分析纯。
1.2 仪 器
1100 Infinity高效液相色谱仪[安捷伦科技（中国）有限公司]，配有二极管阵列紫外检测器；KQ-400DE型超声波清洗仪（昆山禾创超声仪器有限公司）；PHS-3CW型pH计（上海班特仪器有限公司）；PSAN-5型全自动氮吹浓缩仪（杭州米欧仪器有限公司）；SQP型电子天平（赛多利斯科学仪器有限公司）；超纯水系统（美国Millipore Milli-Q Gradient公司）；Tecnai G2 F30透射电子显微镜(美国FEI公司)；振动样品磁强计(美国Lake Shore公司)；D8 X射线衍射仪（德国Bruker公司）。
1.3 溶液的配制
1.3.1 样品溶液的配制
分别称取4种非甾体抗炎药标准品适量，用甲醇溶解并定量稀释制成每毫升中约含非甾体抗炎药1 mg的溶液。用超纯水逐级稀释制成所需浓度的混合标准工作溶液，于4 ℃下避光保存。
1.3.2 缓冲液的配制
称取Na2HPO4·12H2O适量，用超纯水溶解并稀释制成浓度为0.2 mol/L的Na2HPO4溶液；按照同法制得浓度为0.2 mol/L的NaH2PO4溶液。量取0.2 mol/L Na2HPO4溶液和0.2 mol/L NaH2PO4溶液适量，用超纯水稀释制成浓度为10 mmol/L PBS缓冲液。
1.4 色谱条件
以十八烷基硅烷键合硅胶为填充剂（岛津Ankylo C18，4.6 mm×250 mm，5 μm）；以甲醇-0.1%甲酸水溶液（80︰20）为流动相；流速1.0 mL/min；进样量10 μL；柱温30 ℃；KPF、NPX、DCF和TOL的检查波长分别为254、262、276、230 nm。
1.5 材料的制备
1.5.1 Fe3O4-NH2的制备
采用一锅溶剂热法合成了Fe3O4-NH2。具体步骤如下：称取 FeCl3·6H2O 1.6 g在超声波的辅助下溶解于乙二醇48 mL中形成橙黄色溶液。向上述溶液中加入无水乙酸钠3.2 g和1,6-己二胺10.4 g，并在室温下剧烈搅拌30 min。然后将混合物转移至高压反应釜中，置于198 ℃下加热6 h。待高压反应釜自然冷却后，借助外加磁场收集产物，分别用超纯水和乙醇交替清洗3次。在冷冻干燥24 h后可得到Fe3O4-NH2纳米颗粒约450 mg。
1.5.2 Fe3O4-CHO的制备
取上述步骤已制得的Fe3O4-NH2 100 mg、乙醇10 mL、戊二醛0.325 mL于烧杯中，超声20 min，在超声过程中需不时摇晃，以避免Fe3O4-NH2沉在烧瓶底部。超声结束后于室温下机械搅拌3 h。待反应结束后，借助外加磁场收集产物，用水、乙醇交替洗5~8次，将产物冻干备用。
1.5.3 Fe3O4@PEI的制备
将Fe3O4-CHO 100 mg分散于10 mmol/L PBS缓冲液（pH 7.4）10 mL，超声反应1 h，加入包含了PEI 15 mg的PBS缓冲液（质量浓度为6 mg/mL）2.5 mL和戊二醛15 µL，于60 ℃机械搅拌6 h，用水和乙醇交替洗3次，冻干即得。
1.6 磁固相萃取过程
实际水样采集自镜湖、玄武湖和自来水（中国南京）。镜湖、玄武湖水样的采集方法为在同一水域3个不同位置进行连续采样（自来水样采自不同实验楼），每次500 mL，混合后，将水样静置24 h，然后用0.45 μm聚四氟乙烯滤膜过滤，进一步去除不溶性颗粒，并储存在4 ℃冰箱备用。
称取50 mg磁性吸附剂于50 mL聚丙烯塑料离心管中，加入水样20 mL，置于恒温振荡器中于25 ℃，200 r/min 振摇5min。在外部磁场辅助下去除上清液，加入去离子水对吸附剂淋洗，再次去除上清液。最后加入乙酸-乙腈（1∶99） 1 mL，涡旋5 min对待测物进行洗脱,磁分离后，洗脱液经氮气吹干，用流动相200 µL复溶，经0.22 μm滤膜过滤后，通过HPLC-DAD来测定溶液中各目标化合物的浓度。
2. 结果与讨论
2.1 茚三铜反应
将Fe3O4、Fe3O4-NH2、Fe3O4-CHO、Fe3O4@PEI分别加入到质量浓度为1 mg/mL的茚三酮缓冲液（pH 5.6）中，90 ℃油浴中反应 15 min，直接观察溶液颜色变化。可以直观地判断Fe3O4、Fe3O4-NH2、Fe3O4-CHO、Fe3O4@PEI表面-NH2的含量。如图1-A所示，对于合成时未加1,6-己二胺的Fe3O4测试液为无色，说明材料结构中不含氨基；Fe3O4-NH2测试液为淡紫色，说明该材料结构中含有氨基；而 Fe3O4-CHO测试液为淡黄色，这是由于经醛基修饰后，材料结构中氨基含量降低所致；Fe3O4@PEI的溶液为深紫色，说明经PEI修饰后，材料表面的氨基含量显著增高，有力地证实了Fe3O4@PEI的成功制备。
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Figure 1. Results of characterization of relevant materialsResults of characterization of relevant materials A:Ninhydrin colorimetry(a. Fe3O4; b. Fe3O4-NH2; c. Fe3O4-CHO; d. Fe3O4@PEI); B:SEM diagram of Fe3O4@PEI, inset is particle size distribution of Fe3O4@PEI; C: VSM diagram for Fe3O4-NH2 and Fe3O4@PEI; D:XRD pattern of Fe3O4@PEI, inset is its physical image2.2 表 征
采用TEM研究了Fe3O4-NH2和Fe3O4@PEI的表面形貌。如图1-B所示，可以观察到Fe3O4@PEI与Fe3O4-NH2的形态和尺寸相似，均呈现球形，从统计的粒径分布来看，Fe3O4@PEI的粒径分布范围为90~180 nm。TEM图像中心区域的亮度和外围的暗度之间的对比证明这些磁性纳米粒子具有空心结构。其次，可以看出Fe3O4@PEI空心球是由更小的颗粒组成的，而不是由一个均匀的外壳形成的。这种中空球体的略微松散的结构既有利于PEI的接枝，其所提供的大比表面积和丰富的孔隙结构也将有助于NSAIDs在纳米吸附剂表面的吸附和洗脱。
在样品前处理过程中，实现吸附剂与分散液的简单且快速的分离，对环境样品的监测具有重要意义。如图1-C所示，通过VSM获得了Fe3O4-NH2和Fe3O4@PEI的磁滞回线，它们呈现出超顺磁性。显然，Fe3O4-NH2具有相当高的饱和磁化强度，为80.2 emu/g，而Fe3O4@PEI为65.7 emu/g，表明磁性吸附剂的制备是成功的。此外，从结果可以看出，PEI的引入对Fe3O4-NH2的磁性影响不大。Fe3O4@PEI出色的磁性和分散性使其很容易被外部磁场从分散液中迅速收集（图1-C）。此外，强磁性也使其成为大规模废水处理中可回收吸附剂的优秀候选者。
图1-D的XRD图谱可以看出，Fe3O4@PEI在2θ=30.1°、35.4°、43.0°、56.9°和62.5°处有5个明显尖锐的衍射峰，与JCPDS No.65-
3107 标准卡片对比，这些峰分别对应于（220）、（311）、（400）、（511）和（440）晶面，表明存在Fe3O4的立方结构。Fe3O4@PEI和Fe3O4-NH2呈现出了类似的XRD图谱。这表明PEI均匀地分布在Fe3O4@PEI的表面，PEI的修饰反应并未破坏Fe3O4的晶体结构，这与TEM的结果一致。通过元素分析的表征结果，对比了Fe3O4-NH2、Fe3O4-CHO和Fe3O4@PEI材料中C、H和N 3种元素的含量。Fe3O4-NH2中C、H和N的元素含量分别为2.04%、0.37%和0.13%。Fe3O4-NH2中检测到的少量N元素证实了其表面-NH2官能团的存在。随着戊二醛的引入，Fe3O4-NH2表面的-NH2官能团通过席夫碱反应被转化为C-N官能团，Fe3O4-CHO表面暴露的官能团以-CHO为主。因此，该材料中碳元素的含量增加至2.25%，而氮元素的相对含量显著减少。相比之下，Fe3O4@PEI中C、H和N 3种元素的含量最高，分别为3.65%、0.50%和0.71%。这主要是由于PEI分子结构中含有大量的-CH2、-NH2、-NH-和-N+-官能团，随着其成功键合于Fe3O4@PEI表面，引入了更多的有机元素。该实验结果与3种材料的茚三酮实验结果相一致。
以上表征结果充分证明了Fe3O4@PEI纳米颗粒的成功制备，其所展示出的中空介孔及表面多氨基官能团的物理化学组成结构，使其在酸性污染物的检测及去除领域具有巨大的应用潜力。因此，本实验尝试将其应用于水体中NSAIDs的检查，并对其性能进行了系统的优化及评价。
2.3 前处理条件的优化
固相萃取通常包括吸附材料的选择、萃取、淋洗和洗脱几个关键步骤，为了得到最佳的富集效果，本研究对可能影响前处理效率的参数进行了优化。
2.3.1 吸附材料的选择及优化
取Fe3O4-NH2/Fe3O4@PEI材料2 mg，以质量浓度为1 µg/mL的4种非甾体抗炎药的混合标准工作液1 mL上样，比较两种材料对酮洛芬、萘普生、双氯芬酸和托芬那酸4种代表药物的吸附效果，结果如图2-A所示。可以明显看出，Fe3O4@PEI对NSAIDs的吸附效果更好，这主要是因为PEI具有独特的树枝状结构，可以产生更利于吸附的空间结构，并且PEI结构中带有丰富的伯胺和仲胺基团，可以提供更多的吸附位点，因此在后续的实验中选择Fe3O4@PEI作为吸附剂进行制备和前处理条件的系统优化，以期达到最佳的样品净化效果。首先考察了材料制备步骤中所加入的PEI质量浓度的影响，选取的PEI的质量浓度范围为6~12 mg/mL，结果如图2-B所示。可以明显看出，不同PEI加入量所制得的Fe3O4@PEI对双氯芬酸和托芬那酸吸附的影响可以忽略不计，随着PEI量的增多，酮洛芬和萘普生的吸附量和回收率随之快速增高。这是由于PEI的投入量增加，所制得的Fe3O4@PEI的表面的氨基的数量增多，能提供给酸性非甾体抗炎药的结合位点增多，所以对酸性阴离子药物的吸附效果更好。当PEI的质量浓度为12 mg/mL时制备得到的Fe3O4@PEI对4种非甾体抗炎药均展示出了最佳的吸附效果，因此确定材料制备时PEI的反应浓度为12 mg/mL。
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Figure 2. Selection of adsorbent and optimization of preparation conditions($\bar{x} \pm s,\;n=3 $) A:Selection of adsorbent; B:Effect of concentration of PEI on extraction efficiencies of NSAIDs KPF: Ketoprofen; NPX: Naproxen; DCF: Dclofenac; TOL: Tolfenamic acid2.3.2 上样时间的影响
萃取时间作为影响萃取效率的主要因素，因此选择萃取时间在1~60 min范围内进行优化。从图3-A可以看出，当时间由1 min增加至5 min时，回收率有所增加，而随着时间进一步延长，酮洛芬、萘普生和双氯芬酸的回收率进一步增高，而托芬那酸的回收率显著降低。综合考虑时间成本及吸附效果，选择5 min为最佳萃取时间。
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Figure 3. Optimization of sample pretreatment conditions($\bar{x} \pm s,\;n=3 $) A:Effect of adsorption time on extraction efficiencies of NSAIDs; B:Effect of pH on extraction efficiencies of NSAIDs; C:Effect of amount of adsorbent on extraction efficiencies of NSAIDs; D:Effect of various elute agents on extraction efficiencies of NSAIDs; E:Effect of desorption time on extraction efficiencies of NSAIDs2.3.3 pH的影响
溶液的pH决定了目标分析物的存在形式和吸附剂的表面电荷，进而影响MSPE过程的萃取效率。NSAIDs包含羰基、羧基和芳环，与PEI的胺基、亚胺基之间会产生氢键和静电相互作用。NSAIDs和Fe3O4@PEI的电荷在不同pH条件下会发生变化。虽然NSAIDs的化学结构相似，但由于pKa不同（pKa 3.66～4.84），吸附时的保留行为可能存在些许差异。如图3-B所示，相较中性和碱性条件而言，当上样液呈酸性时，Fe3O4@PEI对NSAIDs的吸附效果更好，这是因为酸性条件促进了Fe3O4@PEI表面胺基官能团的电离，从而利于吸附剂与吸附质间静电相互作用的形成。当初始pH为4.0时，4种NSAIDs的萃取效率达到最高，因此选择将上样液pH调整为4.0进行后续实验。
2.3.4 吸附剂用量的影响
通常，吸附剂的量会影响目标分析物在萃取和解吸过程中的传质。因此考察了吸附剂用量对NSAIDs萃取效果的影响，结果如图3-C所示。随着吸附剂用量的增加，4种NSAIDs的萃取效率均呈现上升趋势，并在吸附剂用量为2.5 mg时，4种NSAIDs的回收率达到最佳，均在80%以上。因此，后续实验中选择2.5 mg/mL为吸附剂用量。
2.3.5 洗脱溶剂的选择
萃取后有必要将吸附剂上吸附的目标分析物解吸到溶剂中，以便进行HPLC-DAD分析。通过目标化合物的回收率对洗脱溶剂的解吸能力进行了考察。首先选择并测试了多种洗脱溶剂，包括乙腈、甲醇、乙酸-甲醇（1∶99）、乙酸-乙腈（1∶99）和氨水-乙腈（1∶95）。如图3-D所示，甲醇和乙腈不能完全洗脱4种目标分析物，回收率不够理想，这是由于有机溶剂无法打断目标分析物与Fe3O4@PEI之间的氢键和静电相互作用。当在有机溶剂中混合少量有机酸或碱时，洗脱溶剂表现出更强的解吸能力，其中乙酸-乙腈（1∶99）表现出了最高的洗脱能力。因此，在后续实验中选择乙酸-乙腈（1∶99）作为洗脱溶剂。
2.3.6 洗脱时间的影响
洗脱时间可直接影响MSPE中分析物的洗脱效率。因此，有必要提供足够的时间用于洗脱溶剂对吸附在材料上的NSAIDs的解吸反应。短时间可能不足以达到解吸平衡，而长时间可能导致过程烦琐。考察了解吸时间分别为5、10、30、45和60 min时NSAIDs的洗脱效果。图3-E的结果表明，所有目标分析物的回收率随着解吸时间的增加而增加，在5 min时足以实现所有目标分析物的洗脱（回收率89.8%~100.4%）。因此，在后续实验中选择5 min作为解析时间。
2.4 方法学考察
在基质溶液中添加混合标准工作溶液，在优化的前处理及色谱条件下考察了4种NSAIDs的专属性、线性范围、检出限及定量限，具体结果见图4及表1。可以看出，经MSPE处理后空白水样对4种待测物的检测均无干扰（从内插图可以看到仅在约 4.5 min处存在响应微弱的杂质峰），各待测物间的分离度良好，分别为2.3、1.2、3.4和14.3，各色谱峰所对应的光谱图与标准对照品相一致，纯度因子均大于999，且各组分的峰面积（y）和质量浓度（x，μg/L）间呈良好的线性关系，线性相关系数（r2）均大于0.998。4种NSAIDs的LOQ范围为0.29~0.75 μg/L（S/N = 3）。
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Figure 4. Specificity of Fe3O4@PEI to NSAIDs in water sample (a) injection after MSPE treatment (blank water sample), Inset: magnified chromatogram of (a); (b) injection after MSPE treatment (50 mL of water sample with 10 µg/L standard solution)1: KPF, 2: NPX, 3: DCF, 4: TOLTable 1. Linear ranges, linear equations, correlation coefficients (r2) and limits of quantitation(LOQ) for 4 analytesAnalyte Linear range/ (μg/L) Regression equation r2 LOQ/(μg/L) KPF 1−500 y = 49.26x+30.06 0.9997 0.69 NPX 1−500 y = 48.33x+47.74 0.9989 0.56 DCF 1−500 y = 108.22x+81.74 0.9996 0.29 TOL 1−500 y = 19.31x+117.16 0.9988 0.75 2.5 加标回收率试验
为验证所发展方法的实用性，应用本方法对南京市3处不同水源的水样进行了以上4种NSAIDs的检测，均未检出。选取镜湖水进行加标回收率试验，加标质量浓度分别为5、50和250 μg/L。结果样品在3种不同添加水平下的加标回收率在85.6%～107.8%之间，日内精密度均小于7.8%（n = 6），日间精密度均小于9.5%（n = 3）。
3. 结 论
本研究合成了一种聚乙烯亚胺接枝的磁性纳米粒（Fe3O4@PEI），该材料表面具有丰富的胺基官能团，使其对弱酸性的NSAIDs具有良好的吸附能力。样品预处理方法简单、快速、经济且节省溶剂。同时该Fe3O4-NH2对NSAIDs具有较好的富集浓缩能力，适用于大体积水样的现场采样及富集浓缩，将其与高效液相色谱联用可实现环境水样中酮洛芬、萘普生、双氯芬酸和托芬那酸4种NSAIDs的高效测定。
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Figure 1. Common solid-state forms and physicochemical properties of drugs, and the characterization techniques as well as chemometrics for the qualitative and quantitative analysis of solid-state drugs
ASD:Amorphous solid dispersion;SVM: Support vector machine; ANN:Artificial neural network; HCA:Hierarchical cluster analysis; PCA:Principal component analysis;PXRD:Powder X-ray diffraction;IR:Infrared spectroscopy; NIR:Near infrared reflectance spectroscopy;DSC: Differential scanning calorimetry; PLM:Polarized light microscopy
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Figure 2. Quantitative analysis of niclosamide polymorphs during different preparation processes using Raman, IR and NIR spectroscopy techniques combined with PLS chemometric method [15]
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Figure 3. (A) Selected Raman spectra showing the recrystallization behavior of amorphous fenofibrate at the temperature ranging from -180 to 80 ℃; (B) Scores plots of fenofibrate from PCA analysis of its Raman spectra [33]
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Figure 4. Quantitative analysis of crystal and amorphous forms in rivaroxaban ASD system using ATR-FTIR characterization and artificial neural network (ANN) method [21]
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Figure 5. In-line Raman spectroscopy and chemometrics for monitoring the formation of ibuprofen-nicotinamide cocrystal prepared using hot melt extrusion (HME) technique [49]
Table 1 Introduction of various quantitative techniques
Technique PXRD IR Raman ss-NMR DSC IMC DVS Sample weight/mg 200−400 5−50 2000 500−700 4−10 20−300 5−50 Probable LOD/LOQ −10% 1%−2% <1% 0.5% ~5% <5% 0.05% Internal standard Yes/No No No No No No No Calibration required No No No Yes Yes Yes Yes Destructive No No No No Yes Yes Yes Phase detection Crystalline Crystalline/
amorphousCrystalline/
amorphousCrystalline/
amorphousCrystalline/
amorphousAmorphous Amorphous Ability to differentiate surface/bulk amorphicity No No No No No Yes No Limitations Existence of preferred orientation Existence of peaks overlapping, interlacing Used as a complementary quantitative technique to IR Long data acquisition time, expensive Vulnerable to sample particle size, etc. Low specificity Vulnerable to excipient interference 
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Table 2 Chemometrics-assisted determination of API crystal content
Drug Characterization method Chemometric method Modeling area Observations Ref. Azithromycin NIR PLS 1100−2500 cm−1 Various factors (e.g., treatment method, wavelength range and moisture content) were investigated and optimized [27] LOD: 0.2%; LOQ: 0.8% Entecavir PXRD PLS 14°−34° 2θ An accurate and reliable method was developed for the quantitative determination of entecavir polymorphs in their binary mixtures [3] ATR-FTIR 400−2 000 cm−1 Furosemide Raman PLS 122−3167 cm−1 PLS can be used to quickly and accurately measure the content of various crystal forms of furosemide [28] Meloxicam IR PLS 600−4000 cm−1 Smart radial diagrams approach for selecting spectral pre-treatment techniques was presented [5] NIR 4000−12500 cm−1 Raman 1030−1650 cm−1 Niclosamide IR PLS 1380−1700 cm−1 The combination of three spectral techniques and PLS model was able to predict the polymorphic transformation of drug during the real-time processing like ball milling and wet granulation [15] NIR 4545−5000 cm−1 Raman 1050−1800 cm−1 Nimodipine ATR-FTIR MCR-ALS 1650−600 cm−1 Method is suitable for the analysis of nimodipine polymorphs and enables study of their possible thermally promoted interconversions [29] 3600−2500 cm−1 Paracetamol FT-Raman PLS 0−4000 cm−1 A fast and simple method for the quantitative analysis of form Ⅰ and form Ⅱ of paracetamol was developed [30] Piracetam PXRD PLS 8°−35° 2θ NIR combined with PLS had the highest accuracy for the drug detection [31] Raman 250−3310 cm−1 NIR 4000−10000 cm−1
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Table 3 Chemometrics-assisted monitoring of polymorphic transformations
Drug Form transformation Characterization method Chemometric method Observations Ref. Carbamazepine Anhydrate→Dihydrate ATR-FTIR MCR-ALS The polymorphic transformation rate is delayed by HPC and HPMC [34] Cimetidine Monohydrate→Form B →Amorphous ATR-FTIR MCR-ALS The ATR-FTIR/MCR association is a promising and useful technique for monitoring solid-state phase transformations of cimetidine [35] Fenofibrate Amorphous→ Form II→Form I→liquid Raman PCA Multiple solid-state forms, including the metastable crystalline form, could be observed [33] Indomethacin Amorphous→α Raman PLS Solution-mediated transformation
The transition of polymorphism slowed down the drug dissolution rate[36] ε→ζ→η→α ATR-FTIR PCA Three new crystal forms were observed and their transitions process were monitored [37] Nitrofurantoin Monohydrate→
Amorphous→Anhydrate→MeltPXRD PCA The critical temperatures (120 ℃,140 ℃,190 ℃) were identified easily using the PCA [38] Ranitidine HCl Form I&II→Amorphous;
Amorphous→Form I&IIPXRD PLS Forms I and II could be fully amorphized within 30 min.
After being stored for 14 days under dry conditions (silica gel), amorphous samples recrystallized into form I and II[39] Theophylline Anhydrate→ Monohydrate NIR PLS Real-time monitoring of crystal form transformation during wet granulation and drying processes [40]
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Table 4 Chemometrics-assisted determination of ASD crystallinity
Drug Characterization method Chemometric method Modeling area Observations Ref. Itraconazole Raman PCA 464−1 852 cm−1 The mass ratios of crystal form and amorphous form of API in drug tablets was analyzed and the content of residual crystalline API in ASD was determined [42] PLS Lopinavir NIR PLS 4100−8000 cm1 Lopinavir ASD was developed to improve dissolution, stability [41] The PLS model was validated by external samples Metoprolol Raman PLS 50−150 cm−1 A PLS model was developed and validated for drug crystal content monitoring during HME process [43] MK-A Raman PLS 490−805 cm−1 A quantitative method was developed using PLS model with ss-NMR as the reference method [44] 1653−1689 cm−1 LOD: 4.5% Piroxicam Raman MCR-ALS 1073−1661 cm−1 Quantitative analysis of piroxicam crystal formed during storage were carried out by Raman combined with MCR-ALS methods [45] Rebamipide PXRD PCA 5°−30° 2θ To investigate the effect of polymers and relative humidity on the phase transformation of amorphous rebamipide and its solid dispersion using chemometrics based on multiple datasets [46] NIR 900−1700 cm−1 Rivaroxaban ATR-FTIR ANN, PLS 800−1800 cm−1 ANN showed the superior analysis ability for the detection of drug crystal and amorphous content [21] PCR 2800−3500 cm−1 Tacrolimus PXRD PCA 4°−15.5° 2θ The selected data region showed the maximum differences in the spectra between the amorphous and crystalline tacrolimus [47] Ss-NMR PLS 6−60 (×10−6) LOQPXRD: 4%; LOQNMR: 2.5%
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Table 5 Chemometrics-assisted determination of cocrystal/coamorphous
Drug Characterization method Chemometric method Modeling area Observations Ref. Caffeine:Glutaric
acid CC (1∶1)Raman PLS 40−105 cm−1 The Raman spectrum was analyzed by PLS to determine the content of CC in the model tablets [51] Carbamazepine/Ibuprofen: Nicotinamide CC (1∶1) Raman ANN 150−2700 cm−1 A quantitative method for the determination of CC content was established [25] ATR-FTIR PLS 900−1700 cm−1 ANN has a better fitting superiority than PLS 2700−4000 cm−1 Carbamazepine:Nicotinamide CC (1∶1) Raman MCR-ALS 285−1708 cm−1 The preparation processes of CC were monitored by Raman coupled with MCR-ALS [52] PLS Carbamazepine:Succinic acid CC (2∶1) Raman PLS 200−1800 cm−1 LOD: 2.00%; LOQ: 6.06% [53] Ibuprofen:Nicotinamide CC (1∶1) Raman PLS 100−3425 cm−1 In-line Raman in combination with PLS has been proved to be a promising non-invasive technique for real-time monitoring of CC formation during HME [49] Indomethacin/Furosemide:Tryptophan CM (1∶1) Ss-NMR PCA 0−200(×10-6) Amorphization was observed as reductions in PXRD reflections and was quantified based on normalized PCA scores of the ss-NMR spectra [54] Naproxen:
Indomethacin CM (1∶1)PXRD PLS 5°−35° 2θ PXRD combined with PLS enables simultaneous determination of up to four solid state fractions [19] Olanzapine:
Saccharin CM (1∶1)PXRD RIR 20.7°−21.2° 2θ A model was developed to predict the fraction of amorphous and olanzapine CM present in samples of tablets immediately after tableting [50] NIR PLS 6094−5577 cm−1 LODNIR: 0.2%; LOQNIR: 0.6% IR 1500−1620 cm−1
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Table 6 Chemometrics-assisted determination of active pharmaceutical ingredients(APIs) in preparations
Drug Characterization method Chemometric method Modeling area Observations Ref. Canagliflozin
(Tablet)PXRD
NIR
ATR-FTIR
RamanPLS 2°−35° 2θ
6850−7 100 cm−1
400−4 000 cm−1
100−3 200 cm−1NIR was the best method in accuracy, repeatability and stability, followed by Raman, ATR-FTIR and PXRD methods
LODNIR: 0.01%; LOQNIR: 0.05%[55] Carbamazepine
(Tablet)NIR PCR 860−1680 nm
1245−1285 nmThe double-sided data set is more robust than the single-sided data set [56] Griseofulvin
(Tablet)Raman PLS 940−1750 cm−1 The PLS models based on the FT-Raman and low-frequency Raman data are suitable for quality control purposes
LOD: 0.58%; LOQ: 1.77%[57] Indomethacin
(Tablet)Raman PLS 1520−1730 cm−1 The method is suited for precise quantification of microanalysis of drug substances and drug products, particularly at the surface and interior of the tablet
LOD: 0.2%[58] Irbesartan
(Tablet)NIR PLS 4385−4410 cm−1 The content of trace amount of irbesartan form B in Avalide@ tablets was successfully quantified, and the accuracy was verified by ss-NMR
LOD: 1.3%; LOQ: 3.9%[59] Valsartan
(Tablet)Raman PLS 110−1100 cm−1 An analytical method was developed to simultaneously quantify crystalline and amorphous valsartan by Raman in the presence of excipients [60]
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