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Article(id=1208489269786686051, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1208489265789518263, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2021-0600, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1619020800000, receivedDateStr=2021-04-22, revisedDate=1624377600000, revisedDateStr=2021-06-23, acceptedDate=null, acceptedDateStr=null, onlineDate=1766055894562, onlineDateStr=2025-12-18, pubDate=1636646400000, pubDateStr=2021-11-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766055894562, onlineIssueDateStr=2025-12-18, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766055894561, creator=13701087609, updateTime=1766055894561, updator=13701087609, issue=Issue{id=1208489265789518263, tenantId=1146029695717560320, journalId=1189982191388893191, year='2021', volume='56', issue='11', pageStart='2881', pageEnd='3202', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1766055893609, creator=13701087609, updateTime=1766137012710, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208829504026448153, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1208489265789518263, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208829504026448154, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1208489265789518263, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=3166, endPage=3172, ext={EN=ArticleExt(id=1208489270239670913, articleId=1208489269786686051, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Effect of crystal form and filler on the compressibility of clarithromycin, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Clarithromycin (CLA) belongs to the second generation macrolide antibiotic. The commercial crystal form of CLA is form Ⅱ, and it exhibits the poor compressibility during the tablet pressing process. Since the crystal form of drugs has a significant effect on their mechanical properties, from the perspective of crystallography, this study investigated the difference of the compressibility between CLA form Ⅰ and form Ⅱ, and analyzed the mechanism that led to such difference. On the other hand, from the perspective of pharmaceutics, we also studied the effect of filler on the compressibility of form Ⅱ. It was found that CLA form Ⅰ had improved plastic deformation than form Ⅱ because of the slip planes in its crystal structure leading to the better compressibility. Moreover, microcrystalline cellulose, pre-gelatinized starch and lactose monohydrate could improve the compressibility of form Ⅱ, and microcrystalline cellulose showed the best effect. We improve the compressibility of CLA from crystal form and filler, and also lay a foundation for the development of CLA solid preparations.

, correspAuthors=Yuan GAO, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2021 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Heng-qing ZHU, Xiao-fang GAO, Dao-yi ZHENG, Wen-hui MENG, Zun-ting PANG, Yuan GAO), CN=ArticleExt(id=1208489274563998628, articleId=1208489269786686051, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=晶型及填充剂对克拉霉素压缩成型性的影响, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

克拉霉素是第二代大环内酯类抗生素。市售克拉霉素原料药为稳定晶型（晶型Ⅱ），其在压片过程存在压缩成型性差的问题。由于堆积方式不同，不同晶型的机械性质可能存在较大的差异性，本研究一方面从多晶型角度研究了克拉霉素晶型Ⅰ（亚稳晶型）与晶型Ⅱ压缩成型性的差异及产生差异的机制；另一方面从制剂学角度考察了常用填充剂对晶型Ⅱ压缩成型性的影响。结果表明，由于晶型Ⅰ晶体结构中存在滑移面，可增加颗粒塑性形变，从而表现出显著优于晶型Ⅱ的压缩成型性；微晶纤维素、预胶化淀粉和乳糖一水合物均可提高晶型Ⅱ压缩成型性，其中微晶纤维素改善效果最优。从晶型及填充剂两个角度提高克拉霉素可压性，为克拉霉素的固体制剂开发奠定基础。

, correspAuthors=高缘, authorNote=null, correspAuthorsNote=
*高缘, Tel/Fax: 86-25-83379418, E-mail:
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form Ⅱ and the physical mixtures of form Ⅱ and MCC with different ratios , figureFileSmall=0g8h2kjIhWD2CQD6JxclUQ==, figureFileBig=rNZQ2NdJULafaH9w1x1Wgw==, tableContent=null), ArticleFig(id=1208489284655493969, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489269786686051, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Pressure/MPaCLA form ⅠCLA form Ⅱ
7524.39 ± 0.9320.90 ± 1.94
11027.68 ± 1.9724.71 ± 8.07
15032.46 ± 1.1922.66 ± 2.93
18031.25 ± 4.0722.12 ± 3.14
22030.54 ± 1.3919.62 ± 0.74
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Hardnees of CLA form Ⅰ and form Ⅱ. n = 3, $ \overline{x} $ ± s

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Pressure/MPaCLA form ⅠCLA form Ⅱ
7524.39 ± 0.9320.90 ± 1.94
11027.68 ± 1.9724.71 ± 8.07
15032.46 ± 1.1922.66 ± 2.93
18031.25 ± 4.0722.12 ± 3.14
22030.54 ± 1.3919.62 ± 0.74
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晶型及填充剂对克拉霉素压缩成型性的影响
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朱恒清 1 , 高晓芳 2 , 郑道一 2 , 孟文卉 2 , 庞遵霆 1 , 高缘 1, *
药学学报 | 研究论文 2021,56(11): 3166-3172
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药学学报 | 研究论文 2021, 56(11): 3166-3172
晶型及填充剂对克拉霉素压缩成型性的影响
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朱恒清1, 高晓芳2, 郑道一2, 孟文卉2, 庞遵霆1, 高缘1, *
作者信息
  • 1.中国药科大学中药学院, 江苏 南京 211198
  • 2.中国药科大学药学院, 江苏 南京 211198

通讯作者:

*高缘, Tel/Fax: 86-25-83379418, E-mail:
Effect of crystal form and filler on the compressibility of clarithromycin
Heng-qing ZHU1, Xiao-fang GAO2, Dao-yi ZHENG2, Wen-hui MENG2, Zun-ting PANG1, Yuan GAO1, *
Affiliations
  • 1. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
  • 2. School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
出版时间: 2021-11-12 doi: 10.16438/j.0513-4870.2021-0600
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摘要
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克拉霉素是第二代大环内酯类抗生素。市售克拉霉素原料药为稳定晶型（晶型Ⅱ），其在压片过程存在压缩成型性差的问题。由于堆积方式不同，不同晶型的机械性质可能存在较大的差异性，本研究一方面从多晶型角度研究了克拉霉素晶型Ⅰ（亚稳晶型）与晶型Ⅱ压缩成型性的差异及产生差异的机制；另一方面从制剂学角度考察了常用填充剂对晶型Ⅱ压缩成型性的影响。结果表明，由于晶型Ⅰ晶体结构中存在滑移面，可增加颗粒塑性形变，从而表现出显著优于晶型Ⅱ的压缩成型性；微晶纤维素、预胶化淀粉和乳糖一水合物均可提高晶型Ⅱ压缩成型性，其中微晶纤维素改善效果最优。从晶型及填充剂两个角度提高克拉霉素可压性，为克拉霉素的固体制剂开发奠定基础。

克拉霉素  /  压缩成型性  /  晶型  /  滑移面  /  填充剂

Clarithromycin (CLA) belongs to the second generation macrolide antibiotic. The commercial crystal form of CLA is form Ⅱ, and it exhibits the poor compressibility during the tablet pressing process. Since the crystal form of drugs has a significant effect on their mechanical properties, from the perspective of crystallography, this study investigated the difference of the compressibility between CLA form Ⅰ and form Ⅱ, and analyzed the mechanism that led to such difference. On the other hand, from the perspective of pharmaceutics, we also studied the effect of filler on the compressibility of form Ⅱ. It was found that CLA form Ⅰ had improved plastic deformation than form Ⅱ because of the slip planes in its crystal structure leading to the better compressibility. Moreover, microcrystalline cellulose, pre-gelatinized starch and lactose monohydrate could improve the compressibility of form Ⅱ, and microcrystalline cellulose showed the best effect. We improve the compressibility of CLA from crystal form and filler, and also lay a foundation for the development of CLA solid preparations.

clarithromycin  /  compressibility  /  polymorphism  /  slip plane  /  filler
朱恒清, 高晓芳, 郑道一, 孟文卉, 庞遵霆, 高缘. 晶型及填充剂对克拉霉素压缩成型性的影响. 药学学报, 2021 , 56 (11) : 3166 -3172 . DOI: 10.16438/j.0513-4870.2021-0600
Heng-qing ZHU, Xiao-fang GAO, Dao-yi ZHENG, Wen-hui MENG, Zun-ting PANG, Yuan GAO. Effect of crystal form and filler on the compressibility of clarithromycin[J]. Acta Pharmaceutica Sinica, 2021 , 56 (11) : 3166 -3172 . DOI: 10.16438/j.0513-4870.2021-0600
正文
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克拉霉素(clarithromycin, CLA, 图 1) 是一种14元环半合成红霉素衍生物, 为白色或类白色结晶性粉末, 属于第二代大环内酯类抗生素, 抗菌谱广, 抗菌活性强[1]。临床应用广泛, 主要用于治疗幽门螺旋杆菌[2]和慢性鼻-鼻窦炎[3]等; 也可与其他药物联合用药, 如辅佐莫西沙星治疗耐多药肺结核患者[4], 联合雷贝拉唑和阿莫西林治疗胃溃疡[5]等。CLA存在多晶型现象, 主要有晶型Ⅰ[6]、晶型Ⅱ[7], 乙醇化物(晶型O)[8]和乙腈化物晶型(晶型Ⅲ) 等[9, 10]。其中, 晶型Ⅱ为市售稳定型晶型, 在其处方开发过程中发现该晶型存在压缩成型性差的问题。药物多晶型间由于晶体结构与分子堆积方式的不同, 可能会引起其机械性质的差异[11], 如由于平行柱状堆积结构的存在, 吲哚美辛晶型α比晶型γ有更好的机械性质[12]。此外, 制剂中常通过辅料改善主药机械性质, 尤其填充剂作为片剂中占比最大的辅料, 对主药的机械性质有重要影响, 如微晶纤维素可以改善发酵虫草菌粉可压性[13]。考虑到克拉霉素晶型Ⅰ为非溶剂化物, 相对于溶剂化物(晶型O与晶型Ⅲ) 安全性高, 因此, 本研究一方面从多晶型角度分析晶型Ⅰ与晶型Ⅱ压缩成型性的差异及存在差异的机制; 另一方面考察了常见填充剂微晶纤维素PH101 (microcrystalline cellulose, MCC)、预胶化淀粉(pre-gelatinized starch, PGS) 和乳糖一水合物(lactose monohydrate, LAC) 对晶型Ⅱ压缩成型性的影响, 为CLA的固体制剂开发奠定基础。
材料与方法
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药品及试剂  克拉霉素(纯度98.0%, 晶型Ⅱ, 批号A001163011); PH101型微晶纤维素(德国JRS集团药用辅料公司); PC-10型预胶化淀粉(日本旭化成株式会社); 乳糖一水合物(上海品诚医药科技有限公司); 乙醇(分析纯, 南京化学试剂有限公司)。
仪器  液压式压片机(美国Carver公司); YD-20智能片剂硬度仪(天大天发科技有限公司); AccuPyc 1330全自动真密度分析仪(美国Micromeritics公司); Netzsch 204F1 Phoenix差示扫描热分析仪(德国Netzsch公司); PM6000透反射偏光显微镜(南京江南永新光学有限公司); S-3400N Ⅱ扫描电子显微镜(日本Hitachi公司); D8 Advance X射线衍射仪(德国Bruker公司)。
克拉霉素晶型Ⅰ的制备  采用降温法制备克拉霉素晶型Ⅰ[7]。称取克拉霉素晶型Ⅱ 5.4 g, 于70 ℃水浴条件下使其快速溶解于180 mL乙醇中。将所得药物溶液于冰浴条件下冷却3 h后收集析出的固体产物, 经25 ℃减压干燥3 h, 即得。
固态表征
偏光显微镜法(polarizing microscope, PLM)  分别取适量克拉霉素晶型Ⅱ与降温法结晶产物于载玻片上, 经液体石蜡分散均匀, 盖上盖玻片, 置于偏光显微镜下观察样品固体形态。
差示扫描量热法(differential scanning calorimetry, DCS)  取2~5 mg样品, 置于带孔铝坩埚中加热, 升温速率10 ℃·min-1, 升温范围为30~350 ℃, 氮气吹扫速率设为20 mL·min-1。数据用Netzsch Proteus热分析软件(Version 4.2) 处理。
粉末X射线衍射法(powder X-ray diffraction, PXRD)  为避免晶体择优取向的影响, 将各样品分别过200目筛(75 μm)。PXRD实验采用Cu-Kα靶, 波长设定为1.540 562 Å, 管压40 kV, 管流40 mA, 步长0.02°, 步时0.3 s, 扫描速度4 °·min-1, 扫描范围2θ = 3°~40°。
扫描电子显微镜(scanning electron microscopy, SEM)  样品的微观形态通过SEM进行研究。将样品固定在金属样品板上, 对样品的表面镀金(厚度15~20 nm) 后通过SEM进行扫描, 激发电压为20 kV, 电势为2.0 kV, 电流为25 mA, 观察并记录图片。
弹性复原率  称取克拉霉素晶型Ⅰ、晶型Ⅱ各200 mg, 使用液压式压片机在180 MPa压力下压制成圆形药片, 压制时间为10 s。压片后在25 ℃, 湿度20%~30% RH环境下分别放置24 h后, 用游标卡尺(0.01 mm) 精密测定各片剂厚度, 各测3片, 取平均值。按照公式(1) 计算百分弹性恢复率(E)[14]。
$ E=100{\times }_{}\frac{H-Hc}{Hc} $
其中, Hc: 片剂推出冲模时的厚度; H: 片剂推出冲模后放置24 h后的厚度。
真密度  使用全自动真密度分析仪测定克拉霉素晶型Ⅰ、晶型Ⅱ、微晶纤维素、预胶化淀粉和乳糖一水合物真密度, 测定10次, 取平均值。
松密度  取一个10 mL量筒, 用漏斗匀速注入待测粉末至刻度, 精确称重, 计算粉体松密度, 测定3次, 取平均值。
压缩成型性  称取克拉霉素晶型Ⅰ与晶型Ⅱ各200 mg, 应用液压机分别在75、110、150、180和220 MPa压力下压制成圆形药片, 压制时间为10 s。为避免压片过程中药物弹性形变对其压缩成型性的影响, 将压制后的片剂于25 ℃/20%~30% RH条件下放置2天, 待弹性形变恢复完全后, 测定片剂片重、厚度与直径, 并应用智能硬度仪测定其硬度(即破碎力), 分别按照公式(2) 和(3) 计算片剂抗张强度(σ) 与孔隙率(ε)[15]。
$ \sigma =2F/\pi dh $
其中, F为破碎力(N); d为片剂直径(mm); h为片剂厚度(mm)。
$ \varepsilon =1-\rho /{\rho }_{\mathrm{t}\mathrm{u}\mathrm{r}\mathrm{e}} $
其中, ρ为片剂压实密度, 由片剂片重和体积可算得; ρture为粉体的真密度。
填充剂对克拉霉素晶型Ⅱ机械性质的影响  考察塑性材料微晶纤维素、弹性材料预胶化淀粉及脆性材料乳糖一水合物对克拉霉素晶型Ⅱ机械性质的影响。将预胶化淀粉、乳糖一水合物与晶型Ⅱ分别按1∶1比例混合均匀; 微晶纤维素与晶型Ⅱ分别按1∶1、1∶2及1∶3比例混合均匀; 称取适量克拉霉素、微晶纤维素、预胶化淀粉、乳糖一水合物及上述物理混合物样品按压缩成型性项下方法计算其抗张强度。
结果与讨论
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1 固态表征
1.1 PLM
各样品PLM图如图 2所示。克拉霉素晶型Ⅱ与降温法所制产物均具有明显的双折射现象, 表明其均为晶态物质, 但二者形态上有所差异。晶型Ⅱ为不规则块状, 而所制产物为长方形板状。
1.2 DSC
各样品DSC图如图 3所示。克拉霉素晶型Ⅱ在228.7 ℃处有一尖锐的吸热熔融峰, 在303.0 ℃处有一较宽的吸热峰, 这是由于其化学降解造成的, 与专利[6]所述一致。降温法所制产物在142.0 ℃处有一个放热峰, 随后药物的熔融峰、降解峰的位置与峰型与晶型Ⅱ相同, 这与专利[7]报道的克拉霉素晶型Ⅰ的DSC曲线一致, 初步确定所制产物为克拉霉素晶型Ⅰ, 其在142.0 ℃处的放热峰可能是由于晶型Ⅰ在加热过程中发生晶型转变, 形成稳定的晶型Ⅱ。
1.3 PXRD
各样品的PXRD图谱如图 4所示。克拉霉素晶型Ⅱ在8.6、9.5、10.9、11.5、12.4、13.8、15.2、17.0、17.3、19.1、20.5、22.2°/2θ处呈现特征衍射峰, 而降温法所制产物在4.6、6.5、7.6、9.2、10.3、13.7、14.8、17.0、18.2°/2θ处呈现特征衍射峰, 这与报道的克拉霉素晶型Ⅰ的PXRD图谱一致[7, 16]。因此, 降温法所制产物为克拉霉素晶型Ⅰ。
1.4 SEM
在SEM下对克拉霉素两种晶型的微观形态进行观察。由图 5可知, 克拉霉素晶型Ⅱ为表面粗糙的不规则的块状物, 而克拉霉素晶型Ⅰ为表面光滑的长方形板状, 与PLM结果一致。晶型Ⅰ更为规则, 且表面光滑, 推测其具有更小的孔隙率及更好的压缩成型性。
2 弹性复原率
药物粉末在压制完成后会发生两种形变[14], 第一种是压制片消除压力后立即产生的瞬间变形, 其由于弹性膨胀而使压制片体积迅速增大; 第二种是压制片在放置过程中发生的蠕动变形, 其体积变化缓慢。本文测定第二种蠕动变形, 克拉霉素晶型Ⅰ在放置24 h内弹性复原率仅为0.36%, 而晶型Ⅱ的弹性复原率高于晶型Ⅰ, 为1.68%, 推测晶型Ⅱ更易裂片, 故可压性更差。
3 硬度
如表 1所示, 在相同压力下, 克拉霉素晶型Ⅰ片剂的硬度高于晶型Ⅱ片剂, 且晶型Ⅱ片剂更易裂片, 结合SEM和弹性复原率结果推测克拉霉素晶型Ⅰ可压性优于晶型Ⅱ。
4 压缩成型性
片剂的压缩成型性可以用可压片性(tabletability)、可压缩性(compressibility) 和可压实性(compactibility) 三种特性进行系统地评估[17]。其中, 可压片性指在给定的压片压力下, 粉体转变成一定强度的片剂的能力, 通常以片剂的抗张强度对压片压力作图来进行表征; 片剂中颗粒间结合面积(bonding area, BA) 通常通过粉体的可压缩性来定量评估, 可压缩性由片剂孔隙率对压片压力作图来表示; 片剂的结合力(bonding strength, BS) 通常通过可压实性来定量评估, 其中可压实性由片剂抗张强度对孔隙率作图表示。由图 6可知, 在75~220 MPa压力范围内, 克拉霉素晶型Ⅰ的抗张强度均大于晶型Ⅱ, 且高压力下晶型Ⅱ更易裂片。因此, 晶型Ⅰ表现出显著提高的可压片性。由可压缩性曲线可知(图 7), 在研究范围内, 晶型Ⅰ片剂的孔隙率在各压力下均小于晶型Ⅱ片剂, 表现出了更好的可压缩性。片剂的孔隙率越低, 意味着片剂中颗粒排列更加紧密, 颗粒间接触面积更大, 因此BA也越大。由可压实性曲线可知(图 8), 在相同孔隙率下, 晶型Ⅰ片剂的抗张强度高于晶型Ⅱ, 这表明晶型Ⅰ片剂中单位面积上颗粒间结合强度更高, 即BS更大。
片剂的压缩过程是药物在狭窄的空间中受力后, 体积减小、粉体被压制成一定形状的固体聚集体的过程[18]。影响片剂可压性的主要因素是粉末的变形行为, 包括弹性变形、塑性变形和脆性变形, 其中塑性变形是增加粒子间结合面积, 提高片剂成片性的重要因素之一[19, 20]。晶体结构中滑移面的存在可以使得晶体具有良好的塑性。滑移面是指晶体中的某个特定晶面, 在该晶面上分子呈层状排列, 相邻的分子层之间间距较大且相互作用力较小。因此, 在应力作用下相邻层之间容易发生相对滑动(slipping), 从而容易发生塑性形变滑移[21-23]。克拉霉素晶型Ⅰ与晶型Ⅱ晶体结构中分子堆积方式的不同会导致其滑移面体系存在差异, 根据剑桥晶体数据中心收录的克拉霉素晶型Ⅰ与晶型Ⅱ的单晶结构, 应用Mercury软件对其滑移面体系进行分析。如图 9所示, 沿b轴观察晶型Ⅰ与晶型Ⅱ的分子堆积图, 晶型Ⅰ可见明显的滑移面(图中绿色线框), 能使分子发生相对滑动和错位, 从而具有良好的塑形; 而晶型Ⅱ中分子间交叉连接, 形成三维网状结构, 没有明显滑移面, 使分子很难发生移动和错位, 塑性较差。
5 Heckel分析
Heckel方程可用公式(4) 表示[24]:
$ \mathrm{l}\mathrm{n}\frac{1}{1-\rho }=KP+\mathrm{A} $
其中, P为压片压力; ρ为片剂压实密度; A为常数。斜率K越大表明粉体塑形越好, K与粉体屈服压力(PY) 间存在负相关性, 即PY = 1/K。根据Heckel方程可算得PY, 当PY小于40 MPa时, 颗粒非常柔软, 当PY在40~80 MPa时颗粒柔软、在80~200 MPa时颗粒稍硬、大于200 MPa时颗粒很硬[25-27]。以P对ln[1/(1-ρ)] 作图, 克拉霉素晶型Ⅰ与晶型Ⅱ的曲线图如图 10所示。由图可知, P与ln[1/(1-ρ)] 间具有较好的线性关系, 通过斜率K可算得晶型Ⅰ与晶型Ⅱ的PY值分别为157.73与154.08, 故二者均属于中等硬度, 且由于晶型Ⅰ有较大的PY值, 其塑性变形优于晶型Ⅱ[24]。
6 Kawakita分析
川北方程(Kawakita equation) 也常用来评价粉体的可压缩特性[28], 其表达如下:
$ \frac{P}{C}=\frac{P}{\mathrm{a}}+\frac{1}{\mathrm{a}\mathrm{b}} $
其中, P为压片压力; C = (V0-V)/ V0; V0为粉体初始体积(可用粉体质量与松密度计算); V为片剂体积; a、b为常数, a越小、1/b值越大表示粉体压缩性越差[29]。根据Kawakita方程, 以1/C对1/P作图, 可计算得到a和b值, 以判断其塑性。如图 11所示, 1/C与1/P间具有良好的线性关系, 对晶型Ⅰ而言, 其a、1/b值分别为0.820和2.368; 对晶型Ⅱ而言, 其a、1/b值分别为0.683和8.073。晶型Ⅰ比晶型Ⅱ具有更大的a值与更小的1/b值, 这说明晶型Ⅰ较晶型Ⅱ具有更好的塑性, 这与Heckel分析结果一致。
7 填充剂对克拉霉素晶型Ⅱ机械性质的影响
如图 12所示, 克拉霉素及各填充剂可压片性排序为微晶纤维素 > 乳糖一水合物 > 预胶化淀粉 > 克拉霉素。由图 13可知, 在测试压力范围内, 微晶纤维素、预胶化淀粉和乳糖一水合物与克拉霉素晶型Ⅱ混合物均可改善其可压性, 且改善趋势与各填充剂可压片性强弱顺序吻合; 其中, 微晶纤维素改善效果最佳并可改善其高压裂片趋势, 乳糖一水合物和预胶化淀粉可提高片剂抗张强度, 但无法改善高压裂片性质。由图 14可知, 增加微晶纤维素比例均可提高对克拉霉素晶型Ⅱ机械性质的改善。
结论
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本研究通过压缩成型性实验及数据拟合结果发现市售克拉霉素晶型Ⅱ可压性与晶型Ⅰ相比更差, 比较两种晶型晶体结构可知, 晶型Ⅱ结构为分子间交联的三维网状结构, 不利于分子发生相对滑动和错位, 导致其塑性较差; 而晶型Ⅰ结构中存在滑移面, 有利于分子发生相对滑动和错位, 从而具有良好的塑形。通过研究填充剂的影响发现乳糖一水合物、微晶纤维素和预胶化淀粉均可改善克拉霉素的可压性, 其中微晶纤维素改善效果最佳。故在片剂压制时出现片剂强度低等压缩成型性差的问题时, 可从药物晶体结构考虑, 开发塑性更高、压缩成型性更好的晶型; 也可添加可压性较好的辅料, 改善药物片剂的抗张强度, 以提高药物可压性。本研究从晶型及填充剂两个角度提高克拉霉素可压性, 也为其他片剂的可压性改善提供思路。
作者贡献: 朱恒清、庞遵霆负责实验操作、结果分析及起草、撰写文章; 高晓芳、郑道一和孟文卉负责实验操作、结果分析; 高缘负责修改文章。
利益冲突: 作者排名顺序无争议, 稿件不涉及泄密和知识产权争议。
基金
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  • 国家自然科学基金资助项目(81773675)
  • 国家自然科学基金资助项目(81873012)
  • 国家自然科学基金资助项目(82074029)
  • 中国药科大学“双一流”建设(CPU2018GY11)
  • 中国药科大学“双一流”建设(CPU2018GY27)
  • 大学生创新创业训练计划项目(202110316034)
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doi: 10.16438/j.0513-4870.2021-0600
  • 接收时间：2021-04-22
  • 首发时间：2025-12-18
  • 出版时间：2021-11-12
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  • 收稿日期：2021-04-22
  • 修回日期：2021-06-23
基金
国家自然科学基金资助项目(81773675)
国家自然科学基金资助项目(81873012)
国家自然科学基金资助项目(82074029)
中国药科大学“双一流”建设(CPU2018GY11)
中国药科大学“双一流”建设(CPU2018GY27)
大学生创新创业训练计划项目(202110316034)
作者信息
    1.中国药科大学中药学院, 江苏 南京 211198
    2.中国药科大学药学院, 江苏 南京 211198

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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