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Particle formation by rapid expansion of supercritical solutions.

机译：通过超临界溶液的快速膨胀形成颗粒。

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摘要

This body of work is intended to serve as a proof of concept for the application of supramolecular chemistry in drug development. More specifically, this work is designed to evaluate crystal doping by recrystallization from supercritical media. The rapid nucleation and growth implicit to supercritical fluid based crystallizations were tested in doping drug crystals with structurally related impurities. The ultimate motive was to tailor the physicochemical properties of active pharmaceutical ingredients (API) through crystal doping. This, in turn provides the ability to tie functionality to API's at early stages of drug discovery and synthesis. The rapid expansion of supercritical solution (RESS) process was evaluated for these purposes. Pure and co-solvent modified supercritical fluid CO2 was used as the recrystallizing solvent. The supercritical region investigated for these studies included pressures from 1071–9000psi and temperatures ranging from 31–100°C. The pharmaceutical solids studied included α-naphthalene acetic acid, aspirin, benzoic acid, caffeine, chlorpropamide, indomethacin, naproxen, phenytoin, piroxicam, salicylic acid, theobromine, theophylline, tolbutamide and urea. For comparison purposes, model chlorpropamide+urea system was also recrystallized from three liquid organic solvents using evaporative crystallization. The composition, morphology and the energetics of the crystals thus produced are characterized utilizing techniques such as microscopy (polarizing optical, SEM), thermal analysis (DSC, mDSC, TGA and thermomicroscopy) and HPLC. Selective extraction and a reduction in crystallinity were consistently seen in all of the drug-impurity mixtures co-crystallized by RESS process. In addition, a number of interesting phenomena were revealed. These include habit modification, solubility enhancement, particle size reduction, eutectic formation, amorphous conversion, hydrate formation and polymorph conversion. In viewing each of these phenomena from an application standpoint, this work serves as proof of concept for enhancing the physicochemical and mechanical attributes of API's using supercritical fluid crystal doping. Comparative evaluation studies indicated RESS to be superior to organic solvent-based recrystallizations in crystal doping. In summary, RESS offers great promise as a hybrid technique to control both the crystalline and the particle morphologies of APIs in a single stage.
机译：本工作旨在作为超分子化学在药物开发中的应用的概念证明。更具体地说，这项工作旨在通过从超临界介质中重结晶来评估晶体掺杂。在用结构相关杂质掺杂药物晶体中，测试了超临界流体基结晶隐含的快速成核和生长。最终动机是通过晶体掺杂来调整活性药物成分（API）的物理化学性质。反过来，这提供了在药物发现和合成的早期将功能与API关联的能力。为此，对超临界溶液（RESS）工艺的快速膨胀进行了评估。使用纯共溶剂改性的超临界流体CO 2 作为重结晶溶剂。这些研究中研究的超临界区域包括压力范围为1071–9000psi和温度范围为31–100°C。研究的药物固体包括α-萘乙酸，阿司匹林，苯甲酸，咖啡因，氯丙酰胺，消炎痛，萘普生，苯妥英钠，吡罗昔康，水杨酸，可可碱，茶碱，甲苯磺丁酰胺和尿素。为了进行比较，还使用蒸发结晶从三种液体有机溶剂中重结晶了模型氯丙酰胺+脲系统。由此产生的晶体的组成，形态和高能学利用诸如显微技术（偏振光学，SEM），热分析（DSC，mDSC，TGA和热显微术）和HPLC的技术来表征。在通过RESS工艺共结晶的所有药物杂质混合物中，始终可以看到选择性萃取和结晶度降低。此外，还发现了许多有趣的现象。这些包括习惯改变，溶解度提高，粒度减小，共晶形成，无定形转化，水合物形成和多晶型物转化。从应用的角度看待这些现象中的每一种，这项工作可作为概念证明，以使用超临界液晶掺杂增强API的物理化学和机械特性。对比评估研究表明，RESS在晶体掺杂方面优于基于有机溶剂的重结晶。总而言之，RESS作为一种在单个阶段控制API的晶体和颗粒形态的混合技术，具有广阔的前景。

著录项

  • 作者

    Vemavarapu, Chandra S.;

  • 作者单位

    University of Rhode Island.;

  • 授予单位 University of Rhode Island.;
  • 学科 Chemistry Pharmaceutical.; Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 360 p.
  • 总页数 360
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药物化学;药剂学;
  • 关键词

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