这份手稿基于以前发表的文章5。转载自5，版权到 2015 年，约翰 · 威利父子公司的许可。
我们很感激我们管理，珍妮特戚浩霖博士、 弗朗西斯科 · 阿尔瓦雷斯博士、 博士 Arwinder 凪博士大卫谢明，为他们的支持、 兴趣和鼓励执行这一研究项目，以及敏慧马博士和罗伯特 · 芒格，提供与我们甲状旁腺激素盐酸，其配方的片剂和药物有关的信息。我们也要感谢博士迈克尔 · 伯恩斯坦、 曼努埃尔 · 佩雷斯博士和博士圣地亚哥 · 多明格斯的建设性支持和发展目前商业版本的 Mnova 软件进行讨论，如它适用于 TD 核磁共振数据定量。此外，特别感谢你向先生 Regnar L.Madarang F.N.P.为我们提供通用环丙沙星片来进行我们的研究。

注意: 请使用任何化学品前咨询所有相关的材料安全数据表 (MSDS)。药物的物质通常是有毒，应使用适当的个人防护装备 (PPE; 处理例如， 手套、 安全眼镜、 白大褂、 全长的裤子和封闭的鞋子），在权衡粉末材料时特别小心。这推荐使用放置在罩与良好的空气流动平衡尽量把粉末从固体材料散发出周围平衡地区。
 注意: 软件指令是特定的 RINMR、 ri 值校正和 Mnova。对于其他 TD 核磁共振供应商设备和软件包，指示将会发生变化。
 1.制备的样品事先到 19 F TD 核磁共振测量 <ol><li>重校准 （粉原料药或活性药物成分 (API)） 样品中适当的核磁共振管 （2.5-3-5-，10-18-和 25 毫米 OD 核磁共振管） 直到标线 （为核磁共振探头线圈的高度），或在高度在 30 毫米左右。通知，高度可能取决于探头。 
	注: 甲状旁腺激素盐酸是 API 用于校准来确定甲状旁腺激素商业片中的药物含量的一个例子。重量将取决于密度的粉末。在甲状旁腺激素盐酸，权重的 API 时，周围 7.2、 3.5、 1.0、 0.3、 0.1，0.07 g 分别填土高度为 25-18-10-，5-，3-、 2.5 毫米核磁共振管，线圈。</li>
	<li>重配方的药物产品样本 （药片或胶囊） 在适当的核磁共振管直到标线 （为核磁共振探头线圈的高度） 或约 30 毫米的高度，如上文所述。 
	注意: 25-18 毫米管是适合于大型片胶囊或足够配方的药物产品不可用时。对于小片/胶囊或当没有足够的配方的药物产品是可用，但信号噪声比可能仍有足够的测量，使用 10 毫米管。直接，测量平板电脑或粉碎如果需要。他们的测量结果的变化没有观察观察了在这里，讨论 中所述。
	<ol><li>时准备商业片的甲状旁腺激素，重量大约十五个 90 毫克片剂 25 毫米核磁共振管 (约 9.2 g) 中，在 25 毫米核磁共振管 (约 9.6 g)，二十二个 30 毫克片剂 18 毫米 NMR 中的五十 30 毫克片剂管 (约 4.2 g)和 25 毫米核磁共振管 (约 8.8 g) 二十三 60 毫克片剂。</li>
	</ol></li></ol> 2。核磁共振仪的测量制备 <ol><li>调谐核磁共振仪器到 19 F <ol><li>进行的永磁核磁共振在温度测量仪器。在这里，使用 40 ° C;温度控制是没有供 26 毫米 19 F 核磁共振探头，用在这里。进行所有测量在 19 F 23 兆赫 （为 1 H) 核磁共振仪 22.0 兆赫频率。</li>
		<li>在 25 或 26 毫米核磁共振管内的铁氟龙标准样品并将其放入磁铁内的探头。允许为 5-10 分钟左右的平衡和调整到 19 F.选择仪器 &#34; 自动 O1 &#34; 下 &#34; 命令 &#34; RINMR 软件中的菜单。重复测量，至少 3 次，并采取 O 1 参数 （频率偏移量） 的最后一个值。</li>
	</ol></li> <li>19 F 90 度脉冲标定 <ol><li>F-19 与使用标准的自动的校准序列可用在文书中的铁氟龙标样标定 90 度脉冲。选择 &#34; 自动 P90 &#34; 下 &#34; 命令 &#34; RINMR 软件中的菜单。 
		注意: 通常情况下，90 度脉冲并不需要经常测量，除非该文书不执行或探针不用于一些时间。获取与这里使用 26 毫米 19 F 核磁共振探头铁氟龙为 7.05 微秒的 90 度值。</li>
	</ol></li></ol> 3。纯 API 标样的 T 1 或纵向弛豫时间测量 <ol><li>为更好的信号噪声比，放置在 25 毫米核磁共振管内 F-19 探头安装在磁铁的 API 样品让它平衡至少 10 分钟</li>
	<li>测量 T 1 弛豫时间，仪器手册，每个 API 示例，该示例使用一个标准的实验为反转恢复从 RINMR 软件的说明。 
	注: 推荐的试验参数都是 16 扫描收集与 0.1 微秒停留时间;8 个数据点;90 度脉冲，如上所述;和 10 微秒 F-19 26 毫米探测器死时间。8 从 100 微秒延误的数组 s (例如， 100 微秒，500 微秒，10 ms，100 ms，300 ms，700 毫秒，1 s，2 s，5 s 和 8 s) 药物与 CF 3 和延迟从 100 微秒到 20 s (如 100 微秒，500 微秒，1 ms，100 ms，500 ms，1 s，5 s，10 s，15 s 和 20 s) 与附加到芳香环的一氟组药物的建议。
	<ol><li>在 RINMR 软件、 负载 &#34; invrec.exe &#34; 脉冲序列，通过选择 &#34; 加载 &#34; 下 &#34; 序列 &#34; 和单击 &#34; 开放。 &#34; 检查的基本参数有正确的价值观，通过单击 &#34; A &#34; 或选择 &#34;收购 &#34; 下 &#34; 参数 &#34; 菜单。</li>
		<li>选择 &#34; 脚本 &#34; 下 &#34; 工具 &#34; 菜单; 将会弹出一个窗口。选择 &#34; T1.ris &#34; 选项卡，然后单击绿色箭头;将弹出一个窗口。选择具有适当时滞的延迟列表文件或单击后创建的列表 &#34; 开放。 &#34; 一旦延迟列表是令人满意，请单击 &#34; OK。 &#34; 注: 一个窗口将显示一个提示创建的文件的所有光谱将在收集为了计算 T 1 值。位置和文件夹和文件的名称是由用户。</li>
		单击 <li>&#34; 保存 &#34; 仪器开始获取数据并自动选定文件夹中保存的文件延误。 
		注: RIMNR 软件会创建 T 1 松弛曲线和计算 T 1 弛豫时间为每个案件。与 T 1 松弛曲线和时间常数或 T 1 值 . 会弹出一个窗口在这里，甲状旁腺激素 HCl T1 的值是 2.4 s.</li>
	</ol></li></ol> 4。测量校准样品与纯 API <ol><li>测量 API 样品建立校准曲线 <ol><li>地方一校准样品在磁铁为一个特定的 API。平衡为最小的小管 5 分钟，10 分钟大管样品。</li>
		<li>获得自由感应衰减 (FID) 或固体 (90 x 90y FID) 实验与仪器手册中的说明适当的参数。在 RINMR 软件中，加载 &#34; solid.exe &#34; (或 &#34; fid.exe &#34;) 脉冲序列，通过选择 &#34; 加载 &#34; 下 &#34; 序列 &#34; 并单击 &#34; 开放。 &#34; 注: 推荐的试验是固体固体材料的快速放松与短 T 2 s （横向弛豫时间）。推荐的实验参数是 128 扫描收集，与 0.1 微秒停留时间，1,024 的数据点，90 度脉冲 （在本例中，calibr 7.05 微秒使用铁氟龙不等式），和 10 微秒 19 F 26 毫米探测器死时间。7.5 循环延迟药物与 CF 3 组和 20 s s 药物与附加到芳香 （由于长 T 1 弛豫时间） 的 F 组有用于案件在这里，提出了一种基于其 T 1测量。</li>
		<li>测量所有样品的每一个 API 编写后他们都到了磁铁为 5-10 分钟来生成每个 API 示例的校准曲线的温度平衡。将数据保存在文件夹中，给每个实验运行一个不同的名称。</li>
		<li>计算量在每个管和考虑纯度的大管中的 API 示例是基于样品的重量百分比。</li>
	</ol></li></ol> 5。药物产品测量样品作为平板电脑 <ol><li>早已准备好的地方制定药物产品样本 （药片或胶囊） 的磁铁来衡量他们一次。平衡 5 分钟小核磁共振管或样品的更大的核磁共振管 10 分钟样本。</li>
	<li>获得相同核磁共振实验 （即 固体） 与校准样品相同的条件为每个特定 API。</li>
</ol> 6。一代的校准曲线与纯 API 示例添加数据从药物产品样本作为片剂的校准曲线 <ol><li>在这些情况下，选择该区域的固体实验从 5 到 300 点来创建校准曲线。如下所述，可以在三种不同的方式，分析了的数据。</li>
	<li>打开 RI 校准软件。通过单击要打开的 FID 或固体的文件从一个特定的 API 的剪辑符号撤回所有固体的数据。对于样本测的情况下，输入下的重量百分比 &#8220; 浓 &#8221; 列和下的重量 &#8220; 大众 &#8221; 列。选择相应的区域 （5-300 分） 使用平均方法来建立校准曲线 (打开的图标 &#8220; 显示核磁共振数据 &#8221; 选择范围的计算点)。保存的校准曲线。 
	注: Cal 列将提供药物测定样品中的百分比。</li>
	<li>在 RI 校准软件相同的选定区域 （5-300 点），与使用拟合的方法来建立校准曲线。保存的校准曲线。按照相同的说明与步骤 4.2.2。</li>
	<li>打开软件 （例如，Mnova）。从一个特定的 API 拖出固体的所有数据并输入重量百分比的标准样品;可以通过单击找到手动说明 &#8220; 内容 &#8221; 下 &#8220; 帮助 &#8221; 菜单。在 &#8220; 先进 &#8221; 菜单上，选择 &#8220; 时间域 &#8221;，然后 &#8220; 定量; &#8221; 将会弹出一个窗口。单击蓝色的加号来选择一体化区域。整合，相应的区域 （5-300 分） 用震级模式打造的校准曲线。</li>
	<li>保存校准曲线。在表中，输入每个样品的药物的百分比只根据标准 &#8220; 浓度 (x) &#8221; 列和下全部样品重量 &#8220; 质量 (m) &#8221; 列;校准样品应在红色 （检查）。请确保 &#8220; 信号函数 &#8221; 是 &#8220; y = s/m &#8221; （以正常化到信号/质谱）。</li>
	<li>为重复性、 再现，测量每个样品在不同的日子 3 倍和建立在这两个软件程序包的校准曲线。保存的校准曲线文件。</li>
</ol> 7。API 含氟药物计算重量在制定药物产品使用校准曲线 <ol><li>计算每片/胶囊的含氟 API 的重量百分比和平均剂量药物配方药物产品 <ol><li>使用的文件从 RI 校准软件和平均校准曲线法。从测得的片 （或胶囊） 读取核磁共振数据并输入他们的权重，以确定氟 API 在配方的药片或胶囊从校准曲线的重量百分比。 
		注: &#8220; Cal &#8221; 列将提供药物 （校准和商业片或未知） 所测样品中的百分比。请注意，O1 参数必须相同校准样品和片剂或胶囊为 RI 校准软件。</li>
		<li>使用该文件从 RI 校准软件校准曲线，拟合的方法。读片 （或胶囊） 的核磁共振数据测量和输入他们的权重，以确定氟 API 在配方的药片或胶囊从校准曲线的重量百分比。按照步骤 5.2.1 相同的说明。请注意，O 1 参数必须相同校准样品和片剂或胶囊为 RI 校准软件。</li>
		<li>使用 Mnova 文件和拖动所获得的 NMR 数据为制定 API （或测量它们都在同一天）。请按照步骤 4.2.4 中的说明。输入的权重确定氟 API 在配方的药片或胶囊从校准曲线的重量百分比。 
		注: 在表中，校准样品将红色 （检查） 和未知或商业片/胶囊的蓝色 （未选中）。&#8220; 浓度 (x) &#8221; 列会显示未知样品商业片的计算的值在基于值的校准样品在红色的蓝色。该软件不需要使用相同的 O1 参数，计算重量百分比的通知。</li>
		<li>作为平均值从下面公式计算每药片或胶囊含氟药物的量 (D = API 在毫克，W 核磁共振 剂量 = 重量百分比的 API 获得从校准曲线，w = 总重量制定产品从配方药物来自测量的片剂或胶囊和 N 的重量 = 一些配方的药片或胶囊用于测量) 与基于软件计算值比较校准曲线: <img alt="Equation 1"src="/files/ftp_upload/55850/55850eq1.jpg"/></li></ol></li></ol>

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作者没有透露。

随着在市场上更多的氟化药物可用，我们开发了一个具体和简单的方法，测量平均药物含量的含氟药物产品采用低场19F TD-核磁共振5。我们测试这个方法对三种商业药物产品: 含盐酸，甲状旁腺激素含有兰索拉唑，胶囊和片剂含环丙沙星盐酸盐单水合物。这种方法的优点是辅料和它的简单性氟缺乏特异性。我们测试的测量功能完整的配方 （胶囊或片剂） 甲状旁腺激素和?...

在制药行业，药物物质在他们单位的剂量形式 （例如，片剂和胶囊） 的含量必须在标签声称要满足质量控制和性能准则的范围内。高性能液相色谱法 (HPLC) 是用来衡量在他们制定的形式的药物的含量均匀度的常规分析技术。然而，该方法是冗长和破坏性，需要使用适当的溶剂分析前其配制成药物的溶出。甚至与自动化，过程可能需要 1-3 h 每个样品，根据适当的分析方法1，，23的发展。高效液相色谱法，除了近红外 (NIR) 被用作为同一目的和 PAT 的工具，有的需要的数据，使其执行长和更复杂4的化学计量学分析警告。这两种技术都具有破坏性，分析后丢弃的配方药物。
在这份手稿，我们描述了以前公布的5就我们组来测量含氟药物剂量形式 （例如，片剂和胶囊） 的平均含量方法的分步协议使用低场19F核磁共振。多年来，含氟药物通过世界各地的监管机构，作为制订的药物产品市场上的比例增至 2 %1970 年 2013年625%。因此，我们相信有需求，开发更简单，但更具体的方法，比当前可用的含氟药物在他们制定的形式内容的质量控制的方法。
药物含有氟-19 (19F) 在其结构中有优势的很容易被检测到19F 核磁共振由于相对于质子7其 100%的丰度和 83%的敏感性。1H TD-NMR 直接测量不是有用的因为有质子，赋形剂和 API 和总质子信号来自的药物产品，使得无法衡量药物产品使用1中的 API 内容的所有组件H TD-核磁共振。因此，测定药物含量的含氟药物产品采用19F TD-核磁共振的优点的赋形剂氟缺乏无干扰。为了展示我们的含氟药物产品平均药物含量测定的方法，我们选择了含氟的不同剂量范围内的三个商业配方的药物产品。图 1描述了药物选择，在两个结构的他们-甲状旁腺激素盐酸8和兰索拉唑9-三氟甲基 (CF3) 组在它们的结构，有剂量从 15 到 90 毫克和第三个其中一个环丙沙星-盐酸盐一水合物10 -包含一个附加到一个苯环，500 毫克剂量的氟原子。
在这里，我们表明我们有制定5量化使用低场台式 TD 核磁共振仪器 （23.4 兆赫为1H 和 22.0 兆赫为19F） 含氟药物产品的平均药物含量的方法。我们也比较两个软件包 （RI 校准和 Mnova 软件），可以用来报告结果。

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	<tbody>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">MQC-23</td>
			<td style="width:191px;">Oxford Instruments</td>
			<td style="width:199px;">52-AM4044</td>
			<td style="width:317px;">23.4 MHz for 1H and 22.0 MHz for 19F</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">26 mm Probe (19F)</td>
			<td style="width:191px;">Oxford Instruments</td>
			<td style="width:199px;">52-AM4061</td>
			<td style="width:317px;">19F NMR probe</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Cinacalcet HCl</td>
			<td style="width:191px;">Amgen</td>
			<td style="width:199px;">Lot 005002 M</td>
			<td style="width:317px;">Purity 99.8%</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Cinacalcet commercial tablets</td>
			<td style="width:191px;">Amgen</td>
			<td style="width:199px;">Lot 0010021308</td>
			<td style="width:317px;">30 mg tablets</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Cinacalcet commercial tablets</td>
			<td style="width:191px;">Amgen</td>
			<td style="width:199px;">Lot D1026396</td>
			<td style="width:317px;">30 mg tablets</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Cinacalcet commercial tablets</td>
			<td style="width:191px;">Amgen</td>
			<td style="width:199px;">Lot D118714</td>
			<td style="width:317px;">30 mg tablets</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Cinacalcet commercial tablets</td>
			<td style="width:191px;">Amgen</td>
			<td style="width:199px;">Lot D061829</td>
			<td style="width:317px;">60 mg tablets</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Cinacalcet commercial tablets</td>
			<td style="width:191px;">Amgen</td>
			<td style="width:199px;">Lot 00100213</td>
			<td style="width:317px;">90 mg tablets</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Cinacalcet commercial tablets</td>
			<td style="width:191px;">Amgen</td>
			<td style="width:199px;">Lot D064074</td>
			<td style="width:317px;">90 mg tablets</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Cinacalcet commercial tablets</td>
			<td style="width:191px;">Amgen</td>
			<td style="width:199px;">Lot 1026356</td>
			<td style="width:317px;">90 mg tablets</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Lansoprazole</td>
			<td style="width:191px;">Fluka</td>
			<td style="width:199px;">Lot LRAA1897</td>
			<td style="width:317px;">Purity 99.7%</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Brand name Lansoprazole</td>
			<td style="width:191px;">Novartis</td>
			<td style="width:199px;">Lot DV1891</td>
			<td style="width:317px;">15 mg capsules</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Lansoprazole generic</td>
			<td style="width:191px;">SUPERVALUE INC</td>
			<td style="width:199px;">Lot 2GE2027</td>
			<td style="width:317px;">15 mg capsules</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Ciprofloxacin free base</td>
			<td style="width:191px;">Fluka</td>
			<td style="width:199px;">Lot BCBM7969V</td>
			<td style="width:317px;">99.9% purity</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Ciprofloxacin HCl monohydrate</td>
			<td style="width:191px;">Fluka</td>
			<td style="width:199px;">Lot P500044</td>
			<td style="width:317px;">94% purity as HCl salt</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">Cipro generic</td>
			<td style="width:191px;">Pack Pharmaceuticals</td>
			<td style="width:199px;">Lot PUB3033</td>
			<td style="width:317px;">500 mg tablets</td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">25 mm NMR tube</td>
			<td style="width:191px;">New Era Enterprises</td>
			<td style="width:199px;">NE-25TD-200-FB</td>
			<td style="width:317px;"></td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">18 mm NMR tube</td>
			<td style="width:191px;">New Era Enterprises</td>
			<td style="width:199px;">NE-18TD-200-FB</td>
			<td style="width:317px;"></td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">10 mm NMR tube</td>
			<td style="width:191px;">New Era Enterprises</td>
			<td style="width:199px;">NE-10TD-200-FB</td>
			<td style="width:317px;"></td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">5 mm NMR tube</td>
			<td style="width:191px;">New Era Enterprises</td>
			<td style="width:199px;">NE-HL5-7</td>
			<td style="width:317px;"></td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">3 mm NMR tube</td>
			<td style="width:191px;">New Era Enterprises</td>
			<td style="width:199px;">NE-H3-7</td>
			<td style="width:317px;"></td>
		</tr>
		<tr height="46">
			<td height="46" style="height:47px;width:205px;">2.5 mm NMR tube</td>
			<td style="width:191px;">New Era Enterprises</td>
			<td style="width:199px;">NE-H5/2.5</td>
			<td style="width:317px;"></td>
		</tr>
	</tbody>
</table>

application and methodology of the non-destructive 19f time-domain nmr technique to measure the content in fluorine-containing drug products

在这里，我们描述了使用低场氟-19 (19F) 时间域 (TD) 核磁共振 (NMR) 在其制定的药品产品形态测量平均含量的含氟药物我们集团开发的一项议定书: 片剂或胶囊。此方法是特定于含氟药物，因为它检测到只有含量为氟、 避免从缺乏氟辅料的干扰。测量含氟药物使用低场19F TD-核磁共振与高场19F 固体 (SS) 核磁共振的活动内容的优点是方法的简单;低成本;和技术，可恢复完整形式 （例如，粉末，片剂和胶囊），所有样品的非破坏性使这项技术对于任何实验室负担得起。
我们已经测试的方法与三氟化药物可用市场上的产品-甲状旁腺激素、 兰索拉唑和环丙沙星-从 15 至 500 毫克的剂量。分析的结果，测定低场19F TD-核磁、 支持平均药物含量的报告的标签索赔。
我们简单和重现性分析的基础，设想这种方法在任何实验室里，作为一种过程分析技术 (PAT) 工具在制药行业包括制造工厂，正在实施。

我们已经测试低场19F TD-核磁共振 （甲状旁腺激素、 兰索拉唑和环丙沙星） 测量平均药物含量的含氟药物产品的三个商业药物产品。图 1显示了测试药物，结构显示氟原子的位置。
我们测试了几个很多和甲状旁腺激素片剂型 （即， 30、 60、 90 毫克），大量的兰索拉唑胶囊的品牌名称和泛?...

Watch this Scientific Journal Video about Application and Methodology of the Non-destructive 19F Time-domain NMR Technique to Measure the Content in Fluorine-containing Drug Products at JoVE.com

Application and Methodology of the Non-destructive 19F Time-domain NMR Technique to Measure the Content in Fluorine-containing Drug Products

本文提出了一种简单和非破坏性的技术措施制定的药物产品使用低场氟-19 (19F) 时间域 (TD) 核磁共振 (NMR) 含氟药物的平均含量是。可以应用这项技术制造的药物在制药行业的发展。

应用程序和非破坏性19F 时间域核磁共振技术的方法来衡量中含氟药物产品的内容

Here, we describe a protocol developed by our group that uses low-field fluorine-19 (19F) time-domain (TD) nuclear magnetic resonance (NMR) to measure the ...

application-methodology-non-destructive-19f-time-domain-nmr-technique

Research

JoVE Journal

Chemistry

Application and Methodology of the Non-destructive 19F Time-domain NMR Technique to Measure the Content in Fluorine-containing Drug Products

8.3K 次观看.  Amgen, Inc.. 本文提出了一种简单和非破坏性的技术措施制定的药物产品使用低场氟-19 (19F) 时间域 (TD) 核磁共振 (NMR) 含氟药物的平均含量是。可以应用这项技术制造的药物在制药行业的发展。

视频: Application and Methodology of the Non-destructive 19F Time-domain NMR Technique to Measure the Content in Fluorine-containing Drug Products

Structure and Coordination Determination of Peptide-metal Complexes Using 1D and 2D 1H NMR

Copper (I) binding by metallochaperone transport proteins prevents copper oxidation and release of the toxic ions that may participate in harmful redox reactions. The Cu (I) complex of the peptide model of a Cu (I) binding metallochaperone protein, which includes the sequence MTCSGCSRPG (underlined is conserved), was determined in solution under inert conditions by NMR spectroscopy.
NMR is a widely accepted technique for the determination of solution structures of proteins and peptides. Due to difficulty in crystallization to provide single crystals suitable for X-ray crystallography, the NMR technique is extremely valuable, especially as it provides information on the solution state rather than the solid state. Herein we describe all steps that are required for full three-dimensional structure determinations by NMR. The protocol includes sample preparation in an NMR tube, 1D and 2D data collection and processing, peak assignment and integration, molecular mechanics calculations, and structure analysis. Importantly, the analysis was first conducted without any preset metal-ligand bonds, to assure a reliable structure determination in an unbiased manner.

Structure and Coordination Determination of Peptide-metal Complexes Using 1D and 2D 1H NMR

The NMR-solution structure of a metallochaperone model peptide with Cu (I) was determined, and a detailed protocol from sample preparation and 1D and 2D data collection to a three-dimensional structure is described.

Copper (I) binding by metallochaperone transport proteins prevents copper oxidation and release of the toxic ions that may participate in harmful redox ...

科研

化学

Methods to Identify the NMR Resonances of the 13C-Dimethyl N-terminal Amine on Reductively Methylated Proteins

Nuclear magnetic resonance (NMR) spectroscopy is a proven technique for protein structure and dynamic studies. To study proteins with NMR, stable magnetic isotopes are typically incorporated metabolically to improve the sensitivity and allow for sequential resonance assignment. Reductive 13C-methylation is an alternative labeling method for proteins that are not amenable to bacterial host over-expression, the most common method of isotope incorporation. Reductive 13C-methylation is a chemical reaction performed under mild conditions that modifies a protein&#39;s primary amino groups (lysine &#949;-amino groups and the N-terminal &#945;-amino group) to 13C-dimethylamino groups. The structure and function of most proteins are not altered by the modification, making it a viable alternative to metabolic labeling. Because reductive 13C-methylation adds sparse, isotopic labels, traditional methods of assigning the NMR signals are not applicable. An alternative assignment method using mass spectrometry (MS) to aid in the assignment of protein 13C-dimethylamine NMR signals has been developed. The method relies on partial and different amounts of 13C-labeling at each primary amino group. One limitation of the method arises when the protein&#39;s N-terminal residue is a lysine because the &#945;- and &#949;-dimethylamino groups of Lys1 cannot be individually measured with MS. To circumvent this limitation, two methods are described to identify the NMR resonance of the 13C-dimethylamines associated with both the N-terminal &#945;-amine and the side chain &#949;-amine. The NMR signals of the N-terminal &#945;-dimethylamine and the side chain &#949;-dimethylamine of hen egg white lysozyme, Lys1, are identified in 1H-13C heteronuclear single-quantum coherence spectra.

Methods to Identify the NMR Resonances of the 13C-Dimethyl N-terminal Amine on Reductively Methylated Proteins

Two methods for assigning the &#945;- and &#949;-dimethylamine nuclear magnetic resonance signals of a reductively 13C-methylated N-terminal lysine are described. One method utilizes the pH-induced selectivity of the reductive methylation reaction, and the other uses aminopeptidase to selectively remove the N-terminal lysine.

Nuclear magnetic resonance (NMR) spectroscopy is a proven technique for protein structure and dynamic studies. To study proteins with NMR, stable magnetic ...

Synthesis of Hypervalent Iodonium Alkynyl Triflates for the Application of Generating Cyanocarbenes

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent reactions with azides to form cyanocarbene intermediates. The synthesis of hypervalent iodonium alkynyl triflates can be facile, but difficulties stem from their isolation and reactivity. In particular, the necessity to use filtration under inert atmosphere at -45 &deg;C for some HIATs requires special care and equipment. Once isolated, the compounds can be stored and used in reactions with azides to form cyanocarbene intermediates. 
The evidence for cyanocarbene generation is shown by visible extrusion of dinitrogen as well as the characterization of products that occur from O-H insertion, sulfoxide complexation, and cyclopropanation. A side reaction of the cyanocarbene formation is the generation of a vinylidene-carbene and the conditions to control this process are discussed. There is also potential to form a hypervalent iodonium alkenyl triflate and the means of isolation and control of its generation are provided. The O-H insertion reaction involves using a HIAT, sodium azide or tetrabutylammonium azide, and methanol as solvent/substrate. The sulfoxide complexation reaction uses a HIAT, sodium azide or tetrabutylammonium azide, and dimethyl sulfoxide as solvent. The cyclopropanations can be performed with or without the use of solvent. The azide source must be tetrabutylammonium azide and the substrate shown is styrene.

Herein is described the synthesis, isolation, and reactions of hypervalent iodonium alkynyl triflates (HIATs) with azides to generate cyanocarbenes. The procedures will involve air-sensitive and cryogen techniques, including cold filtration under an inert atmosphere. Handling and safety of the synthesized compounds will also be discussed.

高价碘鎓炔基三氟甲磺酸酯的生成Cyanocarbenes的合成应用

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent ...

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of trifluoromethoxylated aromatic compounds remains a formidable challenge in organic synthesis. Conventional approaches often suffer from poor substrate scope, or require use of highly toxic, difficult-to-handle, and/or thermally labile reagents. Herein, we report a user-friendly protocol for the synthesis of methyl 4-acetamido-3-(trifluoromethoxy)benzoate using 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni reagent II). Treating methyl 4-(N-hydroxyacetamido)benzoate (1a) with Togni reagent II in the presence of a catalytic amount of cesium carbonate (Cs2CO3) in chloroform at RT afforded methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2a). This intermediate was then converted to the final product methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3a) in nitromethane at 120 &#176;C. This procedure is general and can be applied to the synthesis of a broad spectrum of ortho-trifluoromethoxylated aniline derivatives, which could serve as useful synthetic building blocks for the discovery and development of new pharmaceuticals, agrochemicals, and functional materials.

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

An operationally simple procedure for the synthesis of ortho-trifluoromethoxylated aniline derivatives via a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxyacetamide followed by thermally induced intramolecular OCF3-migration is reported.

协议的合成<em&gt;邻</em&gt; -trifluoromethoxylated苯胺类化合物

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of ...

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the development of antibody drug conjugates (ADCs) and nanomedicine, fluorescent microscopy and systems chemistry. For many of these applications, specificity of the bioconjugation method used is of prime concern. The Michael addition of maleimides with cysteine(s) on the target proteins is highly selective and proceeds rapidly under mild conditions, making it one of the most popular methods for protein bioconjugation.
We demonstrate here the modification of the only surface-accessible cysteine residue on yeast cytochrome c with a ruthenium(II) bisterpyridine maleimide. The protein bioconjugation is verified by gel electrophoresis and purified by aqueous-based fast protein liquid chromatography in 27% yield of isolated protein material. Structural characterization with MALDI-TOF MS and UV-Vis is then used to verify that the bioconjugation is successful. The protocol shown here is easily applicable to other cysteine - maleimide coupling of proteins to other proteins, dyes, drugs or polymers.

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

This protocol details the important steps required for the bioconjugation of a cysteine containing protein to a maleimide, including reagent purification, reaction conditions, bioconjugate purification and bioconjugate characterization.

蛋白质生物缀合物的合成<em&gt;通过</em&gt;半胱氨酸马来酰亚胺化学

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the ...

NMR Spectroscopy as a Robust Tool for the Rapid Evaluation of the Lipid Profile of Fish Oil Supplements

The western diet is poor in n-3 fatty acids, therefore the consumption of fish oil supplements is recommended to increase the intake of these essential nutrients. The objective of this work is to demonstrate the qualitative and quantitative analysis of encapsulated fish oil supplements using high-resolution 1H and 13C NMR spectroscopy utilizing two different NMR instruments; a 500 MHz and an 850 MHz instrument. Both proton (1H) and carbon (13C) NMR spectra can be used for the quantitative determination of the major constituents of fish oil supplements. Quantification of the lipids in fish oil supplements is achieved through integration of the appropriate NMR signals in the relevant 1D spectra. Results obtained by 1H and 13C NMR are in good agreement with each other, despite the difference in resolution and sensitivity between the two nuclei and the two instruments. 1H NMR offers a more rapid analysis compared to 13C NMR, as the spectrum can be recorded in less than 1 min, in contrast to 13C NMR analysis, which lasts from 10 min to one hour. The 13C NMR spectrum, however, is much more informative. It can provide quantitative data for a greater number of individual fatty acids and can be used for determining the positional distribution of fatty acids on the glycerol backbone. Both nuclei can provide quantitative information in just one experiment without the need of purification or separation steps. The strength of the magnetic field mostly affects the 1H NMR spectra due to its lower resolution with respect to 13C NMR, however, even lower cost NMR instruments can be efficiently applied as a standard method by the food industry and quality control laboratories.

Here, high-resolution 1H and 13C Nuclear Magnetic Resonance (NMR) spectroscopy was used as a rapid and reliable tool for quantitative and qualitative analysis of encapsulated fish oil supplements.

核磁共振作为鱼油补充剂的血脂的快速评价一个强大的工具

The western diet is poor in n-3 fatty acids, therefore the consumption of fish oil supplements is recommended to increase the intake of these essential ...

Preparation of Chitosan-based Injectable Hydrogels and Its Application in 3D Cell Culture

The protocol presents a facile, efficient, and versatile method to prepare chitosan-based hydrogels using dynamic imine chemistry. The hydrogel is prepared by mixing solutions of glycol chitosan with a synthesized benzaldehyde terminated polymer gelator, and hydrogels are efficiently obtained in several minutes at room temperature. By varying ratios between glycol chitosan, polymer gelator, and water contents, versatile hydrogels with different gelation times and stiffness are obtained. When damaged, the hydrogel can recover its appearances and modulus, due to the reversibility of the dynamic imine bonds as crosslinkages. This self-healable property enables the hydrogel to be injectable since it can be self-healed from squeezed pieces to an integral bulk hydrogel after the injection process. The hydrogel is also multi-responsive to many bio-active stimuli due to different equilibration statuses of the dynamic imine bonds. This hydrogel was confirmed as bio-compatible, and L929 mouse fibroblast cells were embedded following standard procedures and the cell proliferation was easily assessed by a 3D cell cultivation process. The hydrogel can offer an adjustable platform for different research where a physiological mimic of a 3D environment for cells is profited. Along with its multi-responsive, self-healable, and injectable properties, the hydrogels can potentially be applied as multiple carriers for drugs and cells in future bio-medical applications.

Here we describe a facile preparation of chitosan-based injectable hydrogels using dynamic imine chemistry. Methods to adjust the hydrogel&#8217;s mechanical strength and its application in 3D cell culture are presented.

糖注射水凝胶的制备及其在3D 细胞培养中的应用

The protocol presents a facile, efficient, and versatile method to prepare chitosan-based hydrogels using dynamic imine chemistry. The hydrogel is ...

Application of Elemental Lanthanides in the Selective C-F Activation of Trifluoromethylated Benzofulvenes Providing Access to Various Difluoroalkenes

The selective activation of one carbon-fluorine bond in polyfluorinated aromatic molecules or in trifluoromethyl-containing substrates offers the possibility of accessing unique fluorine-containing molecules, which are difficult to obtain by other synthetic pathways. Among various metals, which can undergo C-F activation, lanthanides (Ln) are good candidates as they form strong Ln-F bonds. Lanthanide metals are strong reducing agents with a redox potential Ln3+/Ln&#160;of approximately -2.3 V, which is comparable to the value of the Mg2+/Mg&#160;redox couple. In addition, lanthanide metals display a promising functional group tolerance and their reactivity can vary along the lanthanide series, making them suitable reagents for fine-tuning reaction conditions in organic and organometallic transformations. However, due to their oxophilicity, lanthanides react readily with oxygen and water and therefore require special conditions for storage, handling, preparation, and activation. These factors have limited a more widespread use in organic synthesis. We herein present how dysprosium metal - and by analogy all lanthanide metals - can be freshly prepared under anhydrous conditions using glovebox and Schlenk techniques. The freshly filed metal, in combination with aluminum chloride, initiates the selective C-F activation in trifluoromethylated benzofulvenes. The resulting reaction intermediates react with nitroalkenes to obtain a new family of difluoroalkenes.

This protocol describes the preparation of elemental lanthanides under inert atmosphere and their application in a selective C-F activation process involving trifluoromethylated benzofulvenes.

元素镧在选择性 c-F 活化 Trifluoromethylated Benzofulvenes 中的应用提供各种 Difluoroalkenes 的访问

The selective activation of one carbon-fluorine bond in polyfluorinated aromatic molecules or in trifluoromethyl-containing substrates offers the ...

Generation of Electronic Cigarette Aerosol by a Third-Generation Machine-Vaping Device: Application to Toxicological Studies

Electronic-cigarette (e-cig) devices use heat to produce an inhalable aerosol from a liquid (e-liquid) composed mainly of humectants, nicotine, and flavoring chemicals. The aerosol produced includes fine and ultrafine particles, and potentially nicotine and aldehydes, which can be harmful to human health. E-cig users inhale these aerosols and, with the third-generation of e-cig devices, control design features (resistance and voltage) in addition to the choice of e-liquids, and the puffing profile. These are key factors that can significantly impact the toxicity of the inhaled aerosols. E-cig research, however, is challenging and complex mostly due to the absence of standardized assessments and to the numerous varieties of e-cig models and brands, as well as e-liquid flavors and solvents that are available on the market. These considerations highlight the urgent need to harmonize e-cig research protocols, starting with e-cig aerosol generation and characterization techniques. The current study focuses on this challenge by describing a detailed step-by-step e-cig aerosol generation technique with specific experimental parameters that are thought to be realistic and representative of real-life exposure scenarios. The methodology is divided into four sections: preparation, exposure, post-exposure analysis, plus cleaning and maintenance of the device. Representative results from using two types of e-liquid and various voltages are presented in terms of mass concentration, particle size distribution, chemical composition and cotinine levels in mice. These data demonstrate the versatility of the e-cig exposure system used, aside from its value for toxicological studies, as it allows for a broad range of computer-controlled exposure scenarios, including automated representative vaping topography profiles.

Electronic cigarette (e-cig) users are increasing worldwide. Little, however, is known about the health effects induced by inhaled e-cig aerosols. This article describes an e-cig aerosol generation technique suitable for animal exposures and subsequent toxicological studies. Such protocols are required to establish experimentally reproducible and standardized e-cig exposure systems.

第三代机械 Vaping 装置生成电子烟气溶胶: 毒理学研究的应用

Electronic-cigarette (e-cig) devices use heat to produce an inhalable aerosol from a liquid (e-liquid) composed mainly of humectants, nicotine, and ...

Employing Pressurized Hot Water Extraction (PHWE) to Explore Natural Products Chemistry in the Undergraduate Laboratory

A recently developed pressurized hot water extraction (PHWE) method which utilizes an unmodified household espresso machine to facilitate natural products research has also found applications as an effective teaching tool. Specifically, this technique has been used to introduce second- and third-year undergraduates to aspects of natural products chemistry in the laboratory. In this report, two experiments are presented: the PHWE of eugenol and acetyleugenol from cloves and the PHWE of seselin and (+)-epoxysuberosin from the endemic Australian plant species Correa reflexa. By employing PHWE in these experiments, the crude clove extract, enriched in eugenol and acetyleugenol, was obtained in 4-9% w/w from cloves by second-year undergraduates and seselin and (+)-epoxysuberosin were isolated in yields of up to 1.1% w/w and 0.9% w/w from C. reflexa by third-year students. The former exercise was developed as a replacement for the traditional steam distillation experiment providing an introduction to extraction and separation techniques, while the latter activity featured guided-inquiry teaching methods in an effort to simulate natural products bioprospecting. This primarily derives from the rapid nature of this PHWE technique relative to traditional extraction methods that are often incompatible with the time constraints associated with undergraduate laboratory experiments. This rapid and practical PHWE method can be used to efficiently isolate various classes of organic molecules from a range of plant species. The complementary nature of this technique relative to more traditional methods has also been demonstrated previously.

Employing Pressurized Hot Water Extraction PHWE to Explore Natural Products Chemistry in the Undergraduate Laboratory

Here, we employ a pressurized hot water extraction (PHWE) method, which utilizes an unmodified household espresso machine to introduce undergraduates to natural products chemistry in the laboratory. Two experiments are presented: PHWE of eugenol and acetyleugenol from cloves and PHWE of seselin and (+)-epoxysuberosin from the Australian plant Correa reflexa.

利用加压热水提取 (phwe) 在本科实验室中探索天然产物化学

A recently developed pressurized hot water extraction (PHWE) method which utilizes an unmodified household espresso machine to facilitate natural products ...