!283296 九、發明說明： 【發明所屬之技術領域】 本發明關於一種分析藥學樣本之方法與裝置。更明確 夕非祕方式獲得在一藥學樣本 置 質内之—化學組份之分子資料的方法和裝 【先前技術】 媒太就轉樣本來說，㈣同時判定—化學組份在 m面ί或母質内的位置及其對應分子資料會报有 rf料可當作藥學樣本在—已知時間的基 〜媒太aseimepn>fiie)且可容許在稍後時間作分析以判 化學，成的變化。從一化學外觀之分析得到的 15283296 IX. Description of the Invention: [Technical Field of the Invention] The present invention relates to a method and apparatus for analyzing a pharmaceutical sample. More specifically, the method and apparatus for obtaining the molecular data of the chemical component in the quality of a pharmaceutical sample [previous technique], the media is too transferred to the sample, (4) simultaneous determination - the chemical component is in the m-plane or The position in the parent material and its corresponding molecular data will be reported as rf material can be used as a pharmaceutical sample in the -known time base ~ medium too aseimepn > fiie) and can be allowed to analyze at a later time to determine the chemical changes . 15 from a chemical appearance analysis
Si/ rb於一藥物配方設計師（fimnUlat()1：：)確認在配t 2 有任何需要改進之處。此外，在—安定性研究當 查： = 定的製程步驟之前或之後以及在多個時間點 方法'。、子7 。因此，需要一種非破壞性且可再現的分析 理^t所分析方法其巾有—些提供有關表面缺陷之物 枯=元素組份的資訊。-般常用的非破壞性結構分析 =含光顯微術（叫紅外線⑻吸收光譜術和掃 抱電子顯微術（SEM)。 =是-相較之下較為簡單的技術，其提供一較低解析 又的樣本影叙能絲偵測大約G5冑米直㈣表面粒 20 1283296 子。LM能夠定位一藥學樣本 可從該表面或是該樣本之母表面上的一個小區域，藉以 在藥學方面的效用有限，^部得到分子資料。然而LM 次微米化學組份。要以人力‘、'、不可能找出並聚焦在單一 極為困難的，要找出區域内顯微鏡搜尋—小區域是 即困難的，次微米目標是無—較小目標縱非不可能也是 IR吸收光譜術是-種常用以光學顯微鏡看見的。 破壞性技術。m吸收光譜術^场得材料之分子鑑定的非 一起之原子的振動。=：^=貞測分子振動或是鍵結在 頻率的人射輕射會被吸收1卜子振動相同頻率之 對輻射波數（波長的倒數）：：㊁通常是透射輻射強度 態頻率的許多透射磁㈣^ ’顯示對應於振動模 間麵合造成—複雜光譜，其:子之不同部位的振動 15 -:有標諸。然而，使用IR技術:繼 peak)限制了 IR對於從 “出現的水峰（water 性。IR技術的另一問題是入射：的獲得分子資料的可用 用於大多數化合物之鑑定的^^尺寸（_如）。 内，從大約2微米到25微来振由動;^^中紅外線範圍 合振動波長以獲得—吸收光^射之波長必須符 射輻射亦在2微米至25微米 蜊量中使用的入 點尺寸與l波县右關a,波長靶圍内。一輻射束的光 長。因此在:關吸收:;=寸的下限即大約是該波 以及合成吸收仲之你隹水、乍業中叉入射輕射照射的區域 米。因為一“本之；V原的區域的直徑得大約是25微 樂予樣本之衫化學組份是切切級尺寸，此 20 1283296 隔離一特定元素以進行分析而言大太對 次Γ =粒子作分析有用則需要一餘小於1微米的照 用在藥學方面亦有限，因从路处、纽^先。曰術）的使 且分子資料之收集來源區因域為不^遽掩了吾人想要的光譜 在SEM術中，將一初級電子束射到一樣本 高於LM術的解析度形成該表面之 導性塗層否則對：方束面幾令乎人一有 ( 勒產生且隨彳__以 塗層材料遮掩了-藥學樣本的表阻 到分子資料。該塗層亦阻止從樣本之4::=: 料。此外，SEM要求樣本要放在一直办二^獲付刀子一貝 持於-不超過10-5 T0rr的負壓 ^至内。该真空室維 少失真。然而，因為真任何水蒸氣並藉以減 日後再次餘分析。因^縣的^變得職化且無法在 對於可再現地從一藥學樣本之. 僅適用於形貌分析，《 料方面效用有限。 面上或母質内獲得分子資 另一種形貌分析技術是掃 SPM包括一系列技術，其中將一二探針顯微術（SPM)。 並以高解析度和精度（亳微米的保持為極接近一表面 量探針與表面間的一些交互作用。刀之幾）掃描。然後測 顯微術中是測量穿隧電流。—舉例來說，在掃描穿隧 —種常用於結構特徵化之 1283296 spM技術為原子力顯微術（AFM)，其中測量探針與表面之 間的力。典型用途包含一樣本上之粗糙度、針孔及其他形 貌特徵的測量。然而，SPM技術和應用對於從一藥學樣本 之表面或母質内獲得分子資料的效用有限。 一般常用於元素分析之其他非破壞性技術包含歐傑發 射能譜術（AES)和X射線螢光光譜術（xrf)。如同SEM 技術’ AES技術涉及將一初級電子束射到樣本。不同於利 用偵測上表面上之原子所發射的次級電子來形成一影像， AES技術測量發射電子的能階以判定表面結構的元素組鲁 份。在XRF技術中，將一初級X射線束射到表面並測量由 在該表面上及該表面底下一些之元素原子發射之合成次級 X射線的能階（或對應波長）。目標材料内的元素原子發射 具有獨一無二特徵能階（或對應波長）的次級X射線。因 此可藉由發射次級X射線的測得能階（或波長）判定在該 表面上或表面底下一些的材料元素組份。此等元素分析技 術對於獲得藥學應用所需之詳細化學組份資料（亦即元素 資料以外的資料）類型來說效用有限。舉例來說，例如AES · 或XRF的技術可能確認一化學元素在一表面上的存在，但 無法判定一具有一不同化學組成之次表面層内之化學組份 的分子資料。對存在於一藥學樣本之一表面層上或内或是 母質内部之真實化學組份在多個時間點的了解可能非常有 仏值’讓熟習此技藝者能夠在製程中的某些點勾勒出一藥 學劑量形式或是其對時間的安定性。 美國專利第6,067，154號提出一種有關半導體晶圓製造 1283296 範疇的裝置和方法，其用於利用入射單能輻射之非彈性散 射栈出一半導體形貌内的製造缺陷並獲得此等缺陷的分子 特徵。 美國專利第4,407,008號提出一種有關利用光誘致 SEM之分析的裝置和方法’其藉由利用多樣彳貞測裝置偵測 樣本所發射之後續激發輻射而允許對樣本特有參數及其二 維分佈作非破壞性鑑定。 〃一 當前可用的技術適用於表面和元素分析，但目前並、、" 有能夠非破壞性地提供一藥學樣本之一表面層:或 母質内部之化學組份的分子資料的方法。“當今 術的侷限，目前並沒有具備能在不同時間就單: 15 S亥樣本之一次微米影像、表面分子資料及， ’、 之能力或是能用於多樣藥學應用和環境匕學組份 說包含做為—藥物製造環境巾的製 二性舉例來 藥學，室環境中之钱性研究測在一 是母質内部之分子資料的方法上或内或 破壞性地獲得在單_藥學樣本之_ 出-種非 好提出1 =-人微h子資料的方法和I置。另外，最 戍内或是母Ϊ壞性地獲得在單—藥學樣本之-表面屏^ 次内k母質内部 〈表面層上 藥學應用和環境中的方法和裝置微“子-貝料且用於多樣 20 1283296 【發明内容】 簡短地說’本發明之裝置為—包括一成 號產生裝置、一偵測裝置和一標繪裴 〜、一信 學樣本之一化學組份的分子資料。該成像裝以得 樣本之-影像。該信號產生和_裳置 射源及用㈣測自該樣本散射之輻 =射輕 標繪褒置提供-在該樣本之母f f ^。該 的位置。 μ自輯传分子資料 本發明之方法包括以下步驟：產生― 像；利用該影像去確認並選擇該樣本之母質上^之—影 獲得分子减。 ^彳科心自此 儘管本發明可有眾多修改型和替代形 舉例方式示於圖式中且會在本說明書中詳細= =解到ί說明書之圖式和詳細說明並非想要將本發明；； 制在說明書中提及㈣定形式。相反地，本發明涵 本發明之說明書暨中請專利範圍的精神和有= 改型、等效内容及替代方案。 _夕 【實施方式】 在本發明方法及裝置之一實施例中，成像裝置包括一 用來產生_藥學樣本影.魏掃描電子賴鏡（咖μ) 及一讓樣本可再現地放上的ESEM自動檯。 1283296Si/rb in a pharmaceutical formulator (fimnUlat() 1::) confirmed that there is any need for improvement in the distribution of t 2 . In addition, in the - stability study, check: = before or after the process steps and at multiple points in time. , child 7. Therefore, there is a need for a non-destructive and reproducible analytical method that provides information about the surface defects of the elements. - Commonly used non-destructive structural analysis = light microscopy (called infrared (8) absorption spectroscopy and sweep electron microscopy (SEM). = Yes - a relatively simple technique, which provides a lower The analytical sample image can detect about G5 glutinous rice straight (four) surface granules 20 1283296. LM can locate a medicinal sample from the surface or a small area on the mother surface of the sample, thereby pharmacy The utility is limited, and the molecular data is obtained. However, the LM submicron chemical composition is difficult to find and focus on a single extremely difficult one, to find an area for microscopic search - small areas are difficult The sub-micron target is none - the smaller target is not impossible and the IR absorption spectroscopy is a type that is commonly seen with optical microscopy. Destructive technology. m absorption spectroscopy Vibration. =:^= 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 = = = = of Many transmission magnetic (four) ^ 'displays correspond to the complex spectroscopy caused by the vibration mode, which: the vibration of different parts of the sub- 15 -: have the standard. However, using IR technology: following the peak) limits the IR for The water peak (water. Another problem with IR technology is incident: the available molecular data available for the identification of most compounds (_). Inside, from about 2 microns to 25 micrometers In the middle of the infrared range and the vibration wavelength to obtain - the wavelength of the absorption light must be inductive radiation is also used in the 2 micron to 25 micron volume of the entry point size and l wave county right off a, within the wavelength target The light of a radiation beam is long. Therefore, the lower limit of the absorption:;= inch is about the wave and the synthetic absorption of the water in the area where you are in the water and the light in the industry. Because of the "this; The diameter of the V-original region is about 25 mils. The chemical composition of the shirt is a cut-off size. This 20 1283296 isolating a specific element for analysis. It is necessary to analyze the particle. Less than 1 micron is also limited in pharmacy. From the road, the new ^ first. The 曰 ) 且 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子 分子The resolution of the surface forms a conductive coating on the surface. Otherwise, the square beam surface is somewhat pleasing (and produced with the coating material) - the surface resistance of the pharmaceutical sample to the molecular data. It also prevents the 4::=: material from the sample. In addition, the SEM requires that the sample be placed in the middle of the machine and the knife is held in a negative pressure of -10 to 10 T0rr. Distortion. However, because of any water vapor, it is used to reduce the analysis after the day. Because ^ County's ^ became professional and could not be reproducibly from a pharmaceutical sample. Only for topographic analysis, "material effect" limited. Molecular resources are obtained on the surface or in the parent material. Another morphological analysis technique is to sweep SPM including a series of techniques, one to two probe microscopy (SPM). It is scanned with high resolution and precision (the retention of 亳 micron is very close to the interaction between a surface probe and the surface. A few of the knives). The tunneling current is then measured during microscopy. - For example, in scanning tunneling, the 1283296 spM technique commonly used for structural characterization is atomic force microscopy (AFM), in which the force between the probe and the surface is measured. Typical uses include measurements of the same roughness, pinholes, and other topographical features. However, SPM techniques and applications have limited utility for obtaining molecular data from the surface or parent material of a pharmaceutical sample. Other non-destructive techniques commonly used for elemental analysis include Auger Emission Spectroscopy (AES) and X-ray Fluorescence Spectroscopy (xrf). As with SEM technology, the AES technique involves projecting a primary electron beam into a sample. Instead of using a secondary electron emitted by an atom on the upper surface to form an image, the AES technique measures the energy level of the emitted electron to determine the elemental composition of the surface structure. In the XRF technique, a primary X-ray beam is directed onto a surface and the energy level (or corresponding wavelength) of the synthesized secondary X-rays emitted by elemental atoms on the surface and underneath the surface is measured. Elemental atomic emission within the target material Secondary X-rays with unique characteristic levels (or corresponding wavelengths). Therefore, some of the material element components on or under the surface can be determined by emitting the measured energy level (or wavelength) of the secondary X-rays. These elemental analysis techniques are of limited utility for obtaining the detailed chemical composition data (i.e., data other than elemental data) required for pharmaceutical applications. For example, techniques such as AES or XRF may confirm the presence of a chemical element on a surface, but cannot determine the molecular data of a chemical component in a subsurface layer having a different chemical composition. Knowledge of the true chemical composition present on or in one of the surface layers of a pharmaceutical sample or within the parent material may be very depreciated at multiple points in time' to allow the skilled artisan to sketch at certain points in the process. A pharmaceutical dosage form or its stability to time. U.S. Patent No. 6,067,154 discloses an apparatus and method for the manufacture of semiconductor wafer fabrication 1283296 for the inelastic scattering of incident single-energy radiation to stack defects in a semiconductor topography and to obtain such defects. feature. U.S. Patent No. 4,407,008, the disclosure of which is incorporated herein incorporated by reference in its entirety in its entire entire entire entire entire entire entire entire entire entire disclosure Destructive identification.当前 The currently available technology is suitable for surface and elemental analysis, but currently, there is a method that provides non-destructive provision of molecular data of one of the surface layers of a pharmaceutical sample: or the chemical component inside the parent material. "The limitations of today's surgery, there is currently no single-micron image, surface molecular data and, ', or the ability to be used in a variety of pharmaceutical applications and environmental dropouts. Included as a pharmacy for the manufacture of environmentally-friendly environmentally-friendly medicinal materials, the glutinous research in the laboratory environment is measured on a method of molecular data inside the parent material or in a destructive manner in a single pharmaceutical sample. A method of non-good 1 =- human micro-h sub-data and I-set. In addition, the most embarrassing or maternal sputum is obtained in the single-pharmaceutical sample - the surface screen ^ inside the k parent material < Method and apparatus for pharmacy application and environment on a surface layer, micro-bee and used for various 20 1283296 [Summary of the Invention] Briefly, the device of the present invention includes - a mass generating device, a detecting device and A molecular data of a chemical component of a sample of 信~, a letter of learning. The image is fitted with a sample-image. The signal is generated and the source is used and (4) is measured from the scattering of the sample. The radiation is provided by the plaque - in the sample f f ^. The location. μ Self-Propagated Molecular Data The method of the present invention comprises the steps of: generating an image; using the image to confirm and select the parent of the sample to obtain a molecular subtraction. The present invention may be embodied in a variety of modifications and alternative forms, and the present invention is not limited to the details and the detailed description in the specification. The system refers to (4) the form in the specification. On the contrary, the invention is intended to cover the invention and the scope of [Embodiment] In an embodiment of the method and apparatus of the present invention, the imaging device includes an ESEM for generating a _ pharmacy sample image, a Wei scanning electron microscope, and a reproducible placement of the sample. Automatic station. 1283296
本沒變。-料心、㈣化或根 «-BSBM 輻射束。然後由該ESEM谓測 生第政射 合詳細次微米f彡像。該樣本 ^ 束而提供一綜 用來使該信號產生裝置可= = = = = = = 15This has not changed. - Center of care, (four) or root «-BSBM radiation beam. The ESEM is then used to measure the detailed sub-micron image. The sample is provided as a composite to make the signal generating device == = = = = = 15
ESBM 線輻㈣除或抵銷。4此技藝者所知的方式當作基 =知束:=產生裝置的動態使用可藉由熟習此： •11- 1283296 該ESEM影像的大小亦可 小而異。 該掃描區的大小取決於分析所需的 =威這是由樣本大 小、有關所要尋求之分子資料之-藥學組合物内戒上之化 學組用入射韓射束源的數量決定。 本發月實細例包含-咖Μ自動檯，藉以讓樣本可以 :二„自動檯上。此置放方式能促成就一段目標 夺間f 一樣本内或上之料位置收集分子資料且其是由一 亥自動k内之置放裝置提供。所設想的置放裝置容許 :樣本在起料狀後铸且在賴㈣放上以自複數個| :繪：置，額外資料。該置放裝置非侷限性包含一讓一 卞附著的樣本板及—用來將該樣本板可再現地放在 该自動棱上_本板對準裝置。該樣本板鱗裝 性包含S1定於該樣本板與自動檯之_對 ^ 15 :是標記在自動棱上或凹刻入自動楼内之格線或 在本發明方法及裝置之一實施例中 括用來從樣本上或内之一位置產生」:射c置包 個入射輻射束源。 置產生祕‘射㈣的複數儀 20 系二ί:入射輻射源可為利用同時地與-利用-電腦 糸統標疋的標緣位置對準。 电細 韓射ί發Ϊ之實施例包含—拉曼光譜學系統做為第-入射 =射源。第二入射輻射源可為選自一額外的拉曼光譜學系 在本發明方法及裝置之一實施例中，偵測裝置包括用 -10 1283296 來偵測來自該位置之散射輻射彳 裝置。 文為为子資料的複數個偵測 該複數個偵測裝置包含從—笛 置選出的至少一個偵測裝置。 第一和第二偵測裝 本：明實施例包含-做為第，裝 系統。第二偵測裝置可為選自一額 又尤”曰予 , At ；額外的拉曼光譜學系統。 第一偵裝置可為選自此蕙分散χ射線 EDX得為在需要元素分析時加人以料—樣本的^素先址 /?A4 本說明書中所述 '、拉曼光譜學系統 sPeCt騰。Py system)M系指用以從一樣本獲得分子資 散射輻射強度和頻率的任何測量方式。在—拉 15 統中’-來自-雷射之單能細束人射在1分析ϋ = 且偵測因分子振動而散射的_。大部分輕射是彈 射，是以在散射過程中沒有能量或頻率變化。 月 ，會改變-分子之極化度的分子振動，一小部:;的輕 疋非彈性散射。此等振動被稱為是、、拉曼活性（RanJ a—1。散射輻射是利用一單色器和偵測器獲 射輻射之強度是對上波數標繪且在入射輻射之波數包括L 大波峰及在該大波峰之任一側包括一群小波峰，二者是在 較高和較低的波數。一拉曼波峰之波數與入射輻射之^數 之間的差對應於相關振動模式的頻率。因此，類似於其他 光譜學方式（例如IR吸收光譜術），得到—給定化學組份 之—特有標誌。然而，拉曼光譜學具有入射輻射之頻率^ -Π - 20 1283296 一定要符合欲偵測振動模式之頻 =:=r:r 一雷=== 率、—射能在欲分析 因此，-拉曼光譜學系統的使用讓 ESEM影像提供之細節和精度相符，免；J ; :技，之其他娜式(非二= 幻如光干顯彳政術、SEM和IR)的問題。 10 本發明實施例包含一種方法及裝置，其中最好該拉曼 3學系統是餘曼微探針構造。在此—構造巾，入射拉 j射束聚域-大約丨微㈣光點，且藉此從照射光點 的^鄰附近收缝雜曼輻射。依此方式，可分析一樣本 ^ 一非常小輯。樣本位置所分析到騎度取決於入射拉 支束的穿透深度，而此穿透深度是取決於入射拉曼束被樣 士，收的程度。由於吸收率是取決於入射輻射的能量，較 面能量的輻射會被更強力吸收，輻射之穿透深度可由改變 其能量的方式改變。 因此，在使用一拉曼光譜學系統時，對一藥學樣本上 或内之位置的分析可藉由改變入射拉曼束之能量而增強。 舉例來說’分析可能是限制在樣本表面以查驗表面化學組 份’或者是在一加大深度進行以查驗在樣本母質内部的化 學組份。 在本發明方法及裝置之一實施例中，標繪裝置包括用 來標繪和儲存一位置所在並將分子資料與該位置匹配的成 20 1283296 像軟體及-用來使信號產生裝置對準ESEM影像上之位置 所在的整合系統。 -旦從藥學樣本上或内之—位置獲得賴分子資料， 成像軟K #定ESEM f彡像標繪並儲存錄置所在及對 應为子:貝料此幸人體亦容許一位置圖和一選定esem影像 引入且與位置所在相互關聯以供一真實樣本作後續分析。 後續分子資料亦經儲存並提供作比較。 、用來,心號產生裝置與就- ESEM影像標繪之位置對 ，的整：系統彡i%接於信號產生系統並與其聯絡的電腦 糸統4電⑹彡、统針對任何指㈣標纟t位置控制複數個入 ^輻射源的^和校直且將這些位置通知該信號產生裝 货署^撼號產生裴置使得樣本之選定位置與信號產生 裝置對準。 15 +整&系、先亦可包含能同時以—人射ESEM束進行樣 子資E=M影像且以—人射拉曼束掃描而獲得分 測二未標繪樣本二方;:區^用拉曼光_量_ 20 白動統經由一自細交直裝置控制簡 置，弊該自動檯連接於該自動檯校直裝 轉運‘和心運2檯回應於電腦系統指令在-水平面内旋 褒置 μ運動’從而使樣本之敎位置對準信號產生 射技==動檯校直裝置包含一用以施行-雷射反 射和偵測器，藉此對準藥學樣本以建立一起始 -15- 1283296 =考位置。視需要，該電腦系統儲存一給定樣本 水平旋轉和徑向坐標做為一特定影像之一位置圖。 些掃描系統具有5丨人—位置圖的能力。在掃描美 =的情況中，需要相t,j、_修改以促成掃糾置與二 描硬:t:校直’因為該系統在系統基本構造中包㈣ =一方面，拉曼光譜學並非原本就是一掃描基測 式。有關一樣本之組成的資訊可從在單一位置的一個 獲得，其中記錄著拉曼散射輻射的強度對上波數。因此: =曼光譜學綠的基本構造糾―定要包含掃描硬體和軟 本發明的修改型一其中一拉曼光譜學系 ESEM之照明區對準一次微米化學組份之一選定:一 置-遠大於其他靠基丨_情況所要求。此外，與:位 一併使用之拉曼光譜學迄今為止未曾用於藥業^ Μ 藥學樣本之一表面層或母質。 、一分析 因此，一掃描基系統與一拉曼光譜學系 驗此等化學組份的組合呈現出本發明所解決的查 此外，預期中本發明裝置是以一大致不同於當今减。 之其他組合掃描基系統（非侷限性舉例來說包人*所知 學顯微鏡、電子顯微鏡或SEM結合一 ° =使用一光 統作分析）的方式使用。 ㈣或说光譜學系 特疋言之 个版％权伢就一給定藥學樣本 繪位置之次微米影像，利用一拉曼微探針改變在 1283296 衣度’可再現地定位樣本複數次以在複數個位置 = 業產業進行品質控制之強力工具的 供覃之下，^今所知掃描分析系統僅能就一樣本提 π早的形貌或元素資訊。 j毛明更涵蓋一種用來非破壞性地獲得在單一藥學樣 資ί且或内或是母質内部之不同時間次微米分子 用於夕樣藥學應用和環境的方法。 用該下步驟··產生一藥學樣本之一影像；利 對相4 並選擇該樣本之母質上或内之一位置，使複 測自對準該選定位置且利用複數個偵測裝置偵 組成。" 摘之1^的強度和頻率，藉以自此獲得分子 本發明方法包括以下步驟： 15 動檯本裝載至本發明所述裝置之-樣本板或自 (車又佳來說，將該樣本固定於該樣本板上且 ίϋΐΓ樣t板定位在該自動檯上藉以讓該樣本板可 T準為可在不同時間可再現地置放於該自動檯上）· 以基系統(較佳為利用一職)照射該樣本 从座生一影像； 利用該影像標綠或選擇-在該樣本之母質上或 置（較佳來說’位置圖具有就-給定位置和 不同時間獲得的坐標和分子資料）； 4存之於 使複數個入射輻射源對準於選定位置（較佳來說，其 中至少-人射輻射源設定於i擇為提供—期望的樣本穿 -17- 1283296 透深度的頻率）； 利用複數個偵測裝置偵測自該位置散射之輻射的強度 和頻率〔較佳來說，散射輻射之強度和頻率偏移可與分子 資料（針對一特定化學組份之標準分子資料或是先前在選 定位置獲得之組份分子資料）作比較〕以獲得該位置的分 子資料。 10 20 分析作業可利用不同入射輻射源和頻率及其他位置重 複進行以綜合性地獲得一給定樣本在複數個位置和深度的 複數個形貌、元素暨化學資料。整個程序可同樣地用於其_ 他樣本重複進行。 本發明以一複合的norelgestromin/炔雌醇經由皮膚膏 藥劑量形式之一安定性檢驗應用為例作說明。將一炔雌醇 /舌性藥物分子之位置與一 norelgestromin活性藥物分子作 區分且在膏藥層系列内的黏性層中尋得。ESEM影像能讓 母質内的藥物位置標繪於一毫微米以内且讓其結構受分 析。藉此獲得一炔雌醇活性藥物化學組份的位置和分子資 料。分子資料非侷限性包含濃度範圍，其在與ESEM影像鲁 、七合時此確_體經由皮膚劑量形式内之結晶態或非晶態 的存在與否。在就其他位置重複此程序時，獲得從閉合背 襯層經黏㈣flj黏性處理襯塾之經由皮膚膏藥的母 炔雌醇組成外觀。 、幻 本發明更以對—有掩味塗層之藥錠劑量形式之藥 =應用為例。在藥錠上複數處判定塗層 辦 传用以判定—掩味劑之均勻度的分子資料，從而判定= -18- 1283296 的塗層性能。 在以上及其他涵蓋於本發明範圍内之藥學應用中 壞;=3比較複數個藥物劑量形式之生產批次的非破 母曾ί照f式’圖1纷出一用來從一藥學樣本之表面上或 =之-選定位置獲得—化學組份之分子資 2實施例的側立面圖。在本實施例中，一化 〔 彻拉曼光譜學獲得一樣本3放在—膽Μ : 上且％到來自—ESEM 1之人射輻射束2昭射，夢《 置束:6:7，。推導:‘ 7發送給—拉曼雷射6U由一中繼裝置 ^ _ 7 ^也細糸統9(藉此將坐標6栌 =定咖Μ影像5之一位置圖1〇且為特定樣二 16 , 1 ^ 4 勹匕3 W八将疋樣本3之一位置圖( *；ίΓ™ 動自動動檯校直裝置11旋轉地或徑向地移 =2:選定位置16與拉曼雷射源8對準。因此， 猎由移動拉X雷射源8或ESEM自 擇並麟其他咖Μ影像5和位置16。之位置的方式選 入射輻射束12 (以_具有顯示方 表不)從拉曼雷射源8(其中拉曼雷射源8是== 1283296 n 針構造）產生，且由一拉曼收集系統14收集一 之散射輻射束13(以-具有顯示方向之箭頭自=16 並產生一強度-波數影像15。位置16之分子^虛線表不） 數影像15表現。電腦系統9經由影像分析軟體將波 與強度-波數影像15結合而提供一輸出17。并 圖10 从枝〜挺丄， w因此輸出17提 供-^樣本3之-特u随影像5内複數個位置= 幾何負訊和化學鍵資訊 10 位置坐標6通常是ESEM影像5内—位置16的三維 x-y-z坐標。視需要，位置坐標6可包含其他資訊，例如在# 位置16受分析之區域的大小。位置16之z坐標係從拉曼 雷射源8所產生之入射拉曼束12的頻率推導出。利用多樣 發信裝置’中繼裝置7可將坐標6從電腦系統9送到拉曼 雷射源8及反過來從拉曼雷射源8送到電腦系統9。視需 要，坐標6可以是在中繼裝置7與拉曼雷射源8和電腦系 統9之間有或沒有一永久性連接的狀態下傳送。所設想中 繼裝置非侷限性包含硬體線路、資訊存儲媒體或無線電 波。拉曼雷射源8最好是成一拉曼微探針構造。入射拉曼籲 束12被導往之小區域（通常小於丨微米）使一微探針構造 適合为析在一藥學樣本之表面上或母質内尋得的眾多化學 目標。亦可以位置16之強度-波數影像15與一參考用標準 光譜之強度-波數作比較以更進一步且更快地確認位置16 之一化學組份。 圖2為一由圖1裝置產生之ESEM影像5之一實施例 的透視圖。在本實施例中，一中心點18及離中心點18 一 -20- 20 1283296 段，離之位置16的二維x_y坐標6於ESEM影像$内進行 演算比較並儲存於電腦系統9内。利用中心點18當作一參 考點’可從中心點18以三角測量方式定出一 esem影像5 内其他位置16的二維x-y坐標6。 圖3顯不圖1所含ESEM自動棱4之一實施例的透視 圖。在本實施例中，一樣本板19藉由固定在樣本板與自動 楼間之1位銷20可移除地且可定位地在自動檯4上對準。 、、熟I此技藝者會輕易瞭解到本發明提出一種用來辨識 並選擇_學樣本之一表面層上或内或是母質内部之一化春 ίο 學組份的位置且用來獲得該樣本之非破壞性、可再現分子 特徵的方法和裝置。熟習此技藝者在閱覽本說明書時會想 到本發明各項觀點的其他修改和替代實施例。吾人想要以 下申請專利範圍解釋為涵蓋所有此等修改和變化，且因此 應以範例說明而非限制意義來看本說明書及圖式。 15 【圖式簡單說明】 圖1為一本說明書所揭示裝置之一實施例的侧立面圖；_ 圖2為一由圖1所示裝置產生之樣本影像之一實施例 的透視圖；且 20 圖3為一圖1所示自動檯之一實施例的透視圖。 【主要元件符號說明】 代表符號名稱 1 ESEM (環境掃描電子顯微鏡） •21- 1283296 2 入射輻射束 3 樣本 4 ESEM自動檯（散射ESEM束） 5 ESEM影像 6 位置坐標 7 中繼裝置 8 拉曼雷射源 9 電腦系統 10 位置圖 11 自動檯校直裝置 12 入射輻射束 13 散射輻射束 14 拉曼收集系統 15 強度-波數影像 16 位置 17 輸出 18 中心點 19 樣本板 20 對位銷（alignment pins ) -22-ESBM spokes (4) are eliminated or offset. 4 The method known to the skilled person is used as the base = knowing beam: = the dynamic use of the generating device can be obtained by familiarizing itself with this: • 11- 1283296 The size of the ESEM image can vary from small to small. The size of the scan area depends on the amount of fluorescence required for the analysis. This is determined by the size of the sample and the molecular data to be sought - the chemical composition within the pharmaceutical composition is determined by the number of incident Korean beam sources. This month's actual case contains a - curry automatic table, so that the sample can be: two „automatic on-board. This placement method can promote the achievement of a target area. The molecular information in a sample or in the sample is collected and it is It is provided by the placement device in the one-automatic k. The envisaged placement device allows: the sample is cast after the material is taken and placed on the Lai (4) to be self-complexed |: painted: set, additional information. Non-limiting features include a sample plate attached to the cassette and - for reproducibly placing the sample plate on the automatic edge - the plate alignment device. The sample plate includes S1 set to the sample plate and _ _ 15 : is a grid line marked on the automatic edge or recessed into the automatic building or in one embodiment of the method and apparatus of the present invention for generating from one position on or within the sample": The shot c is packaged with an incident radiation beam source. A multi-function device that generates a secret (four) 20 system two: the incident radiation source can be aligned with the position of the edge of the 利用 疋 同时 。. The embodiment of the electric ray 包含 Ϊ 包含 includes a Raman spectroscopy system as the first incidence = source. The second source of incident radiation may be selected from an additional Raman spectroscopy system. In one embodiment of the method and apparatus of the present invention, the detecting means includes -10 1283296 to detect the scattered radiation 彳 device from the location. The text is a plurality of detections of the sub-data. The plurality of detection devices include at least one detection device selected from the flute. The first and second detecting packages: the embodiment includes - as the first, mounting the system. The second detecting device may be selected from the group consisting of one and the other, At; additional Raman spectroscopy system. The first detecting device may be selected from the 蕙 dispersed X-ray EDX to be added when the elemental analysis is required. Material-sample 先 先 / /? A4 ', Raman spectroscopy system sPeCtTeng. Py system) M refers to any measurement method used to obtain the intensity and frequency of scatter radiation from the same source. In the - pull 15 system '--from the laser single-beam fine beam shot in 1 analysis ϋ = and detect the scattering due to molecular vibration _. Most of the light shot is ejected, so there is no scattering process The energy or frequency changes. Months, will change the molecular vibration of the molecular polarization, a small part:; the light and inelastic scattering. These vibrations are called y, Raman activity (RanJ a-1. Scattering Radiation is the intensity of the radiation emitted by a monochromator and detector. The intensity of the upper wave is plotted and the wave number of the incident radiation includes the L large peak and a small peak on either side of the large peak. Is at the higher and lower wavenumbers. The number of waves in a Raman peak and the number of incident radiation The difference corresponds to the frequency of the relevant vibration mode. Therefore, similar to other spectroscopy methods (such as IR absorption spectroscopy), a unique signature for a given chemical component is obtained. However, Raman spectroscopy has the frequency of incident radiation^ -Π - 20 1283296 Be sure to match the frequency of the vibration mode to be detected =:=r:r a mine === rate, - the energy of the shot is to be analyzed, therefore, the use of the Raman spectroscopy system gives the details of the ESEM image Consistent with precision, exempt; J; : technology, other Na's (non-two = illusory, SEM, and IR) problems. 10 Embodiments of the present invention include a method and apparatus, preferably The Raman 3 learning system is a Yuman microprobe construction. Here, the construction towel, the incident j-beam convergence domain - about the micro (four) light spot, and thereby narrowing the neighboring radiation from the vicinity of the illumination spot In this way, the same can be analyzed. The sample position is analyzed according to the penetration depth of the incident pull beam, and the penetration depth is determined by the incident Raman beam. Degree, because the absorption rate is dependent on the energy of the incident radiation, the face The amount of radiation is absorbed more strongly, and the penetration depth of the radiation can be changed by changing its energy. Therefore, when using a Raman spectroscopy system, the analysis of the position on or within a pharmaceutical sample can be made by changing the incidence. The energy of the Raman bundle is enhanced. For example, 'analysis may be limited to the surface of the sample to examine the surface chemical composition' or at an increased depth to examine the chemical composition inside the sample parent material. In one embodiment of the apparatus, the plotting device includes a 20 1283296 image software for mapping and storing a location and matching the molecular data to the location, and - for aligning the signal generating device to the location on the ESEM image The integrated system in which it is located. - The molecular data obtained from the position on or within the pharmaceutical sample, the image of the soft K #定 ESEM f彡 image plot and store the record and correspond to the child: the shell material is also allowed The location map and a selected esem image are introduced and correlated with the location for a real sample for subsequent analysis. Subsequent molecular data is also stored and provided for comparison. , used, the heart number generating device and the location of the - ESEM image plotting, the whole system: 彡i% connected to the signal generation system and connected with the computer system 4 (6) 彡, unified for any finger (four) standard The t position controls a plurality of inputs and alignments of the radiation source and informs the signals of the positions to generate a loading device such that the selected position of the sample is aligned with the signal generating device. 15 + whole & first, can also include the E-M image that can be simultaneously taken by the human-ESEM beam and the two un-sampled samples obtained by the human-shooting Raman beam scan; With Raman light _ quantity _ 20 white mobile system through a self-fine cross-control device control set, the automatic station connected to the automatic station straight-loading transport 'and heart transport 2 in response to computer system instructions in the - horizontal plane Setting the μ motion 'to align the position of the sample with the signal to generate the shot technique == The moving table alignment device includes a laser-reflecting and detecting device for aligning the pharmaceutical sample to establish a start -15 - 1283296 = test position. The computer system stores a given sample horizontal rotation and radial coordinates as a position map for a particular image, as needed. These scanning systems have the ability to have 5 person-position maps. In the case of scanning beauty =, phase t, j, _ modification is required to facilitate sweep correction and second description hard: t: straightening 'because the system is packaged in the basic structure of the system (four) = on the one hand, Raman spectroscopy is not Originally it was a scanning basis test. Information about the composition of the same can be obtained from one at a single location, where the intensity of the Raman scattered radiation versus the number of waves is recorded. Therefore: = The basic structure of the spectroscopy green is determined to include the scanning hardware and the soft modification of the invention. One of the Raman spectroscopy ESEM illumination zones is aligned with one of the micron chemical components selected: - Far greater than other requirements based on the base _ situation. In addition, Raman spectroscopy used in conjunction with: has not been used in the pharmaceutical industry for one of the surface layers or parent materials of pharmaceutical samples. An analysis Thus, a combination of a scanning base system and a Raman spectroscopy system to characterize such chemical components exhibits a solution ascertained by the present invention. Further, it is contemplated that the device of the present invention is substantially different from today's. Other combinations of scanning-based systems (for non-limiting examples, such as microscopy, electron microscopy, or SEM combined with the use of a light system for analysis). (d) or a version of the Department of Spectroscopy special % 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 伢 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 Multiple locations = Under the supply of powerful tools for quality control in the industry, the scanning analysis system known today can only provide the same morphological or elemental information. j Maoming further encompasses a method for non-destructively obtaining sub-micron molecules in a single pharmaceutical sample and/or within the parent material for use in a medicinal application and environment. Using the next step, an image of a medicinal sample is generated; the phase 4 is selected and a position on or within the parent material of the sample is selected, so that the retest is self-aligned to the selected position and is detected by a plurality of detecting devices. . " Extracting the strength and frequency of the 1 ^ to obtain the molecule therefrom, the method of the invention comprises the following steps: 15 loading the table to the device of the invention - the sample plate or from (the car is also good, the sample Fixed on the sample plate and positioned on the automatic stage so that the sample plate can be reproducibly placed on the automatic stage at different times. a job) illuminating the sample from the image of the seat; using the image to mark the green or select - on the parent of the sample or (preferably the position map has the coordinates obtained at the given position and at different times) Molecular data); 4 is present for aligning a plurality of incident radiation sources to selected locations (preferably, at least - the human radiation source is set to provide a desired - the desired sample penetrates the depth of the -17 - 1283296 penetration) Frequency); detecting the intensity and frequency of radiation scattered from the location using a plurality of detection devices (preferably, the intensity and frequency offset of the scattered radiation can be correlated with molecular data (standard molecular data for a particular chemical component) Or previously selected The molecular data of the component obtained by the position is compared] to obtain the molecular data of the position. 10 20 Analytical operations can be repeated using different sources of incident radiation and frequency and other locations to comprehensively obtain a plurality of topographical, elemental, and chemical data for a given sample at a plurality of locations and depths. The entire program can be used equally for its _ other samples to be repeated. The present invention is exemplified by a composite norelgestromin/ethinylestradiol via a stability test application of a skin cream dosage form. The position of the ethinyl estradiol/tongue drug molecule is distinguished from a norelgestromin active drug molecule and found in the viscous layer within the plaster layer series. The ESEM image allows the position of the drug in the parent material to be plotted within one nanometer and its structure to be analyzed. Thereby, the position and molecular information of the chemical component of the active drug of ethinyl estradiol are obtained. The non-limiting nature of the molecular data includes the concentration range, which is the presence or absence of a crystalline or amorphous state within the skin dosage form when it is combined with the ESEM image. When this procedure was repeated for other locations, the appearance of the ethinyl estradiol via the skin plaster from the closed backing layer via the sticky (iv) flj viscous treatment liner was obtained. The invention is further exemplified by the use of a drug in the form of a dosage form of a taste-masking coating. The coating was used to determine the molecular data used to determine the uniformity of the taste-masking agent at a plurality of points on the tablet to determine the coating properties of = 18-1283296. In the above and other pharmaceutical applications covered by the scope of the present invention; = 3 compared to a plurality of pharmaceutical dosage forms of the production batch of the non-broken mother Zeng Li Zhao f formula 'Figure 1 is used to a sample from a pharmaceutical A side elevational view of the embodiment of the chemical component 2 obtained on the surface or at the selected location. In the present embodiment, the chemistry [Cheraman spectroscopy obtains the same as the cholesteric: and the % to the ESEM 1 of the human radiation beam 2, the dream "Bundle: 6:7, . Derivation: '7 sent to - Raman laser 6U by a relay device ^ _ 7 ^ also fine 9 9 (by taking the coordinates 6 栌 = fixed coffee Μ image 5 position 1 〇 and specific sample 2 16 , 1 ^ 4 勹匕 3 W 疋 疋 疋 3 之一 之一 之一 疋 疋 ( ( ( ( ( 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋8 Alignment. Therefore, the hunter is selected by moving the X-ray source 8 or ESEM and selecting the position of the other curry image 5 and the position 16. The incident radiation beam 12 (with _ having the display side not) is pulled from A Man Ray source 8 (where the Raman source 8 is == 1283296 n needle configuration) is generated and a scattered radiation beam 13 is collected by a Raman collection system 14 (with - an arrow with a display direction from = 16 and An intensity-wavenumber image 15 is generated. The numerator of position 16 is shown by the dashed line. The number of images 15 is represented. The computer system 9 combines the wave with the intensity-wavenumber image 15 via the image analysis software to provide an output 17 and Figure 10 Branch ~ quite 丄, w so the output 17 provides -^ sample 3 - special u with image 5 within multiple positions = geometric and chemical information 10 position coordinates 6 is usually ESEM image 5 - the three-dimensional xyz coordinates of position 16. The position coordinates 6 may contain other information, such as the size of the region being analyzed at # position 16. The z coordinate of position 16 is incident from the Raman laser source 8. The frequency of the Raman beam 12 is derived. The relay device 7 can be used to send the coordinates 6 from the computer system 9 to the Raman laser source 8 and vice versa from the Raman laser source 8 to the computer system 9 If desired, the coordinates 6 may be transmitted with or without a permanent connection between the relay device 7 and the Raman laser source 8 and the computer system 9. The relay device is not limited to include hardware circuits. , information storage medium or radio waves. Raman laser source 8 is preferably constructed as a Raman microprobe. The incident Raman beam 12 is directed to a small area (usually less than 丨 micron) to make a microprobe construction suitable For the analysis of many chemical targets found on the surface of a pharmaceutical sample or in the parent material, the intensity-wavenumber image 15 of position 16 can be compared with the intensity-wavenumber of a reference standard spectrum to further and faster. Confirm the chemical component of position 16. Figure 2 shows A perspective view of an embodiment of an ESEM image 5 produced by the apparatus of Figure 1. In the present embodiment, a center point 18 and a center point 18 - 20 - 20 1283296, a two-dimensional x_y coordinate from position 16 6 Calculated and stored in the ESEM image $ and stored in the computer system 9. Using the center point 18 as a reference point, a two-dimensional xy of another position 16 in the esem image 5 can be determined from the center point 18 by triangulation. Coordinate 6. Figure 3 shows a perspective view of one embodiment of the ESEM automatic rib 4 included in Figure 1. In this embodiment, the same plate 19 is movable by a pin 1 fixed between the sample plate and the automatic floor. Aligned on the automatic table 4 in addition to the ground. The skilled person will readily appreciate that the present invention proposes a position for identifying and selecting one of the surface layers on or within the surface of the sample or the internal component of the parent material and used to obtain the A method and apparatus for non-destructive, reproducible molecular features of a sample. Other modifications and alternative embodiments of the various aspects of the invention will be apparent to those skilled in the art. The scope of the following patent application is intended to cover all such modifications and variations, and therefore, the description and drawings are intended to be illustrative and not restrictive. 15 is a side elevational view of one embodiment of the apparatus disclosed in the specification; FIG. 2 is a perspective view of an embodiment of a sample image produced by the apparatus of FIG. 1; 20 is a perspective view of an embodiment of the automatic station shown in FIG. 1. [Main component symbol description] Representative symbol name 1 ESEM (Environmental Scanning Electron Microscope) • 21- 1283296 2 Incident beam 3 Sample 4 ESEM automatic table (scattered ESEM beam) 5 ESEM image 6 Position coordinates 7 Relay device 8 Raman Ray Source 9 Computer System 10 Location Figure 11 Automatic Table Straightening Device 12 Incident Radiation Beam 13 Scattered Radiation Beam 14 Raman Collection System 15 Intensity - Wave Number Image 16 Position 17 Output 18 Center Point 19 Sample Plate 20 Alignment Pins ) -twenty two-