TW200800354A - Concentration crystallizer and method - Google Patents

Concentration crystallizer and method Download PDF

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TW200800354A
TW200800354A TW095139925A TW95139925A TW200800354A TW 200800354 A TW200800354 A TW 200800354A TW 095139925 A TW095139925 A TW 095139925A TW 95139925 A TW95139925 A TW 95139925A TW 200800354 A TW200800354 A TW 200800354A
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concentration
concentrated liquid
conductivity
concentrated
acid
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TW095139925A
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Motoharu Kinoshita
Hideki Murata
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Kyowa Hakko Kogyo Kk
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Description

200800354 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種用以分離精製胺基酸、 — 核酸驗基、核芽、類、或者維生素類之天;：物、三肽、 万汝t具體而吕，本發明提供一種用以_ ▲ 天然物之裝置及方法，直由* 6人士 精氣焉純度 缺物進行:農缩”“ 有天然物之溶液中將天 …、物進仃/辰鈿晶析時，測定供給至濃縮 量，且控制為適當之濃缩产，蕤 、 之鹽的總 田芡/辰細度，猎此進行分離 【先前技術】 " 作為自含有胺基酸或胜肽等天㈣或成 液中分離精製目標成分之方法’例如目前 等之結晶化。 辰％日曰析 例如，於曰本專利第觸56號說明書中，揭示有 吸附於離子交換樹財，屬進行溶離再進行晶析之先^ 方去中之排水處理問題’並且併用用以以高回收率分離古 品質胺基酸之濃縮晶析及冷卻晶析之方法。又， 2 利第3525 126號說明蚩中，福+古叮 〜兄“中’揭不有可利用溫差來獲得控制 夕曰S型之胺基酸結晶之濃縮晶析方法。 於濃縮晶析中’將含有目標物質的溶液濃縮度設定為較 高係與高回收率相關的，因此必須盡可能設定為高濃縮 度。然而’通常於天然物之被濃縮液中，除目標物質以 外，作為使天然物以發酵等方法進行製造時的添加物，或 對天然物進行精製時之酸處理、鹼處理或中和處理中所使 用之處理劑’亦包含如硫酸鈉、磷酸銨、氯化鈉等鹽之強 115786.doc 200800354 電解質。因此，若 — 標物質而且有強電解質::=農縮:控制，則不僅有目 純度降低。 出，《而導致目標物質之 為控制濃縮度而伴拄 a 中所含鹽之總量。若二：：壤縮度，必須瞭解被濃縮液 液之鹽濃度求出鹽她量。=㈣晶析’則易於根據投入 (若以連續方式持二 缩曰4的；辰縮晶析，則中止濃 ==濃縮罐…料全部排出，重新二： 方式）之情形時，並不-直將聲濃度固 疋之被？辰縮液供給至濃_I 又 均句…，又無法於濃縮裝置内獲得 因此、「 此難以求出供給至濃縮裝置内之鹽總量。 物質之鹽結晶意外地析出為了避免並非目的 析出必須將濃縮度設定於如鹽濃度 達到鹽析出濃度的具有餘地之低濃縮度β k因此，業者一直在謀求於連續式或者饋料批次（feed batch)式濃縮晶析中控制適當濃縮度之方法。 [專利文獻1]日本專利第2668956號說明書 [專利文獻2]日本專利第3525126號說明書 [發明所欲解決之問題] 本發明之目的在於提供一種於連續式或者饋料批次式濃 縮B曰析中，控制適當濃縮度，而以高回收率分離品質穩定 天然物之方法。 【發明内容】 本發明係關於以下（1)至（14)項者。 115786.doc 200800354 (1) 一種濃縮裝置，其特徵在於：其包含容納應進行濃縮 處理之被濃縮液之機構、將被濃縮液供給至容納上述被濃 縮液的機構之機構、以及將被濃縮液的溶劑蒸發以進行濃 縮處理之蒸發機構； 能夠連續測定在供給上述被濃縮液機構内流動的被濃縮 液之導電度及供給流量之、測定被濃縮液的導電度之機構
以及測m至容納上述被濃縮液機構中的被濃縮液供給 流量之機構。 (2) 如第（1)項之濃縮裝置，其進而包含演算導電度與供 給流量的乘積之演算機構、以及將所獲得之乘積進行累: 之累計機構。 其進而包含具有能夠監控導 供給流量的乘積的累計值之 (3)如第（2)項之濃縮裝置， 電度、供給流量以及導電度與 功能之機構。 (4) 一種濃縮方法
至容納被濃縮液之機構中 行濃縮處理之濃縮方法； 其特徵在於··其係於將被濃縮液供給 Μ而蒸發被濃縮液的溶劑以進 測定在供給被濃縮液的機構内流動的被濃縮液之導電度 及供給流量，演算_定的導電度與供給流量之乘積，進 之 而於藉由將該乘積進行¥ e 系°十而獲仔的累計值達到特定值 時間點結束濃縮處理。 &，其中 之溶液， (5)如第（4)項之濃縮方 弱電解質與強電解質共存 被濃縮液係非電解質或 將非電解質或弱電解質 115786.doc 200800354 進行濃縮晶析。 (6 )如弟（5)項之、、歲 + 質，係選自含中性:二法’其中非電解質或者弱電解 類、以及維生素類之群胜肽、核酸驗基、μ、， (7)如第（6)項 > :曲w ^ 胺酸、穀胺酸、、丙^ 其中中性胺基酸係選自含絲
胺—丙胺酸、亮胺酸、纈胺酸、異亮胺酸、甘 *夂本丙胺酸、脯胺酸、酪胺酸、蘇胺酸、色胺酸、甲 石瓜胺酸:半胱胺酸、胱胺酸及天冬醯胺酸之群。 ()如第（6)項之濃縮方法，其中胜肽為二肽或三狀。
(9)如第（6)項$ :普^ L 、，辰細方法，其中胜肽為丙胺醯基麩醯胺 或谷胱甘肽。 (〇)如第(6)項之濃縮方法，其中核酸鹼基係選自含腺嘌 呤、胞嘧啶、良過„入 ^ 75 ^ 久頁σ票呤、胸腺p密咬、尿,咬及黃 嘌呤之群。 、 0 1)如第（6)項之方法，其中核普係選自含腺普、胞會咬 核苷、鳥苷（guanosine)、肌苷及尿苷（uHdine)之群。 (12)如第（6)項之濃縮方法，其中醣類為單糖或2〜5糖之 募糖。 (13) 如第（6)項之濃縮方法，其中醣類為6糖以上之寡 糖。 (14) 如第（6)項之濃縮方法，其中維生素類係選自含維生 素B1、維生素B2、維生素Βό、菸鹼酸、泛酸（pantothenic acid)葉8义生物素（biotin)、肌醇（inositol)、膽驗、維生 素B12、維生素c、維生素L1 '雄生素p、對胺基苯甲酸、 115786.doc 200800354 類脂酸（li—add)、維生素扣、肉驗（㈣niUne)及甲基甲 硫胺酸之群。 本U之/辰Ifs裝置中包含：作為容納應進行濃縮處理之 被濃縮液的機構之濃縮罐、作為將被濃縮液供給至上述容 T被濃縮液機構的機構之被濃縮液供給管、以及作為將被 浪縮液的溶劑蒸發進行濃縮處理的蒸發機構之加熱裝置 或真空裝置。 於本發明中，藉由加熱、減壓或者減壓加熱而使溶劑蒸 發，藉此進行被濃縮液之濃縮晶析。 進而，本發明之濃縮裝置中包含：測定被濃縮液的導電 度之電導計以及測定向容納上述被濃縮液的機構供給被濃 縮液的供給流量之流量計。 因本杳明之裝置包含上述構成，故若較好的是將所供給 的被濃縮液的濃度設為不出現結晶程度之濃度，則亦不會 引起導電度之測定異常，從而可進行長期測定。因此，並 不產生以下問題··於濃縮罐内部包含電導計的裝置中所見 之於濃縮罐内所生成的結晶等固形物所造成的測定值之不 正確性、Α因高濃度溶液而造成於電導計的感測器部中所 產生的定標所導致之測定異常。 於本心明中連績性地測定被濃縮液之導電度以及供給 流量。因導電度與被濃縮液的鹽濃度相關，故導電度與供 給流量之乘積’表示每_單位時間内間接性地供給至濃縮 罐中之鹽量。可根據將該乘積自濃縮開始時起至某時刻為 止進行累計所求得之累計值，而求得至此時刻為止供給至 115786.doc -10- 200800354 濃縮罐中的鹽之總量。 若濃縮罐内的被濃縮液量為固定 定此時濃縮鏺负& ^ 很據累计值來確 物質為：= 縮液之鹽濃度。於濃縮而得之目標 罐2曲Γ質之情形時，藉由測定導電度而求得的濃縮 質之，〆 …辰度可直接表轉騎質之麟強電解 产一吉:生因此可藉由將結束濃縮晶析之時間點之鹽滚 ΐ作為：:恆定值’而進行品質穩定之濃縮…預先確 疋作為雜質之鹽並不析 她Θ 析出所付結阳純度不降低的最大鹽 總1，設定對應於其最她 人—、里之特疋值。在累計值達到 特疋值之時間點結束澧 朴 7 辰縮處理，糟此可成為高濃縮度下之 “，可以高回收率製造高純度結晶。 所，Ρ，/辰％所侍之目標物f係於水溶液中產生電離之物 曰使用目軚物質不產生電離之溶液或者目標物質的 荨電點附近的湓、為从& ^冰 、 / 為被》辰縮液的溶劑，而經由測定導電 度而求得的濃縮罐內曲 内的被浪細液之鹽濃度亦可直接表示作 為雜質的鹽即強雷% _ 解質之丨辰度。因此，如上所述，能夠進 行高濃縮度之濃縮， 、 從而可以鬲回收率製造高純度結晶。 於濃縮所得之目姆 ^^物質為弱電解質、即在被濃縮液中幾 乎不電離而溶解之私併 物貝之炀形時，由該物質的一部分產生 電離所引起之導雷择 、 奄度，幾乎不影響導電度測定，因此藉由 測定導電度而求错+、曲 # 一、 之;辰縮罐内的被濃縮液濃度，可看作直 接表示作為雜質之踏 、 氣的》辰度、即強電解質之濃度。因此， 如上所述，能夠谁么丄 订南〉辰縮度之濃縮，從而可以高回收率 曰曰 〇 製造高純度結曰 U57S6.doc 200800354 作為弱電解質，可列舉：在以1 度溶解於被濃 縮液時之電離度為0.05以下、較好的是〇 〇1以下之物質。 作為可適應本發明之濃縮方法而作為結晶獲得之非電解 質或弱電解質，可列舉：於被濃縮液中以1 m〇1几濃度溶解 時之電離度為0·05以下、較好的是〇〇1以下之物質；可列 舉：中性胺基酸、胜肽、核酸驗基、核皆、酶類、或者維 生素類，較好的是，可列舉：中性胺基酸、胜肽、或者聽 類。 作為中性胺基酸，例如可加斑.μ & a 】々了歹】舉·絲胺酸、縠胺酸、丙胺 酸、亮胺酸、绳胺酸'異亮胺酸、甘胺酸、苯丙胺酸、脯 胺酸、赂胺酸、蘇胺酸、色胺酸、甲硫胺酸、半胱胺酸、 胱胺酸、天冬醯胺酸。 作為胜肽，可列棄·-邮立一 、 盆 肽；料二肽，例如可列 舉·丙fe醯基麩醯胺；作 一 肽。 妝，作為二肽，例如可列舉：谷胱甘 作為核酸鹼基，例如可兴.β 呤、次黃嘌呤、胸胰“牛示胞嘧啶、鳥嘌 兴胸腺嘴啶、尿嘧啶、黃嘌呤。 作為核苷’例如可列爽 普、尿努。 “ ·腺皆、胞喷咬核苦、鳥普、肌 作為醣類，例如可列與·。 之寡糖。 牛早’ 、2〜5糖之寡糖或6糖以上 作為維生素類，例 地丄 可列舉：維生素Β1、維座备no 、准生素Βό、菸鹼酸、 、生素Β2、 維生素β12、維生辛c "、葉酸、生物素、肌醇、膽鹼、 素c、維生素u、維生素p、對胺基苯甲 I15786.doc 200800354 酸、類脂酸、乳清酸、肉鹼、甲基甲硫胺酸。 於本發明中，作為被濃縮液中所含有之強 =在將其則,视濃度溶解於被濃縮斜時的電^ ㈣上、較好的是〇.5以上、更好W上、最好= 〇·9以上之物質，無機物或有機物之鹽。例如可列兴：f 鹽、銨鹽、卸鹽、飼臨算· 一 甲皿^專，具體而言，可列舉：硫酸鈉、 鋼、賴銨、硫酸銨、氯化錄、錢銨、硫酸鉀、二
化鉀、磷酸鉀、硫酸鈣、氯化鈣、磷酸鈣等無機鹽。乳 作為以本發明之方法而供給之被濃縮液，若係含有非電 解質或弱電解質及強電解質之溶液，則可為任意者，可列 舉：自將具有I生非電解質或弱電解質能力的微生物加以 心養而獲得之培養物巾除去微生物之溶液、含有使用酶或 重組微生物等生物觸媒而生成的非電解質或弱電解質之溶 液、含有化學合成所生成的非電解質或弱電解質之溶液 [發明之效果] 根據本發明，於連續式或者饋料批次式濃縮晶析中，可 以高回收率獲得品質穩定之天然物之分離體。 【實施方式】 圖1表示本發明之濃縮裝置之一具體例。利用泵3經由被 濃縮液供給管4，將被濃縮液自被濃縮液貯槽2供給至濃縮 罐1 〇 於被濃縮液供給管4中安裝有流量計5及導電度計6，可 連續性地測定被濃縮液之供給流量導電度C。 115786.doc 200800354 於濃縮罐1之外侧包含外套7,可自蒸氣供給口8供給蒸 氣以加熱濃縮罐1 ’從而使被濃縮液的溶劑蒸發。所供給 之?备氣由热氣排出口 9中排出。又，亦可使用真空裝置（未 圖示）經由真空管丨0使濃縮罐丨内成為減壓狀態，於低溫下 將使濃縮液的溶劑蒸發。又，亦可於減壓狀態下進行加熱 以使濃縮液的落劑蒸發。 /辰縮罐1内的被濃縮液之量，係以經常維持固定液面之 φ 方式、以安裝於濃縮罐1側面的液面計11來控制。 濃縮晶析結束後，解除減壓加熱，排出，將自管12中所 得之漿料排出。 圖2中所示之方塊圖，係表示本發明之濃縮程序者。 作為濃縮晶析之前準備，係將濃縮罐丨減壓，且加熱。 又，輸入對應於應加入濃縮罐i内的被濃縮液中的鹽總量 之特定值V。特定值v取決於獲得結晶之目標物質以及含 有目標物質之被濃縮液成分。 籲 料特定值V’可直接使用應加入濃縮罐】内的被濃縮液 中的鹽總量。又，如上所述，@導電度與被濃縮液的鹽濃 度相關，故導電度與供給總量之乘積，表示間接供給至濃 縮罐之鹽總量。因此’作為特定值V’亦可使用導電度與 供給總量之乘積。 藉由將被濃縮液供給至濃縮罐]，而開始濃縮（將濃縮開 始時設定為測定時刻t=tG)。於開始濃縮之同時，利用流 置計5及導電度計6，開始測定被濃縮液之供給流量F及導 電度C。 115786.doc • 14 - 200800354 :1秒將各自之測定值輸入演算、控制部(未 =之乘積P(，)。自時刻to至測定時刻t，將各時刻的 乘積P值進行累計而·得值為 管出㈣l )。根據該乘積值Q計 内的鹽總量。供給流D、導電度C及乘積值 Q於ς不於，中的監視器’因而能夠進行線上確認。 扩以…t值Q相最#輸人的特定值ν之時間點，結束 農縮之時間點’結束供給被濃縮液，解除減壓加 =排峨。於結束聚料排出之時間點，進行用於 下面濃縮之前準傷。 爹考例1 批==中料之濃縮裝置，應用本發明之方法以饋料 社-人式進行L-党胺酸之濃縮晶析。 於開始濃縮晶析之同時，以導電度計（Endress + H靡[ 公司製’ S職tee c CL則）測仏亮胺酸溶液的導電度 C ’且將其與供給流量F 一併輸入演算及控制部即 CENTUM(橫河電機公司製），演算導電度C與供給流量F之 :積(P:C:F)’進而演算乘積p之累計值Q。濃縮晶析結束 後，測疋濃縮罐1内濃縮處理液之導電度&。 將濃縮處理液的導電度與乘積值Q之關係揭示於圖3。 根據該圖，發現滚縮處理液之導電度CT與累計 有相關性。 ’、 比較例1 現就利用先前方法之L-異亮 為了與實施例1進行比較 115786.doc -15- 200800354 胺酸之濃縮晶析法加以說明。使用圖1中所示之濃縮裝 置，以饋料批次式實施濃縮晶析。於測定條件下，L-異亮 胺酸結晶不析出之最大濃度約為40 g/L，因此將所供給的 L-異亮胺酸溶液之濃度設為35 g/L。又，於該L-異亮胺酸 溶液中，含有由直至獲得溶液之步驟中所添加的硫酸（36 mol/L)及氫氧化納（19 mol/L)所形成之硫酸鈉。 於該先前方法中，僅測定供給流量F，而不進行導電度 測定。 濃縮中，以將漿料的液量保持固定之方式控制供給流 量。此時，所獲得的L-異亮胺酸之回收率為81.0%。將該 胺基酸回收率之結果揭示於表1。 實施例1 現就根據本發明之方法之L-異亮胺酸濃縮晶析法加以說 明。使用圖1中所示之濃縮裝置，以饋料批次式進行濃縮 晶析。於測定條件下，L-異亮胺酸結晶不析出之最大濃度 約為40 g/L，因此將所供給的L_異亮胺酸溶液的濃度設為 35 g/L。又，於該L-異亮胺酸溶液中，含有由直至獲得溶 液為止的過程中所添加的硫酸（36 mol/L)及氫氧化鈉（19 mo 1/L)而形成之硫酸鈉。 於開始濃縮晶析之同時，以導電度計（Endress+Hauser 公司製，Smartec C CLD130)測定L-異亮胺酸溶液之導電 度，將其與供給流量一併輸入作為演算及控制部之 CENTUM(橫河電機公司製），每1秒演算導電度C(mS/cm) 與供給流量F(kL/h)之乘積P，進而演算乘積P之累計值 115786.doc -16- 200800354 Q(kL · mS/cm) 〇 於該累計值Q達到預先輸入的特定值V(kL · mS/cm)之時 間點，停止供給L-異亮胺酸溶液，結束濃縮。相對於L-異 亮胺酸之較佳特定值V之範圍為700〜800 kL · mS/cm，於 本實施例中，將特定值V設定為75 0 kL · mS/cm。 於應用本發明之方法之情形時，L-異亮胺酸溶液之總供 給量，相對於先前方法增加30%，與先前方法相比較濃縮 度亦有所提昇。此時，所獲得之L-異亮胺酸之回收率為 87.4%。將該胺基酸之回收率及純度之結果分別揭示於表1 及表2 〇 實施例2 對L-纈胺酸及L-亮胺酸，亦以與比較例1及實施例1相同 方法實施濃縮晶析。 與測定條件下，L-纈胺酸的結晶不析出之最大濃度約為 60 g/L，因此將所供給之L-纈胺酸溶液濃度設為50 g/L。 又，L-亮胺酸結晶不析出之最大濃度約為25 g/L，因此將 所供給之L-亮胺酸溶液濃度設為23 g/L。 相對於L-纈胺酸之較佳特定值V之範圍為350〜450 kL · mS/cm，於本實施例中，將特定值V設定為400 kL · mS/cm。又，相對於L-亮胺酸之較佳特定值V之範圍為 650〜750 kL · mS/cm，於本實施例中，將特定值V設定為 700 kL · mS/cm ° 將該等胺基酸之回收率及純度之結果分別揭示於表1及 表2 〇 115786.doc 200800354 [表i]
結晶之回收率 本發明之方法 先前方法 L-異亮胺酸 87.4% 81.0% L-纈胺酸 84.7% 80.0% L-亮胺酸 88.5% 78.5% [表2] 結晶之純度及水分量 本發明之方法 先前方法 L-異亮胺酸 70.4% 60-80% (水分 18.8%) (水分 15 — 30%) L-纈胺酸 93.9% 88-97% (水分4.0%) (水分2 —6%) L-亮胺酸 75.2% 70-80% (水分 22.0%) (水分 15 — 25%) 如表1及2所示， 藉由以本發明之方法進行濃縮晶析，而 以與先前方法相同純度之回收率約提昇5〜10%。 【圖式簡單說明】 圖1係本發明中之濃縮裝置之概略圖 0 圖2係本發明中之濃縮程序之方塊圖 〇 圖3係表示本發明中之L-亮胺酸濃縮晶析時的累計值Q與 濃縮處理液的導電度之關係圖。 【主要元件符號說明】 1 濃縮罐 2 被濃縮液貯槽 3 泵 M5786.doc -18- 200800354 4 被濃縮液供給管 5 流量計 6 導電度計 7 外套 8 蒸氣供給口 9 蒸氣排出口 10 真空管 11 液面計 12 漿料排出管 ❿ 115786.doc -19-

Claims (1)

  1. 200800354 十、申請專利範圍： 1 · 一種濃縮裝置，其特徵在於其包含·容納應進行濃縮處 理的被濃縮液之機構、將被濃縮液供給至容納上述被濃 細液的機構之機構、以及使被濃縮液的溶劑蒸發以進行 濃縮處理之蒸發機構，且 上述濃縮裝置中安裝有測定被濃縮液的導電度之機 構、以及測定供給至容納上述被濃縮液機構中的被濃縮
    液供給流量之機構，彼等可連續測定在供給上述被濃縮 液機構内流動的被濃縮液之導電度及供給流量。 2·如請求項1之濃縮裝置，其進而含有演算導電度與供給 流量之乘積之演算機構，以及將所得乘積進行累計之累 計機構。 X 3·如請求項2之濃縮裝置，·其中進而包含具有可監控導^ 度、供給流量以及導電度與供給流量的乘積累計值之工 能之機構。 > 4 · 一種濃縮方法，其特徵在於·使政脸站、曲 竹铖隹於·其係將被濃縮液供給至$ 納被》辰縮液之機福^ ^ rr. μ, -τΗτ 丄 霉、、谨而使被》辰細液的溶劑蒸發以 濃縮處理之濃縮方法，且 測定在供給被濃縮液機構内流動的被濃縮液之 以及供給流量，演瞀奴 J 决^經測定的導電度與供給流量 積，進而於藉由將該乘積 π 谓進仃累计而獲传之累計值逯 特定值之時間點結束濃縮處理。 5·如請求項4之濃縮方法， 、、 /、中被濃縮液係非電解皙弋 電解質與強電解質Α在— 电鮮貝或I …、子之溶液，將非電解質或者弱電角 115786.doc 200800354 質進行濃縮晶析。 6·如咕求項5之濃縮方法，其中非電解質或者弱電解質係 达自由中性胺基酸、胜肽、核酸鹼基、核苷、醣類、及 維生素類所成群。 7·如喷求項6之濃縮方法，其中中性胺基酸係選自由絲胺 秋胺fee、丙胺酸、亮胺酸、纈胺酸、異亮胺酸、甘 本丙私：目文、脯胺酸 '酿胺酸、蘇胺酸、色胺酸、
    曱1胺敲、半胱胺酸、胱胺酸及天冬醯胺酸所成群。 8.如哨求項6之濃縮方法，其中胜肽為二肽或三肽。 9·如請求項6之濃縮方法，其中胜肽為丙胺酿基麩醯胺或 者谷胱甘肽。 一 10·:請求項6之濃縮方法，其中核酸驗基係選自由腺 J胞噹啶、鳥嘌呤、次黃嘌呤、胸腺嘧啶、尿嘧啶 頁嘌呤所成群。 11 ·如請求頊6夕古4 ^ 、 /、中核苷係選自由腺苷、胞嘧啶 甘、鳥苷、肌苷及尿苷所成群。 ::求項6之濃縮方法’其中醣類為單糖或者2〜5糖之 月求項6之滾縮方法，其中醣類 14.如請求項6之濃縮方法，主中維生…上之春糖。 B1、維生辛B 八、、生素類係選自由維i f、肌r ㈣6、终驗酸、泛酸、葉酸。 I辛:針膽驗、維生素Bi2、收 基（甲酸、類脂酸、乳清 甲硫胺酸所成群。 丨』嶮及1 115786.doc
TW095139925A 2005-10-28 2006-10-27 Concentration crystallizer and method TW200800354A (en)

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