分離技術シリーズ 28

分かり易い貧溶媒晶析
久保田

徳

昭

編著

分 離 技 術 会

は じ

め に

この本の書名に用いた「貧溶媒晶析」という言葉は，いかにも印象が悪い．
晶析分野の人々にとってもその感は否めないところだから，晶析のことなど全く知らない人にとっては，なおさらと思われる．実際私はある人に怪訝な顔をされた経験がある．「貧」がいかにも良くない印象を与えるからに違いない．
そんな訳であまり使いたくはないのだが，用語としては定着しているので，止むを得ず使用した．貧溶媒晶析に変わる用語として，「溶媒添加晶析」という用語が晶析研究会のアンケート(註)で使用されているが，この方が貧溶媒晶析
よりも良いかもしれない．「非溶媒晶析」といういい方も見られる．「貧」より
は 幾 分 ま し か も し れ な い ． 貧 溶 媒 晶 析 に 対 応 す る 英 語 は ， Anti-solvent
crystallization である．だからといって，「貧溶媒晶析」が英語由来ということではないと思われる．良溶媒に対して貧溶媒といういい方は，多分以前からあったと思われるし，貧溶媒晶析法そのものが欧米から取り入れられた晶析手法というわけでもないからである．ごく自然に，Anti-solvent crystallization に対応するものとして貧溶媒晶析という用語が生まれたのではないだろうか．英語には，その他に Drowning crystallization，Dilution crystallization，Salting-out
crystallization などが存在する．
貧溶媒晶析は非常に広く使われている．特に，医薬品工業などではそうである(註)．それにもかかわらず，これに関する書籍は見当たらない．また，ハンドブック類にも記述が非常に少ない．不思議と思われるほどである．貧溶媒晶
析に関する技術的知見あるいはノウハウを持っていない企業あるいは技術者が，
貧溶媒晶析プロセスを新たに計画しようとした時，一体何を参考にしたらよい
か困る場合が多いのではないだろうか．本書はそのような企業あるいは技術者に，貧溶媒プロセス開発の「とっかかり」を与えるものとして企画した．貧溶
媒晶析は，操作因子が他の晶析法に比較して多様で，最適化も難しい．しかし，
操作因子が多様性であるということは，製品に対する高度な要求にも応え得る可能性も秘めている．本書の貧溶媒晶析事例をお読みいただけば，操作因子の多様性の一端がうかがえると思う．その意味で，本書は，貧溶媒晶析技術を網羅したものではないものの，ベテランの技術者にも，何らかのヒントが得られるものと思われる．
本書の目指すのは，「とっかかり」と「ヒント」を提供することであるから，とかく難しくなりがちな基礎的および理論的事項は後にまわし，先に貧溶媒晶
析の事例を紹介することにした．
第 1 章では，主として企業で実際に貧溶媒晶析に携わっている技術者の方々に，事例を執筆していただいた．これら事例から，貧溶媒晶析の実際が具体的に理解できると思う．第 2 章では，貧溶媒晶析において望ましくない現象としてのオイル化，あるいは，オイル化に関連する現象としての結晶の凝集およびスケーリングについて解説した．第 3 章では，貧溶媒晶析プロセスにおける結晶収量，生産速度および装置設計の基本を述べた．また，貧溶媒晶析に使用される装置の概要を述べた．さらに第 3 章では，貧溶媒晶析においてどうしても避けることができない廃溶媒の処理，精製もとり扱っている．最後の第 4 章では，貧溶媒晶析における基本的事項として，相平衡と過飽和度，核化と結晶成
長および溶液の撹拌と混合について解説した．
本書には多くの方々に執筆者としてご協力いただいた．いずれも多忙を極める方々である．ご協力を感謝したい．また，分離技術会事務局の三澤氏以下ス
タッフの方々には，出版までの長い道のりを辛抱強くサポートしていただいた．
感謝申し上げたい．なお，この「分かり易い貧溶媒晶析」の企画は，松岡先生(当時農工大教授，現名誉教授)と久保田の両名により 5，6 年前に提案され，その後分離技術会出版委員会で承認された．出版がこのように遅れたのは，ひとえに久保田の怠慢によるものである．関係者にはご迷惑をおかけしてしまっ
た．深くお詫びしたい．
註：大嶋寛，アンケートから見た日本の晶析技術，化学工学, 65 (2001) 38-39

平成 25 年 4 月
久保田徳昭

執筆者一覧
城道

修

南

慶太

日本マイクロバイオファーマ株式会社
味の素株式会社 九州事業所製造部調味料・アミノ酸グループ

岩元和昭

富士フィルムファインケミカルス株式会社 生産技術部

梶原亮二

富士フィルムファインケミカルス株式会社 生産技術部

森川

智文

富士フィルムファインケミカルス株式会社 生産技術部

松尾公博

エーザイ株式会社 減薬研究部プロセス工学研究室

早川正道

東洋合成工業株式会社

大嶋

寛

町谷

晃司

アステラス製薬株式会社

薬事部・CMC 薬事椋田隆司

アステラス製薬株式会社

薬事部・CMC 薬事

百永眞士

藤本化学製品株式会社 品質保証部

大阪市立大学大学院工学研究科化学生物系専攻

加々良耕二

大原薬品工業株式会社 医薬開発研究所

久保田徳昭

岩手大学名誉教授

中田浩彰

三菱化学株式会社 水島事業所開発研究所

松岡正邦

東京農工大学名誉教授

浅谷治生

株式会社 三菱化学科学技術センター 生産技術研究所

目

次

第１章

貧溶媒晶析の実施例 ····························································

1

1.1

医薬品原薬の工業化における貧溶媒晶析法の検討例····················

1

はじめに ·················································································

1

1．医薬品マイトマイシン C のエマルジョン晶析 ····························

31.1

結晶多形 ·······································································

3

1.2

晶析の基本的方法 ···························································

41.3

均一溶媒系における晶析 ··················································

51.4

不均一溶媒系における晶析 ···············································

7

1.5

まとめ ··········································································

92．医薬品ダウノルビシン塩酸塩の結晶多形とスケールアップ···········

9

2.1

晶析方法 ······································································· 102.2工業化検討 ···································································· 12

2.3

まとめ ·········································································· 16

3．医薬品ドキソルビシン塩酸塩の結晶特性の改善·························· 17
3.1

晶析方法 ······································································· 17

3.2

晶析条件の改善検討 ························································ 18

3.3

新晶析条件で得られた結晶の評価 ······································ 21

3.4

まとめ ·········································································· 24

おわりに ················································································· 25
1.2

アミノ酸およびアミノ酸塩類の晶析········································· 27

1．製品品質と晶析条件～結晶表面品質の制御方法～······················· 30
2．不純物として振舞うアミノ酸·················································· 32
3．アミノ酸晶析のスケールアップ··············································· 34
1.3

化成品製造における貧溶媒晶析の事例～粒子サイズ制御に関して～·························································································· 37

1．背景············································································· 37

1.1

晶析のニーズ ································································· 37

1.2

貧溶媒晶析のニーズ ························································ 38

2．実

例············································································· 38

2.1

概要 ············································································· 38

2.2

検討内容 ······································································· 39

3．貧溶媒晶析の利用································································· 42
1.4

医薬品原薬・中間体製造における貧溶媒晶析の検討事例·············· 43

1．なぜ医薬品原薬製造で貧溶媒晶析を使うか································ 43
2．検討事例１：E7070 残留溶媒制御検討 ······································ 44
2.1

水の滴下温度が E7070 結晶中の残留アセトンへ与える影響 ····· 45

2.2

水の滴下時間が E7070 結晶中の残留アセトンへ与える影響 ····· 45

2.3

結論 ············································································· 46

3．検討事例２：ER-116065 貧溶媒晶析，ろ過性改善・結晶多形制御検討············································································· 46

1.5

3.1

ER-116065 のスケールアップ製造とろ過性に関して ··············· 47

3.2

ER-116065 の結晶多形に関して ·········································· 483.3各結晶多形の安定性確認 ·················································· 49

3.4結晶形の選択 ································································· 49

3.5

水滴下時間最適化 ··························································· 51

3.6

ER-116065 の貧溶媒晶析，新処方 ······································· 51

3.7

結論 ············································································· 52

感光剤の晶析方法································································· 53

1．はじめに············································································· 53
2．液晶ディスプレーの回路基板を作成する感光剤·························· 54
2.1

手順 ·········································································· 55

2.2

条件検討のポイント ························································ 55

2.3

条件検討 ······································································· 57

2.4製造に向けて ································································· 58

3．半導体デバイスを作製するための感光剤··································· 58
3.1

手順 ·········································································· 61

3.2

条件検討のポイント ························································ 62

3.3

スラリーにならない場合 ·················································· 64

3.4
1.6

スケールアップ ······························································ 64

貧溶媒晶析におけるチクリナフェンの粒径分布制御とそのスケールアップ ···························································· 66

1．はじめに············································································· 66
2．チクリナフェンの製造法························································ 66
3．貧溶媒晶析における粒径分布制御とそのスケールアップ·············· 69
3.1

結晶化過程と撹拌強度の関連 ············································ 69

3.2

実験方法とその装置 ························································ 70

3.3

粒径分布と粒径に及ぼす撹拌の影響 ··································· 71

3.4

粒子径と撹拌効果 ··························································· 73

3.5

粒径分布と撹拌効果 ························································ 73

第２章

貧溶媒晶析でよく見られる現象 ············································· 77

2.1

晶析操作中の油状物質析出(オイル化)挙動とその回避················· 77

1．オイル化とは何か································································· 78
2．オイル化を分類する······························································ 79
3．オイル化を克服する······························································ 80

2.2

3.1

結晶は得られているがオイル化を回避して製造したい場合 ····· 80

3.2

オイル化はするが結晶が得られない場合 ····························· 82

ろ過性改善を目的とした球状凝集結晶の晶析条件······················· 85

1．はじめに············································································· 85
2．晶析実験および粉体の評価····················································· 88
2.1晶析実験 ······································································· 88

2.2

圧縮性の評価 ································································· 88

2.3

ろ過特性の評価 ······························································ 89

3．操作変数の影響···································································· 89
3.1

晶析温度の影響 ······························································ 893.2撹拌速度の影響 ······························································ 923.3

種晶量の影響 ································································· 92

4．結晶の粒子特性と強度··························································· 92
5．検討結果の評価と実用性の確認··············································· 95
6．おわりに············································································· 95

2.3

貧溶媒晶析でのスケーリングの回避········································· 97

はじめに ················································································· 97
1．フォスミドマイシン精製晶析法の開発······································ 97
1.1

精製晶析法の開発 ··························································· 97

1.2

条件設定 ······································································· 100

2．粒子径制御のためのスケールアップ因子の選定·························· 101
2.1

粒径に関するスケールアップ因子 ······································ 102

2.2

粒径分布に関するスケールアップ因子 ································ 102

3．スケールアップ時のトラブル·················································· 104
おわりに ················································································· 104
第３章

貧溶媒晶析プロセス ···························································· 1053.1

結晶収量，生産速度および装置容積········································· 105

1．溶解度················································································ 105
2．結晶理論収量······································································· 110
3．生産速度············································································· 112
4．装置容積············································································· 1133.2

貧溶媒晶析装置の選定，運転およびそのスケールアップ·············· 115

1．医薬品工業における晶析装置と撹拌翼の選定····························· 115
2．撹拌翼の特性と貧溶媒晶析装置との適性··································· 115
3．貧溶媒滴下位置の影響··························································· 118
4．貧溶媒晶析における装置のスケールアップ································ 119
3.3

廃溶媒の精製・処理······························································ 123

1．分離プロセスの検討······························································ 123
1.1

廃溶媒の前処理 ······························································ 123

1.2

プロセス設計のための物性データ ······································ 1231.3

物性値の推算法 ······························································ 124

1.4

気液平衡関係/共沸点の測定法 ··········································· 1251.5

液液平衡の測定法 ··························································· 128

1.6プロセスの設計

2．分離のための溶媒選定法························································ 131
3．溶媒リサイクルプロセスの実例··············································· 131

第４章

貧溶媒晶析の基礎 ······························································· 1344.1

相平衡と過飽和度································································· 134

1．本節での用語の定義······························································ 134
2． 3 成分系の相平衡································································· 1342.1

三角相図 ······································································· 134

2.2

Gibbs の相律 ·································································· 137

2.3

相図上でみる貧溶媒添加晶析操作 ······································ 138

3．過飽和度の考え方································································· 139
3.1

2 成分系の場合 ······························································ 139

3.2

3 成分系の過飽和度と推進力 ············································ 140

4．多形および擬多形をもつ溶質の貧溶媒添加晶析操作···················· 142

4.2

4.1

多形をもつ系 ································································· 142

4.2

擬多形をもつ系 ······························································ 143

核化と結晶成長···································································· 145

1．核化················································································ 145

1.1

一次核化：均質核化と不均質核化 ······································ 145

1.2

二次核化 ······································································· 1471.3

貧溶媒晶析における核化 ·················································· 148

2．結晶成長············································································· 151

4.3

2.1

表面集積過程 ································································· 1512.2

結晶成長速度の工学的表現 ··············································· 1532.3

貧溶媒晶析における結晶成長 ············································ 154

溶液の混合と撹拌································································· 156

1．はじめに············································································· 156
2．撹拌型晶析槽の撹拌······························································ 158
3．貧溶媒晶析操作と撹拌・混合·················································· 160
4．結索

言················································································ 164

引 ·························································································· 165