1

分離技術シリーズ 35

晶析の基礎と実践
分離技術会 編分 離 技 術 会

｢分離技術シリーズ｣ の継続刊行に当たって研究開発とは，新しい原理や現象を発見することばかりではなく，原理・現象は既知であっても新しい方法を案出するとか，あるいは新しい組み合わせを創案することによって，新しい技術，商品，品質，機能，用途，方法等々を創出することである．
本会は主に化学品の製造に関わる分離技術を包括的に扱う専門の学会であるが，研究者・技術者を糾合して正に関連分野の研究・開発の進展を目指し，急激な変化に対応しようと心がけている．
すでに何冊か刊行された本シリーズのなかには，本会会誌 ｢分離技術｣ 誌に掲載された論文によっているものもある．しかし，論文に記載された技術を取捨選択し，それらの組み合わせを考えて執筆されたものであるから，上述の視点から成書としての価値は高いといえるであろう．
さて，最近あらたな構想のもとに，本委員会よりいろいろな分野の権威者に執筆を依頼し，本シリーズに書き下ろしの著作物が加えられることになったのは誠に慶賀に堪えない次第である．分離技術の益々の発展に寄与することは勿論，読者諸兄姉に研鑽のお役に立つものと信じている．
分離技術シリーズ出版委員会
委員長

山 田明

はし が き工業晶析周辺の技術あるいは，応用分野は年々多様化しており，それらに対応した書籍の要望が多数寄せられるようになってきている．分離技術会では講演会として「晶析の基礎と実践」を開催してきた．その内容は，結晶品質制御，結晶物性評価，センシング技術やスケールアップ，クリスタルエンジニアリングや撹拌技術との接点，連続化など様々であった．その様な経緯で，それらの内容を書籍としてまとめることとした．
晶析操作の目的である，分離精製と粒子群製造の基礎と最新技術をまとめながら，実践的に活用できる応用例までを網羅した．また，最近特にその進歩がめざましい，晶析操作で必要となる分析測定技術や，連続製造技術についても現在活躍している研究者にご執筆頂いた．
晶析操作は新素材開発分野をはじめ，医薬食品関連分野，エネルギー環境関連分野など幅広い応用が望める技術である．本書では，体系化された基本原理や概念から，晶析操作の新分野をある程度網羅して解説した．晶析分野に携わる企業の研究者あるいは，技術者，また大学での研究者にとって，本書が晶析技術を理解する一助となることを願っている．
2021 年 3 月
編集担当

滝山

博

志

目

次

第１章 晶析操作の基礎
1.1

分離精製操作としての工業晶析 ·····································（兵庫県立大学）前田

1
光治

１．熱力学的な溶質あるいは不純物の分配 ··························

1

２．動力学的な不純物の分配 ············································

3

３．機械的な不純物の取り込み ·········································

12

４．精製晶析塔など工業装置による高純度化 ·······················

14５．晶析による高純度化の可能性 ······································

16６．まとめ ····································································

18

粒子群製造操作としての工業晶析 ··································

201.2（東京農工大学）滝山博志

１．はじめに ·································································

20２．非平衡分離としての晶析操作 ······································

22３．結晶多形現象と結晶粒子群品質制御 ·····························

31４．連続フロー晶析 ························································

34

５．まとめ ····································································

37

工業晶析操作の新展開 微粒子生成/環境晶析 ·················

39

1.3（早稲田大学）平沢泉

１．工業晶析分野をどのように展開するか ··························

39２．反応晶析と微粒子生成 ···············································

40

３．環境分野への晶析の実践 ············································

47

第２章 工業晶析操作の実践
2.1

精製を目的とした懸濁型融液晶析 ··································（三菱ケミカル）日野55
智道

１．はじめに ·································································

55

２．メタクリル酸について ···············································

55

３．懸濁型融液晶析法による精製操作 ································

56

４．懸濁型融液晶析に関する既往の研究 ·····························

57

５．懸濁型融液晶析における不純物の影響 ··························

58

６．懸濁型融液晶析槽のスタートアップにおけるスケール
形成機構の解明 ·····················································

61

７．工程パラメータ相関図 ···············································

64８．おわりに ·································································

66

製塩晶析工程における工程管理と計測技術 ······················

68

2.2

（塩事業センター）正岡功士

１．日本の製塩工業の概要 ···············································

68

２．製塩晶析工程と工程管理の概要 ···································

69

３．工程管理に用いられる計測技術 ···································

73

４．おわりに ·································································

83

第３章 医薬関連分野での晶析操作
3.1

結晶化難度の予測とその応用 ········································（塩野義製薬）永松

85
大樹

１．医薬関連分野における結晶化の重要性とその評価 ···········

85

２．過飽和比(S)による結晶化難度の評価 ····························

87c

３．臨界過飽和比(S )による結晶化難度の評価 ····················

92

括 ·································································

97４．総3.2

結晶多形の制御とスケールアップ ··································（アステラス製薬）竹口

１．は じ め に ····························································

98
和宏
98

２．結晶多形の熱力学的安定性評価 ··································· 100
３．結晶多形制御検討 ····················································· 103
４．スケールアップ検討 ·················································· 105
５．まとめ ···································································· 1093.3

医薬品結晶多形の熱力学的安定性評価 ···························· 111（エーザイ）南園

拓真

１．はじめに ································································· 111
２．医薬品における結晶多形 ············································ 111
３．製薬企業の開発結晶形最適化への取り組み ···················· 112
４．結晶多形の熱力学的安定性評価 ··································· 113
５．熱力学的安定性評価の事例 ········································· 115
６．まとめ ···································································· 121

第４章 晶析装置設計
4.1

連続晶析装置設計 ······················································ 123（カツラギ工業）三木秀雄

はじめに ······································································· 123
１．連続晶析装置の形式と選定 ········································· 124
２．ポピュレーションバランス理論による設計 ···················· 126
３．連続晶析操作特性因子を用いた設計理論 ······················· 134
４．連続晶析装置の実務的設計方法 ··································· 139
おわりに ······································································· 147
4.2

連続結晶精製装置設計 ················································ 149（クレハ）大田原健太郎

１．はじめに ································································· 149

２．メルト晶析装置 ························································ 150
３．KCP(クレハ連続結晶精製装置) ··································· 152
４．KCP の設計方法 ······················································· 157
５．横型多段冷却晶析装置(CDC) ······································ 159
６．CDCとKCPを組み合わせた実施例 ································ 163
７．最後に ···································································· 163
4.3

撹拌型晶析装置の設計のための撹拌の定量化 ··················· 165（佐竹化学機械工業）佐藤誠

１．はじめに ································································· 165
２．理想の晶析装置と撹拌の考え方 ··································· 165
３．撹拌装置の選定にあたり定量化すべきポイント ·············· 167
４．撹拌装置の選定と効率化事例 ······································ 170
５．スケールアップの考え方 ············································ 174
６．CFD 解析の活用方法 ················································· 177
７．おわりに ································································· 178

第５章 晶析操作での分析測定技術
5.1

晶析工程のモニタリング·············································· 180（メトラー・トレド）中務真結

１．はじめに ································································· 180
２．進歩する晶析技術と PAT ツール ··································· 180
３．過飽和度を制御するには ············································ 181
４．適切なプロセスパラメータの選択 ································ 183
５．種晶添加によるプロセス一貫性の向上 ·························· 185
６．変化が早く解析困難な晶析メカニズムの観測 ················· 188
７．まとめ ···································································· 190

5.2

X 線分析法の展開 ······················································· 191（リガク）山野昭人・生天目由紀子・金廷恩・白又勇士

１．X 線分析法とは ························································ 191２．単結晶を必要としない構造解析法 ································ 192
３．新しい定量分析 ························································ 205
４． 2 次元回折測定による結晶状態の観察 ·························· 208
５．おわりに ································································· 212
5.3

ラマン分光法を用いた晶析工程中における結晶品質評価 ···· 214（明治薬科大学）井上元基

１．はじめに ································································· 214
２．ラマン分光法の測定原理 ············································ 216
３．ラマンスペクトルの前処理 ········································· 217
４．単変量解析による晶析プロセスのラマンモニタリング ····· 218
５．スペクトル解析のための多変量解析 ····························· 220
６．多変量解析を用いた晶析プロセスのラマンモニタリング ·· 221
７．低波数ラマンスペクトルを用いた結晶形評価 ················· 223
８．お わ り に ···························································· 230
第６章 用語索引 ································································· 232
逆引き索引 ······························································ 235