Crystallization of Organic Compounds

Crystallization of Organic Compounds An Industrial Perspective Hsien-Hsin Tung Edward L. Paul Michael Midler ... 222 Rosewood Drive, Danvers, MA 01923...

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Crystallization of Organic Compounds An Industrial Perspective Hsien-Hsin Tung Edward L. Paul Michael Midler James A. McCauley

Crystallization of Organic Compounds

Crystallization of Organic Compounds An Industrial Perspective Hsien-Hsin Tung Edward L. Paul Michael Midler James A. McCauley

Copyright # 2009 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at Library of Congress Cataloging-in-Publication Data: Crystallization of Organic Compounds: An Industrial Perspective/Hsien-Hsin Tung . . . [et al.]. p. cm. Includes bibliographical references and index. ISBN 978-0-471-46780-9 (cloth) 1. Crystallization--Industrial applications. 2. Pharmaceutical chemistry. 3. Pharmaceutical industry. I. Tung, Hsien-Hsin, 1955-TP156.C7I53 2009 6150 .19--dc22 2008042950 Printed in the United States of America 10 9

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1. Introduction to Crystallization Issues 1.1 1.2 1.3 1.4 1.5 1.6 1.7

Crystal Properties and Polymorphism 2 (Chapters 2 and 3) Nucleation and Growth Kinetics 3 (Chapter 4) Critical Issues (Chapter 5) 3 Mixing and Crystallization 4 (Chapter 6) Crystallization Process Options (Chapters 7 – 10) 4 Special Applications (Chapter 11) 9 Regulatory Issues 10

2. Properties 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10



Solubility 13 Supersaturation, Metastable Zone, 21 and Induction Time Oil, Amorphous, and Crystalline States 25 Polymorphism 29 Solvate 32 Solid Compound, Solid Solution, 34 and Solid Mixture Inclusion and Occlusion 37 Adsorption, Hygroscopicity, and 39 Deliquescence Crystal Morphology 42 Particle Size Distribution and 44 Surface Area

3. Polymorphism 3.1 Phase Rule 49 3.2 Phase Transition 50 3.3 Examples 52 Example 3-1 Indomethacin Example 3-2 Sulindac 55

Example 3-3 Example 3-4 Example 3-5 Example 3-6

Losartan 57 Finasteride 58 Ibuprofen Lysinate 61 HCl Salt of a Drug Candidate 62 Example 3-7 Second HCl Salt of a 66 Drug Candidate Example 3-8 Prednisolone 70 t-Butylacetate Example 3-9 Phthalylsulfathiazole 74 3.4 Future Direction 76 4. Kinetics 4.1 4.2 4.3 4.4 4.5


Supersaturation and Rate Processes 77 Nucleation 79 Crystal Growth 87 Nucleate/Seed Aging and 98 Ostwald Ripening Delivered Product: Size Distribution and Morphology 99

5. Critical Issues in Crystallization Practice 5.1 5.2 5.3 5.4 5.5 5.6 49


Introduction 101 Nucleation 101 Growth 104 Oiling Out, Agglomeration/ 106 Aggregation Seeding 110 Rate of Generation of 115 Supersaturation Summary of Critical Issues

6. Mixing and Crystallization 53

6.1 6.2

Introduction 117 Mixing Considerations


116 117





6.3 6.4

Mixing Effects on Nucleation 119 Mixing Effects on Crystal 123 Growth 6.5 Mixing Scale-up 126 6.6 Crystallization Equipment 127 Example 6-1 135 7. Cooling Crystallization


7.1 Batch Operation 137 7.2 Continuous Operations 143 7.3 Process Design—Examples 147 Example 7-1 Intermediate in a Multistep Synthesis 147 Example 7-2 Pure Crystallization 150 of an API Example 7-3 Crystallization Using the Heel from the Previous Batch as 154 Seed Example 7-4 Resolution of Ibuprofen Via Stereospecific Crystallization 155 Example 7-5 Crystallization of Pure Bulk with Polymorphism 160 Example 7-6 Continuous Separation 161 of Stereoisomers 8. Evaporative Crystallization


8.1 8.2 8.3

Introduction 167 Solubility Diagrams 167 Factors Affecting Nucleation and 170 Growth 8.4 Scale-up 171 8.5 Equipment 171 Example 8-1 Crystallization of a Pharmaceutical Intermediate Salt 175 Example 8-2 Crystallization of the Sodium Salt of a Drug Candidate 177 9. Antisolvent Crystallization 9.1 Semibatch Operation 179 Example 9-1 Crystallization of an 184 Intermediate

Example 9-2

Rejection of Isomeric Impurities of Final Bulk Active Product 185 Example 9-3 Crystallization of a Pharmaceutical Product with Poor Nucleation and Growth Characteristics 188 Example 9-4 Impact of Solvent and Supersaturation on Particle Size and 192 Crystal Form 9.2 In-Line Mixing Crystallization 196 Example 9-5 Crystallization of an API Using 197 Impinging Jets Example 9-6 Crystallization of a Pharmaceutical Product Candidate Using an Impinging Jet with 204 Recycle 10. Reactive Crystallization 10.1 10.2 10.3

Introduction 207 Control of Particle Size 209 Key Issues in Organic Reactive Crystallization 210 10.4 Scale-up 218 Example 10-1 Reactive Crystallization of an API 218 Example 10-2 Reactive Crystallization 223 of an Intermediate Example 10-3 Reactive Crystallization of a Sodium Salt of an 225 API Example 10-4 Reactive Crystallization 228 of an API 10.5 Creation of Fine Particles—In-Line Reactive Crystallization 231 11. Special Applications



11.1 11.2 11.3 11.4


Introduction 235 Crystallization with Supercritical 236 Fluids Ultrasound in Crystallization 237 Computational Fluid Dynamics in 238 Crystallization


Example 11-1 Example 11-2

Example 11-3

Example 11-4

Sterile Crystallization of Imipenem 238 Enhanced Selectivity of a Consecutive-Competitive Reaction by Crystallization of the Desired Product 243 During the Reaction Applying Solubility to Improve Reaction 246 Selectivity Melt Crystallization of 251 Dimethyl Sulfoxide


Example 11-5

Freeze Crystallization of Imipenem 255 Example 11-6 Continuous Separation of 259 Stereoisomers 11.5 Strategic Considerations for Development of a New Crystallization 272 Process References





Crystallization is an essential operation in pharmaceutical manufacturing because the majority of active pharmaceutical ingredients (APIs) are produced in solid form. Yet, this subject is much less a part of the academic curriculum compared to other topics such as distillation, extraction, and reaction. Very often engineers will learn crystallization process development on the job through trial and error, and it is not surprising that wheels are reinvented from time to time, despite hard work and effort. In terms of resource utilization, this approach is certainly inefficient. Added to this deficiency is the lack of a mechanism to pass on the knowledge and expertise developed from previous efforts. Over the years, one way to accomplish this has been via memos and process reports. But memos are generally project specific. Therefore, it is not a trivial task to uncover the technical knowledge and know-how buried in various memos and reports. Combining a summary of relevant theory and illustrative examples in a book to fill this gap seems to be a good mechanism for the transfer of information on principles and suggested practice. The idea of writing a book on crystallization to fulfill this need was first conceived in mid-1990. At that time, few books were available which dealt with crystallization development. These books appeared to overemphasize theory, and the majority of examples concerned crystallization of inorganic compounds. Over the past 10 years, several new crystallization books have been published which provide wider applications and richer information for development scientists and engineers. Unfortunately, the practical aspects of crystallization in our industries and actual industrial examples have not been adequately described. This book has two goals. One is to facilitate the understanding of the fundamental properties of crystallization and the impact of these properties on crystallization process development. The second is to aid practitioners in problem-solving using actual industrial examples under real process constraints. This book begins with fundamental thermodynamic properties (Chapters 2 and 3), nucleation and crystal growth kinetics (Chapter 4), and process dynamics and scale-up considerations (Chapters 5 and 6). Subsequent chapters cover modes of crystallization operation: cooling (Chapter 7), evaporation (Chapter 8), antisolvent (Chapter 9), reaction (Chapter 10), and special cases of crystallization (Chapter 11). As mentioned, real industrial examples are provided in each chapter. We would like to express our sincere thanks to the late Omar Davidson for his diligent support throughout the preparation of this book. We also want to thank our colleagues, Lou Crocker, Albert Epstein, Brian Johnson, Mamoud Kaba, Joe Kukura, Amar Mahajan, Jim Meyer, Russ Lander, Karen Larson, Chuck Orella, Cindy Starbuck, Jose Tabora, and Mike Thien, who have graciously spent their time in reviewing individual chapters of this book (and in several cases, more than that). Their recommendations have significantly enriched the content of this book. Needless to say, we are truly grateful to our spouses




and family members for their understanding and support during the long period of preparation. Our goal is to help reader develop the crystallization process. Matthew: 12:33, “Either declare the tree good and its fruit is good, or declare the tree rotten and its fruit is rotten, for a tree is known by its fruit.” It is our hope that you, as readers, will find this book useful for your work. If so, this will be the nicest reward for us.



Introduction to Crystallization Issues Crystallization has been the most important separation and purification process in the pharmaceutical industry throughout its history. Many parallels exist in the fine chemicals industry as well. Over the past several decades the study of crystallization operations has taken on even higher levels of importance because of several critical factors that require increased control of the crystallization process. These levels of control require better understanding of the fundamentals as well as of the operating characteristics of crystallization equipment, including the critical issue of scale-up. In the pharmaceutical industry, the issue of better control, desirable in itself, is reinforced by the need to assure the regulatory authorities that a continuing supply of active pharmaceutical ingredients (APIs) of high and reproducible quality and bioavailability can be delivered for formulation and finally to the patient. The “product image” (properties, purity, etc.) of this medicine must be the same as that used in the clinical testing carried out to prove the product’s place in the therapeutic marketplace. Some additional comments on regulatory issues are included later in this chapter (Section 1.7). The issues noted above that require increased control, relative to previous practice, include the following: †

Final bulk drug substances must be purified to high levels that are increasingly quantifiable by new and/or improved analytical methods.

Physical attributes of the bulk drug substance must be better controlled to meet formulation needs for reproducibility and bioavailability.

Many APIs now require high levels of chirality. Increased demands are being made for achievement and maintenance of morphology.

† † † †

Increasingly complex molecular structures with higher molecular weights are being processed. Bulk drug solid stability is increasingly being achieved by improved control of crystal growth. The biotechnology sector has increased the use of precipitation of macromolecules for purification and isolation of noncrystalline materials.

Added to this list is the assertion, based on operating experience, that crystallization is difficult to scale up without experiencing changes in physical attributes and impurity Crystallization of Organic Compounds: An Industrial Perspective. By H.-H. Tung, E. L. Paul, M. Midler, and J. A. McCauley Copyright # 2009 John Wiley & Sons, Inc.



Chapter 1 Introduction to Crystallization Issues

rejection. Regulatory requirements for final bulk drug substances, as noted above, now include the necessity for duplication of physical attributes including particle size distribution, bulk density, and surface area within narrow ranges when scaling from pilot plant to manufacturing scale. When compared to the development of models and methods for other unit operations, it is obvious that crystallization has not been generalized to the degree that has been accomplished for distillation, extraction, adsorption, etc. This situation is changing rapidly, however, with increasing research now being carried out at academic and industrial centers on crystallization fundamentals to model and predict nucleation and/or growth rates as well as other key properties, including polymorph formation. Control of crystallization processes requires modulation of either nucleation or growth or, as is most often the case, both modes of crystal development simultaneously. Each operation must be evaluated to determine which of these process objectives is most critical, from the point of view of overall outcome, to determine whether nucleation or growth should be the dominant phase. Much of the literature is focused on nucleation for the obvious reason that the number and size of nuclei initially formed can dominate the remainder of the operation. However, it is generally agreed that nucleation can be difficult to control, since there are several factors that can play a role in the conditions for nucleation onset, nucleation rate, and number of crystals generated before growth predominates. The demand for increasing control of physical attributes for final bulk pharmaceuticals has necessitated a shift in emphasis from control of nucleation to control of growth. This trend is also finding application for control of purity and improved downstream handling for both intermediates and final bulk products. The obvious critical factors then become seeding and control of supersaturation. Quantification of these factors for each growth process is essential for development of a scalable process. Much of the discussion to follow focuses on the growth process and methods to minimize nucleation. The purpose of this book is to outline the challenges that must be met and the methods that have been and continue to be developed to meet these requirements to develop reproducible crystallization operations and to design equipment with which these goals can be achieved. The four conventional crystallization operations (see Chapters 7, 8, 9, 10) will be discussed in terms of their strengths and weaknesses in achieving specific process objectives. In addition, methods of augmenting the conventional processing methods will be considered, with emphasis on the enhanced control that is often necessary to achieve the specific objectives. This book also includes chapters on the properties of organic compounds (Chapter 2), polymorphism (Chapter 3) and the kinetics of crystallization (Chapter 4), critical issues (Chapter 5), and mixing effects in crystallization (Chapter 6). Chapter 11 includes areas of current crystallization research and development we thought worth mentioning and also some unique crystallization processes that have special features to be considered in process development. To assist in the thought process for organization of a new crystallization process, Chapter 11 also contains a suggested protocol for development and scale-up of a crystallization operation.

1.1 CRYSTAL PROPERTIES AND POLYMORPHISM (CHAPTERS 2 AND 3) Basic crystal properties include solubility, supersaturation, metastable zone width, oil, amorphous solid, polymorphism, occlusion, morphology, and particle size distribution. Clearly.

1.3 Critical Issues


in order to properly design and optimize crystallization processes, it is essential to have a sound understanding of these properties. For pharmaceuticals and special organic chemicals, solution crystallization, in which solvents are used, is the primary method of crystallization compared to other crystallization techniques such as melt or supercritical crystallization. Therefore, the goal of these chapters is to introduce basic properties of solution and crystals related to solution crystallization. The relevance of these basic properties to crystal qualities and crystallization operations will be highlighted with specific examples. Some properties are more clearly defined than others. For example, solubility is defined as the amount of solid in equilibrium with the solvent. Solubility can affect the capacity of the crystallization process, as well as its ability to reject undesired compounds and minimize loss in the mother liquor. In addition, solubility varies widely from compound to compound or solvent to solvent. On the other hand, there are properties that are much less well characterized or understood. For example, the mechanism and condition for the formation of oil or amorphous solid remain unclear. The composition of oil and amorphous solid can be variable, and certainly can contain a much higher level of impurities than that in the crystalline solid, which leads to a real purification challenge. In addition, oil or amorphous solid generally is less stable and can create critical issues in drug formulation and storage stability. One property of a crystalline compound is its ability to form polymorphs, that is, more than one crystal form for the same molecular entity. The phenomenon of polymorphism plays a critical role in the pharmaceutical industry because it affects every phase of drug development, from initial drug discovery to final clinical evaluation, including patent protection and competition in the market. A critical challenge is the early identification of possible polymorphs. Chapters 2 and 3 will address this key issue.


NUCLEATION AND GROWTH KINETICS (CHAPTER 4) Meeting crystal product specifications with a robust, repeatable process requires careful control and balancing of nucleation and growth kinetics. Careful structuring of the environment can dictate the fundamental mechanisms of nucleation and crystal growth and their resultant kinetics. Undesired polymorphs can be often minimized or eliminated by suitable control of rate processes. Understanding of the possible nucleation and crystal growth kinetics for desired (and undesired) compounds can place the process development effort on a considerably shorter path to success. Reference will be made to examples in the other chapters in this book.


CRITICAL ISSUES (CHAPTER 5) Difficulty in controlling crystallization processes in general can be exacerbated when working with complex organic compounds. This problem can be even worse when attempting to develop a nucleation-dominated process, which, even in the best circumstances, can potentially operate over a very wide range of supersaturation, depending on small changes such as varying amounts of very-low-level impurities. Organic compounds are subject to agglomeration/aggregation effects and, even worse, to “oiling out.” All of these problems can potentially result in undesired trapping of solvent and/or impurities in the final crystal. Oiling out, of course, can completely inhibit the formation of a crystalline phase, resulting in a gum or an amorphous solid. These phenomena are discussed qualitatively in Chapter 5.