Chapter 1
Introduction to Crystallization

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 and of itself, is reinforced by the need to satisfy 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 critical issues, quality-by-design, and regulatory issues are included later in this chapter (Section 1.4).

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.
• Many drugs now require high levels of achievement and maintenance of chirality.
• Physical attributes of the bulk drug substance, i.e. crystallinity, amorphism, crystal forms, and particle size distribution (PSD), must be better controlled to meet formulation needs for bioavailability, stability, and reproducibility needs.
• Increased demands are being made for achievement and maintenance of crystal morphology.
• Increasingly complex molecular structures with higher molecular weights are being processed.
• 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 and its downstream operations including filtration and drying can be difficult to scale-up without experiencing changes in physical attributes and impurity rejection. Regulatory requirements for final bulk drug substances, as noted above, now include the necessity for duplication of physical attributes including PSD, 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 and its downstream operations have 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 solubility, polymorph, nucleation, growth rates, and mixing as well as other key properties, such as hydration, dehydration, particle attrition, and agglomeration in drying.

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 the process objectives is the most critical from the point of view of overall outcome, in order to determine whether nucleation or growth should be the dominant phase. The number and size of nuclei initially formed, or equivalently seeded, can dominate the remainder of the operation. However, it is generally agreed that nucleation can be trickier 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 an integration in emphasis from control of initial nucleation as seed to control of growth for the rest of crystallization. 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 process is essential for development of a scalable process.

For downstream filtration/washing and drying, it would require control of both equilibrium and kinetic variables. If mixture of solvents is used for cake washing, fractionation of residual solvent in the wet cake during drying can lead to solvent entrapment in the final dry cake. Improper humidity level during drying of hydrate can also induce dehydration risk. Simultaneous particle attrition and agglomeration would also require a good balance among process operating parameters, cake wetness, particle physical properties, etc. Cake homogeneity has always been a challenge upon scale-up. Again, a sound knowledge of these factors is essential for development of a scalable process.

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 operations and to design equipment in which these goals can be realized.

The four conventional crystallization operations (Chapters 7, 8, 9, and 10) and downstream operations (Chapters 11 and 12) 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 included 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), the kinetics of crystallization (Chapter 4), mixing and scale-up in crystallization (Chapter 5), and critical issues and quality by design (Chapter 6). Selected Topics (Chapter 13) contain 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, and to address the quality-by-design and control strategy topics, Chapter 6 specifically contains a suggested protocol for development and scale-up of a crystallization operation.

1.1 CRYSTAL PROPERTIES AND POLYMORPHS (CHAPTERS 2 AND 3)

Basic crystal properties include solubility, supersaturation, metastable zone width, induction time, oil, amorphous solid, polymorphism, solvate, occlusion, morphology and PSD, and so on. Clearly, in order to properly design and optimize crystallization processes, along with downstream operations to generate desired solids, 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 and supercritical crystallization. Therefore, the goal of these chapters is to introduce basic properties of solution and crystals related to solution crystallization and subsequent downstream operations. 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, and 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 characterized or understood. For example, the mechanism and condition for the formation of oil or amorphous solid remain less clear. 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. In recent years, some amorphous organic compounds are formulated using amorphous solid dispersion technique which contains polymeric or other non-active ingredients to maintain the amorphous state of the organic compounds over sufficient shelf life. The amorphous state of compounds can improve the bioavailability over that of the corresponding crystalline compounds. But special attentions are required on design and processing to ensure both chemical and physical stability of the compounds.

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. It affects every phase of drug development, from initial drug discovery to final clinical evaluation,...