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Process intensification for pharmaceutical crystallization
Accepted Manuscript Title: Process Intensification for Pharmaceutical Crystallization Authors: Jiayuan Wang, Fei Li, Richard Lakerveld PII: DOI: Reference:
S0255-2701(18)30055-2 https://doi.org/10.1016/j.cep.2018.03.018 CEP 7228
To appear in:
Chemical Engineering and Processing
Received date: Revised date: Accepted date:
16-1-2018 17-3-2018 17-3-2018
Please cite this article as: Wang J, Li F, Lakerveld R, Process Intensification for Pharmaceutical Crystallization, Chemical Engineering and Processing (2010), https://doi.org/10.1016/j.cep.2018.03.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Crystallization
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Process Intensification for Pharmaceutical
Jiayuan Wang, Fei Li, Richard Lakerveld*
Department of Chemical and Biological Engineering, The Hong Kong University of Science and
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Technology, Clear Water Bay, Hong Kong
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Email: [email protected]
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Graphical abstract
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Highlights A systematic review on process intensification for pharmaceutical crystallization Principles and examples of process intensification methods for crystallization Perspectives on the opportunities for intensifying pharmaceutical crystallization
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ABSTRACT
Process intensification (PI) provides great opportunities to drastically improve the performance of
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chemical processes within many branches of chemical industry including the pharmaceutical
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industry. Crystallization is an important purification and separation technology within many
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pharmaceutical processes. This paper provides a systematic review on the recent developments of
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PI approaches that are applicable to pharmaceutical crystallization. The various approaches are categorized according to the four fundamental PI domains (space, time, function, energy) that have
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been proposed in literature. Each approach is illustrated with examples from literature with an
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emphasis on the opportunities to intensify pharmaceutical crystallization processes. Finally, some
provided.
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thoughts on the level of maturity for industrial implementation of the various approaches are
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KEYWORDS
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Process Intensification, Pharmaceutical Crystallization, Crystallization, Review
1. Introduction
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Pharmaceutical industry is a trillion dollar industry that produces high value-added products with stringent specifications for quality attributes. Traditionally, the use of methods for process intensification (PI) with step changes in performance has been complicated by the highly regulated
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environment of pharmaceutical industry and a typical business model focusing on molecule discovery and minimizing time-to-market to enjoy long patent protection. Consequently, any process innovations that might be subject to a long approval period are usually avoided. Therefore, the drug production is usually carried out according to a licensed recipe developed at the end of the research and development (R&D) phase even if the process efficiency could be improved
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significantly via methods for process intensification during commercial manufacturing. However,
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in recent years, pharmaceutical industry is challenged by the need for more efficient manufacturing
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processes driven by:
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1. increased competition from the generic market due to patent expirations of many drugs;[1] 2. increased cost of R&D for new drugs;[2]
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3. the growing demand for “greener” products and processes;[3]
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4. a changing mindset within the industry[4] and new regulatory incentives.[5-7]
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Therefore, there is currently an attractive window of opportunities to adopt innovations to the pharmaceutical industry. The systematic use of PI methods can be an important blueprint for such
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change.
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Crystallization is an important unit operation within many pharmaceutical processes for the separation and purification of intermediate compounds and active pharmaceutical ingredients (APIs). In comparison to processes delivering a liquid product, design and control of crystallization processes is complicated by stringent product requirements related to the intrinsic quality attributes
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of the crystalline phase. In particular, besides purity, other properties such as crystal size distribution, shape, and solid-state form should also be taken into consideration, as they have a significant impact on downstream processing (e.g. filtration, drying, milling, tableting) and final
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product performance (e.g., bioavailability). Pharmaceutical crystallization is traditionally not among the frontrunners of PI, nevertheless, step changes in performance of crystallization processes are also desirable in view of the general drivers of innovation in the pharmaceutical industry to meet future challenges. However, although review articles on the challenges and progress of pharmaceutical crystallization exist,[8, 9] a dedicated review on the opportunities of
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PI methods that can be applied to pharmaceutical crystallization is, to the best of our knowledge,
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currently lacking in literature, despite the significant recent development and understanding of PI
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methods that can be applied to pharmaceutical crystallization. Therefore, this paper aims to provide
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a systematic overview of the recent developments of those PI methods that can be applied to
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pharmaceutical crystallization.
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Several definitions have been proposed for the scope of PI based on different perspectives.[10-14]
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Van Gerven and Stankiewicz[11] provide a comprehensive and fundamental vision of PI. Instead of proposing a new definition for PI, they discuss and categorize the underlying principles,
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approaches and application scales of PI. This review paper will follow the framework proposed by Van Gerven and Stankiewicz[11] to present a systematic overview of PI methods for
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pharmaceutical crystallization. In particular, the methods will be categorized into the proposed four domains (i.e., time, space, energy and function) to adopt a fundamental view of PI. This review is not intended to be an exhaustive list of the numerous examples of PI approaches that have been used for various crystallization systems. Instead, we aim to provide a systematic
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overview on how pharmaceutical crystallization can benefit from the use of PI approaches by using a fundamental framework and selected examples. Furthermore, we do not explicitly distinguish between examples applied to pharmaceutical systems or other applications in chemical industry,
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as often there is no strict barrier between different application areas. Instead, we focus on PI methods with potential performance improvements on throughput and product quality control, which are generally most important for pharmaceutical applications. Finally, some perspective on the current opportunities for the implementation of PI approaches for pharmaceutical
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crystallization are discussed.
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2. PI approaches applied to pharmaceutical crystallization
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Solution crystallization involves the formation of a crystalline solid state from a homogeneous
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solution. Supersaturation is the driving force for crystallization, which is defined by the ratio of the chemical potential of the solute in solution and the chemical potential of the solute in the
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crystalline state and is often approximated by the ratio of the solute concentration to the solubility.
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Important material attributes of crystals include the crystal size distribution, shape, purity and
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polymorphic form. These material attributes may be critical to final product performance (i.e., affect critical quality attributes (CQAs) such as stability and bioavailability) when the crystals are
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incorporated in the final product and process throughput (i.e., the amount of crystalline material produced per unit of time[15]) when the crystal attributes affect downstream processes (see Figure
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1).
Crystal attributes are determined by crystallization kinetics in a multicomponent, multiphase system, which are usually complicated due to interdependent physical phenomena. For example,
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crystal growth and various forms of nucleation depend differently and often in a non-linear way on supersaturation. Dissolution of crystals only occurs in an under-saturated solution. Furthermore, agglomeration may take place at high supersaturation due to fast and uncontrolled solid-phase
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formation. Fluid shear induces mixing of a homogeneous liquid phase and improves mass and heat transfer. However, crystal breakage and attrition can also be provoked in areas with high shear, which makes the production of large crystals difficult. In addition, agglomeration is typically insignificant at conditions of either very low or high shear forces due to the competing interplay between the crystal collision rate, which is needed for the formation of agglomerates, and breakage
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of agglomerates. In this respect, one could argue that ultimately any PI approach applied to
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pharmaceutical crystallization needs to improve the independent control over these crystallization
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phenomena, thus, providing opportunities to improve the process flexibility, throughput and
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product quality control.[16] Such improvement would also align well with the concept of quality-
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pharmaceutical industry.
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by-design (QbD),[17, 18] which is currently one of the main regulatory incentives for
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This paper is structured according to the four fundamental PI domains with applications to pharmaceutical crystallization as illustrated in Figure 1. The classification has been developed
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based on the dominant features or intentions of the PI methods developed for crystallization,
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although some of the methods contain elements of several of the PI domains.
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Figure 1. An overview of process intensification for pharmaceutical crystallization.
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2.1 Space domain
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Spatial inhomogeneity complicates control and operation of chemical processes. Therefore, several PI approaches have been developed based on the general strategy to tightly control or
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restrict the processing space such that predictable operating conditions can be created for optimized process design and operation. Predictable operating conditions on a local scale are also
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important for crystallization processes, as the various crystallization phenomena that shape the final product quality have a different and often non-linear dependency on the solution properties.
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Crystallization from a bulk solution is usually difficult to predict and control due to spatial gradients in concentration, temperature, and momentum. Moreover, the spatial distribution of crystals within a crystallizer is often not uniform, which further complicates prediction and control. For example, large crystals tend to accumulate at the bottom of an agitated crystallization vessel.
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Finally, even if spatial gradients in solution properties and the dispersed phase could be well predicted, operation under inhomogeneous conditions remains undesirable since the differences in processing history of the crystals will lead to a non-uniform final product quality. PI approaches
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have been developed in the “space domain” to improve control over processing conditions that are relevant for crystallization. In particular, the PI approaches for crystallization in the space domain can be divided into two main directions: miniaturization and structurization as discussed below.
2.1.1. Miniaturization
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Miniaturization refers to crystallization in a confined space. Compared to crystallization in a bulk
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space, a confined space can create well-defined solution properties as a function of spatial
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coordinates and offers different crystallization behaviour mainly due to inherent volume effects
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and various surface effects. With respect to volume effects, due to the stochastic variability of nucleation, a significantly wider metastable zone may be present with suppressed homogeneous
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primary nucleation at a miniaturized scale.[19] The rapid depletion of supersaturation in a confined
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space due to the physical barriers limit crystal growth, which obviously favours the production of
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small crystals. However, besides crystal size, several studies have also shown that confining the processing volume for crystallization can also affect the polymorphic form of the produced
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crystals.[20-22] Such volume-dependent polymorphic preference has been attributed to the critical nucleus size according to the classical nucleation theory applied to a confined volume.[21]
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Confining crystal growth within pores that have a dimensions at or near the critical nucleus size could lead to stabilization of metastable polymorphs. In terms of surface effects, the miniaturized crystallization space offers a large surface-to-volume ratio, which offers opportunities to exploit
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heterogeneous nucleation to control crystal formation. Three popular approaches for miniaturization are summarized in Table 1 and discussed next.
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Table 1. Examples of enabling technologies for confining the crystallization conditions via miniaturization. Enabling technologies
Objectives
1. Production of small crystals 2. Drug encapsulation and delivery 3. Screening of crystallization conditions
[[23], [24]] [[25-27]] [[28-30]]
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Emulsion crystallization
References
[[31-33]] [34-36]
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1. Crystallization condition screening 2. Control of polymorphic form
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Crystallization on patterned surfaces
1. Drug encapsulation and delivery
[[37-41]]
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Crystallization inside porous materials
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An emulsion is a mixture of at least two immiscible liquids in which one liquid phase is dispersed in a continuous phase of the other liquid. Droplets with a uniform and controllable size from micro
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to nano-meter scale can be obtained during emulsification by using mechanical energy from intensive mixing[42, 43] or by using chemical energy from phase-transition phenomena.[44, 45] Microfluidic devices have also been used to produce emulsions with precise control over droplet size via confinement.[46-48] Emulsion crystallization can be used to produce crystals with a
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uniform and small size. For example, Shekunov et al.[23] crystallized cholesterol acetate from oilin-water emulsions with supersaturation created by supercritical CO2 extraction. The produced particles had a uniform size around 200 nm and were highly crystalline. Trotta et al.[24]
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crystallized griseofulvin from an emulsion using the solvent diffusion method to produce crystals with a size smaller than 100 nm and a low polydispersity. Emulsions, in particular of the oil-inwater type, have also been used for encapsulation and delivery of crystalline hydrophobic APIs to increase the bioavailability.[25] The manufacture of solid lipid nanoparticles loaded with a crystalline API for parental administration from an emulsion is an example of an application of
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such encapsulation.[49, 50] In general, each droplet of the dispersed phase can function as a tiny
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independent crystallizer, which also makes an emulsion system, in particular within microfluidic
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devices, a suitable platform for screening of crystallization conditions and solid-state form.[28-30]
Patterned surfaces can act as an array of tiny wells for crystallization. Each well behaves as an
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isolated crystallizer due to the solid barriers between the wells. The size and shape of the wells can
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be designed and fabricated flexibly via a range of standard lithographic techniques. For example,
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photolithography[51, 52] utilizes UV light to transfer the designed patterns from a mask onto a layer of photoresist material with typical resolutions of up to 300 nm. A higher resolution can also
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be achieved when using electron-beam[53, 54] or a self-assembled blockpolymer substrate.[55] Besides, other methods such as nano-imprint lithography,[56] interference lithography,[57] nano-
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sphere lithography[58] have also been used to fabricate periodic patterns on substrates. In general, the material type, roughness and the curvature (or angle) of a well can have a significant impact on the nucleation kinetics. For example, Diao et al.[35] crystallized aspirin on different polymeric substrates and found that only some polymers were able to induce nucleation under the tested
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conditions. In another work,[34] they studied the influence of surface shape on nucleation kinetics. The results demonstrated that an angular shape can better promote nucleation in a confined space compared to a round shape, as angles in the pore may enhance the orientation of the solute during
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nucleus formation. More recently, Stojaković et al.[36] investigated the heterogeneous nucleation of paracetamol on surfaces with imprinted nanopatterns and found that the nucleation rate varied with the angle of the nanopattern. Optimal results were obtained when the angle matched the intrinsic angle of the paracetamol crystal. Many approaches are available for confining crystallization processes. Similar as when using an emulsion for crystallization, a patterned surface
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can enable high-throughput screening of crystallization conditions with little consumption of
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valuable material.[31, 32] For example, Yang et al.[31] demonstrated a new approach to map the
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attainable polymorphic form of glycine crystals as a function of temperature on a patterned
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polydimethylsiloxane (PDMS) chip with 1330 round wells (~100 μm diameter) per 1 cm2. Zhou et al.[33] probed crystallization conditions for four different proteins on a patterned PDMS patch
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with the total volume of a single droplet of only around 20 nL.
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Porous materials offer another possibility to confine crystallization. Various porous materials such as porous glasses,[59] MCM-41 silica matrix,[60] and alginate gel[61] have been applied for
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crystallization. Confined crystallization of APIs in porous matrices provides opportunities to enhance the bioavailability due to a decrease in the crystal size and potential stabilization of
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metastable polymorphs or amorphous solid states.[22, 62] The use of biocompatible porous materials further enhances the valorisation of this PI approach into real pharmaceutical processes since downstream formulation processes can be simplified. Lee et al.[37] used porous mannitol to confine tadalafil crystallization and obtained an average crystal size below 1 μm. Their in vitro
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release tests confirmed the expected improvement of the dissolution performance. Speybroeck et al.[38] used mesoporous silicate SBA-15 for encapsulating ten different poorly soluble APIs. All the SBA-15 formulations showed enhanced dissolution performance and a high stability after
and carriers for encapsulating and delivering APIs.[39-41]
2.1.2. Structurization
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storage for six months. Finally, various biodegradable polymers have also been used as excipients
The various crystallization phenomena as well as heat and mass transfer rates that shape the final
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product quality and process performance depend on the mixing characteristics of any multiphase
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crystallizer. In the early 1980s, Tavare[63] already reviewed the topic and made a distinction
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between two mixing mechanisms: micromixing at the molecular level and macromixing at the
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macroscopic level, which is related to the residence time distribution of crystals in suspension when continuous crystallizers are used. Mixing is particularly important when the supersaturation
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is generated rapidly, for example by a reaction between different compounds (i.e., so-called
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precipitation or reactive crystallization) or by the mixing of a feed stream with a miscible solvent
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that drastically reduces solubility (i.e., antisolvent crystallization). A lack of rapid mixing can lead to a high supersaturation locally, which affects crystal morphology, purity and size distribution
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often in an unpredictable way.[64-66] Mahajan and Kirwan[67] crystallized L-asparagine monohydrate from aqueous solution using 2-propanol as antisolvent in a device that was designed
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for rapid mixing. They found that crystals with a broader size distribution and a larger mean size were produced when poor mixing was present (i.e., when the induction time was shorter than the characteristic mixing time). Due to the possible large density difference between a solid and a liquid phase, a suspension density distribution may exist in the vertical direction.[68, 69]
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Sufficiently strong macromixing is required to approach ideal homogeneous suspension condition, so that no classification occurs when withdrawing product (e.g., in a continuous flow mode) and
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that all crystals have the same processing history leading to a uniform product.[70]
Many PI methods have been applied to intensify the mixing for crystallization, which are usually based on the introduction of certain structures within the crystallizer. Several recent examples are based on tubular crystallizers. Small tube diameters and low flow rates lead to laminar flow conditions. When sufficient mixing can be provided in radial direction, but not in axial direction
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(i.e., plug-flow conditions), a narrow residence time distribution can be achieved, which favours
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the production of crystals with a uniform product quality.[71-73] Auxiliary structures are often
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necessary to achieve such plug-flow conditions and to avoid classification within the tube or
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clogging.[74] Simply applying a higher velocity to approach more turbulent flow is often not desirable, because a prohibitive long tube would be required to achieve the long residence times
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that are often needed for pharmaceutical applications.
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Figure 2. Examples of the use of structures to intensify mixing in a tubular crystallizer. a)
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oscillatory baffled crystallizer;[75] b) Kenics type static mixer; c) Segmented flow.[76]
The use of oscillatory flow for crystallization is a well-developed technology to intensify the
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mixing.[75, 77, 78] The oscillatory baffled crystallizer is a tubular crystallizer with spatial orifice
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baffles (see Figure 2a). The crystallizer configuration employs a piston to oscillate the motion of the flow along the tube, which leads to the generation and cessation of eddies around baffles.
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Consequently, uniform mixing can be achieved between baffles owing to the strong radial motion.[75] Care should be taken on selecting oscillation amplitude and frequency as the oscillation can introduce axial back mixing and broaden the residence time distribution.[79] Moreover, high shearing from the oscillation flow can also induce much (usually undesired) secondary nucleation.[75] Static mixers have also been used as a PI method for improving the
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mixing in a tube under laminar flow conditions.[80] Static mixers are based on well-defined structures to redistribute the fluid mainly in the radial direction (see Figure 2b). Comparing to the oscillation flow, axial mixing can be reduced by using static mixers, thus, the real residence time
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distribution can better approach plug-flow conditions. Static mixers are commonly used only at the entrance to generate homogeneous supersaturation before crystallization or precipitation via rapid mixing. Alvarez and Myerson[81] demonstrated the use of a static mixer along the entire length of a tubular crystallizer for crystallization of flufenamic acid and L-glutamic acid. Such configuration facilitates dosage of antisolvent via multiple points distributed along the length of
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the crystallizer to produce crystals with a controllable size. The use of segmented flow is another
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example for enabling favourable plug-flow conditions in a tubular crystallizer at low volumetric
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flow rates. The solution (or slurry) is divided into small liquid/slurry segments that are separated
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by a gas or an immiscible liquid.[76, 82-84] The segmented structure avoids back mixing as each segment acts as a small independent crystallizer. Moreover, internal circulation in a segment is
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induced as the segment moves along the tube (see Figure 2c),[85, 86] which makes mixing possible
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without using any internal structures. Similarly, the application of an inert phase to induce mixing
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can also be found in air-lift crystallizers, where the mixing is induced by sparging air bubbles in a column (i.e., riser), which creates a density difference with any column in open connection to the
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riser inducing liquid circulation.[87, 88] Both the segmented flow and the air-lift mechanism
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provide mild and uniform mixing conditions, which can help to supress secondary nucleation.
2.2 Time domain
PI approaches for chemical processes in the time domain in general follow two possible strategies: manipulations of process time scales or dynamic states. In particular, the switch from batch to
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continuous mode is an important application of PI in the time domain for pharmaceutical crystallization, which aligns with the current paradigm shift for the manufacture of pharmaceuticals. Furthermore, periodic operation has also been exploited for crystallization
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processes to create a desired dynamic profile of states. For example, temperature cycling has been applied to control various critical material attributes (CMAs) of crystals such as size distribution, morphology, polymorphic form and chirality. A periodic flow pattern has been demonstrated to provide better suspension mixing and flexibility to manipulate a process residence time.
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2.2.1. Continuous operation
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Pharmaceutical manufacturing is historically dominated by batch-wise processing. However, in
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recent years, the interest in continuous manufacturing to improve efficiency and to enable better
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product-quality control has increased significantly.[89-91] In comparison to batch-wise processing, the potential advantages of continuous processing include smaller inventories,
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elimination of batch-to-batch variability, simplified process control, and reduced costs.[92, 93]
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Continuous processing also enables better integration of all processing equipment within an end-
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to-end process minimizing requirements for storage of intermediate compounds. For example, Mascia et al.[89] described a fully integrated pilot plant of an end-to-end continuous
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pharmaceutical process, which could produce tablets with aliskiren hemifumarate at a rate of around 100 g/h starting from an advanced chemical intermediate. The overall residence time of the
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process was strongly reduced from 300 hours for the batch process to 47 hours for the continuous process. Adamo et al.[90] showed for a different application that further reduction in footprint, processing time, and a high degree of modularization can be achieved. They developed an integrated and re-configurable continuous pharmaceutical manufacturing process with the size of
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a refrigerator that could produce sufficient product to supply hundreds to thousands of doses of four basic drugs per day. Such a flexible and compact manufacturing process has a great potential for on-demand production of pharmaceuticals to adjust locally to fluctuating market demands and,
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ultimately, to align with modern concepts of personalized medicine. Product quality in the pharmaceutical industry is traditionally controlled by strictly following batch recipes and validated by off-line testing. However, under the initiative of regulatory authorities, a QbD approach[94, 95] for pharmaceutical development has been recommended. QbD involves the definition of the target product profile, identification of critical quality attributes, and the design of a manufacturing
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process with appropriate control strategy to ensure that a target product performance is
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achieved.[94] The recent advances in process analytical technologies (PAT) have enabled
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important progress in the ability to measure material attributes in-situ and in real time,[96] which
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allows for effective feedback control methods to be developed.[97] The ability to operate near steady-state conditions and the availability of PAT for real-time control provide new opportunities
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robustness and flexibility.
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to align the operation of a continuous process with QbD principles to improve the process
Crystallization is a key unit operation for the separation and purification of many intermediate
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compounds and APIs in pharmaceutical processes. The paradigm shift towards continuous manufacturing in the pharmaceutical industry has, therefore, renewed the interest in continuous
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crystallization.[98] Two basic types of design for continuous crystallization have been studied: a single or multistage mixed suspension mixed product removal crystallizer (MSMPRC) and a plug flow crystallizer (PFC) (Figure 3).[9] The MSMPRC provides a robust operation, as intensive mixing can easily be achieved mechanically and the surface-to-volume ratio is small, which
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reduces fouling. Moreover, existing equipment traditionally used for batch crystallization can be utilized to realize continuous crystallization with an MSMPRC. However, the residence time distribution in a single MSMPRC is broad, which leads to a different processing history for each
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crystal and, correspondingly a non-uniform product quality. MSMPRCs can be connected sequentially to obtain a narrower residence time distribution at the expense of increased equipment costs. The use of multiple MSMPRCs in sequence also provide more degrees of freedom for design and operation such as a targeted supersaturation profile over the sequence of crystallizers.[99] The PFC offers theoretically a narrow residence time distribution and typically has a higher efficiency
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than the MSMPRC of the same volume, as the latter operates at outlet conditions. The PFC also
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allows for easy process scale-up via parallelization and dedicated feed distribution systems.[100]
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The supersaturation profile along the tube can be manipulated by distributed antisolvent addition
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or temperature control in different segments of the tube. The choice between an MSMPRC and a PFC depends on the crystallization kinetics. In general, an MSMPRC may be better used when a
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long residence time is needed due to the practical problem associated to long tubular crystallizers
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while a PFC is preferred when shorter residence times are allowed for pharmaceutical applications
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due to the superior attainable product quality that can be obtained from a tubular crystallizer. The continuous crystallization using both designs can be further combined with other technologies that
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especially work well in continuous-flow mode, such as membranes or mother liquid recycling to
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reduce waste and increase crystal yields.[101, 102]
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MSMPRC
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PFC
Figure 3. Basic configurations for multistage MSMPRCs (upper diagram) and PFC with
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antisolvent addition and temperature control (lower diagram).
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2.2.2. Periodic operation
Temperature cycling is a commonly used periodic operation strategy for crystallization, which
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employs alternating heating and cooling of the crystal suspension (see Figure 4).[103] The solution
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becomes undersaturated during the heating cycle (C to B), which leads to the (partial) dissolution
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of existing crystals and an increase in the solute concentration. Next, supersaturation is created during the cooling cycle (B to C), which causes the remaining crystals to grow and possibly new
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nuclei to appear (i.e., primary or secondary nucleation). These successive dissolutionrecrystallization cycles can be regarded as an accelerated ripening process. In particular, crystals
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are exposed to varying conditions such that metastable states can be converted to thermodynamically favoured states. Temperature cycling has been successfully used as a strategy to control various crystal quality attributes, such as crystal size distribution,[104] morphology,[105] polymorphism[106] and chirality.[107]
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Figure 4. Schematic illustration of the temperature cycling mechanism.
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Controlling a crystal size distribution is a typical motivation for temperature cycling. Small
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crystals have a larger surface-to-volume ratio and dissolve faster than big crystals, because the
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molecule packing on the surface is energetically less stable than the ordered packing within the
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crystal lattice. Consequently, fines can be removed to support the growth of larger crystals via controlled temperature cycling, which could also be seen as an intensified form of Ostwald
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ripening.[108] Since fines are usually undesired, their potential destruction via temperature cycling has become a popular technique to produce large crystals with a narrow size distribution. For
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example, Saleemi et al.[104] crystallized paracetamol from isopropanol with a narrow unimodal size distribution using temperature cycling. In addition, the temperature cycling was implemented
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in an automated fashion to effectively dissolve fines. Such direct nucleation control relies on the ability to measure the number of fines with PAT, which, for example, can be achieved by the use of focused beam reflectance measurements.[104] In addition to potential improvements of the
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crystals size distribution, temperature cycling may also help to reduce fouling and favours longterm continuous operation.[109]
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Crystal shape can also be modified via temperature cycling, [105, 110, 111] which is conventionally done by altering solvents[112, 113] or by adding growth inhibitors.[114, 115] By taking advantage of the difference between the relative dissolution and growth rates of the different crystal faces, crystals with a large attainable region on the shape can be formed using sequential growth and dissolution cycles.[116] A popular model used for analyzing the crystal shape
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evolution has been proposed by Snyder and Doherty,[117] which is based on the changing of
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perpendicular distances of crystal faces that are governed by a set of linear ordinary differential
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equations. A stable steady-state exists for growth conditions, while an unstable steady-state exists
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for dissolution, which can be demonstrated by an eigenvalue analysis. These two steady-state points can be used to construct a theoretical attainable region of crystal shape to be obtained by
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temperature cycling.[116] The target crystal shape within the attainable region can be obtained by
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applying feedback control as demonstrated recently by Eisenschmidt et al.[118]
Temperature cycling can also be used to promote crystallization of the most stable polymorph, as
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different polymorphic forms have different physical properties (e.g., solubility as a function of temperature). The mechanism of such temperature-cycling strategy can be understood via a
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solubility diagram of a crystal that exhibits two polymorphic forms (see Figure 5).[119] In this example, form II is more stable and, consequently, has a lower solubility than form I. The transformation of crystals of both form I and II to crystals of only form II can be realized by applying the illustrated temperature cycling trajectory. Crystals of form I will dissolve during the
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heating cycle and the additional supersaturation will preferentially be used for the growth of crystals of form II. Feedback control strategies can be applied to polymorphic systems due to the availability of PAT tools. For example, Simone et al.[106] developed an active polymorphic
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feedback control (APFC) strategy enabled by Raman and ATR-UV/vis spectroscopy to monitor
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the polymorphic composition and solute concentration, respectively.
Figure 5. A schematic illustration of a temperature cycling profile for obtaining crystals of a more
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stable polymorphic form (i.e., form II). [119]
Another purpose of temperature cycling can be to obtain pure enantiomers from racemic
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conglomerates. The principle of such deracemization process is based on Viedma ripening, which traditionally uses grinding to induce the chiral symmetry breaking.[120] Viedma ripening is an elegant process based on a complicated interplay between various physical phenomena. A possible mechanism proposed to understand Viedma ripening is illustrated in Figure 6, which involves four main phenomena.[121-123] Attrition by grinding produces clusters of R and S and molecules from
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the bulk crystals continuously, while the reincorporation of these chiral clusters and molecules into large crystals of the same enantiomeric form takes place. Because the reincorporation occurs at a higher rate for the enantiomer that is present in excess in the solid phase, the solution will become
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enriched with the opposite enantiomer, which shifts the racemisation reaction to the side of the solid-excessive enantiomer. Meanwhile, Ostwald ripening ensures that large crystals can keep growing at the expense of smaller crystals. As a consequence, an initially small enantiomeric excess can be amplified due to this autocatalytic effect, which over time transforms the conglomerate completely into one of the enantiomers. Similar as for grinding, temperature cycling
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can also provoke the required dissolution-growth cycles to enable the deracemization process. The
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use of programmed heating-cooling profiles for successful producing enantiomers from
A
conglomerates of a chiral compound and a salt form has been demonstrated experimentally by
A
CC
EP
TE
D
M
Suwannasang et al.[107] and Li et al.,[124] respectively.
Figure 6. Schematic illustration of a proposed mechanism of Viedma ripening.[121]
23
Crystallization processes can also be intensified by operating flows in a periodic fashion. The oscillatory baffled crystallizer is one typical example of such periodic flow as described earlier. Another example is based on operating a periodic flow of a single or multistage MSMPRC.[125,
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126] Instead of feeding and withdrawing materials at a constant flow rate, as is commonly done when operating an MSMPRC in continuous-flow mode, periodic transfer of material is applied (see Figure 7). Due to the possibility of using a high flowrate, fouling and blockage in the transfer line can be prevented by washing out. Such periodic flow operation can also be regarded as a combination of batch and continuous operation, which gives more flexibility to design the mean
EP
TE
D
M
A
N
U
residence time of crystals.
Figure 7. Profiles of inlet and outlet flowrates of a continuously and periodically operated stirred-
A
CC
tank crystallizer.
2.3 Function domain
Executing multiple processing functions in a single physical space is a classical PI strategy. If synergistic effects exist, then the different functions can lead to a better performance compared to when executing the functions separately. Traditional examples include the combination of an
24
equilibrium reaction with a separation leading to reactive distillation,[127] which enables a shift of the reaction equilibrium to the product side. A similar effect can be obtained with membrane reactors.[128] Besides synergistic effects, combining different functions also offers the potential
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to improve the process time and cost efficiency by reducing the equipment costs. Crystallization is a separation and purification method, which, like any separation technology, has kinetic and thermodynamic limitations. Therefore, combining crystallization and other separation techniques is potentially a promising strategy to enable synergistic effects leading to an overall improvement of the separation system performance. Such combination of different separation technologies into
U
an integrated separation system is also known as a hybrid separation process. Typical examples
N
for hybrid separation processes include the combination of crystallization with membranes or with
A
chromatography, which are both discussed in more detail below. Finally, methods for integration
M
of crystallization with downstream processes are discussed, which offer new opportunities to
TE
2.3.1. Hybrid separation
D
simplify a pharmaceutical manufacturing process and to achieve a better product performance.
EP
2.3.1.1. Membrane-assisted crystallization Membranes are an attractive separation technology due to the simple operation and flexibility,
CC
potentially high efficiency and selectivity for specific compounds, low energy requirements, and easy control and scale up.[129, 130] Membranes are standard solutions for many processes such
A
as desalination[131, 132] and reactive separation.[133] Membranes have also been combined with crystallization.[134-136] One main function of membranes when combined with crystallization is solvent removal to generate supersaturation. The solvent can be selectively removed using reverse osmosis[137, 138] or membrane distillation.[139] The former uses a dense membrane over which
25
a high pressure is applied against the osmotic pressure to generate sufficient driving force for solvent permeation. The latter uses a porous membrane to support a vapor-liquid interface. Consequently, heat needs to be supplied to evaporate solvent. Membranes achieve the same
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process function as evaporation. However, membranes offer flexibility to intensify and design the surface area that is available for solvent removal, which can be exploited to manipulate supersaturation generation. Moreover, membranes, in particular reverse osmosis membranes, enable solvent removal with lower energy requirements compared to evaporation, as no liquidvapor phase transition is required.[138, 140] In a solvent removal application, the membrane
U
module is typically installed within a circulation loop that operates at higher temperature, thus
N
below saturated conditions (see Figure 8).[134, 138] Therefore, crystallization in principle only
A
happens in the crystallizer and severe membrane fouling is avoided. Furthermore, if some
M
classification device is used, the membrane circulation loop can also act as a fines destruction loop. The decoupling between crystallization and membrane conditions can improve operational
D
flexibility and give better control over crystallization phenomena.[136, 141] Instead of solvent
TE
removal, the selective transport function of membranes has also been used recently for the
EP
separation of impurities[101] and solvent/antisolvent.[142] The combination of a membrane surface in contact with a solution of high concentration may promote nucleation.[143, 144]
CC
Although nucleation on the membrane or within its pores usually prevents long-term operation, the reduced induction time and different nucleation conditions can lead to different nucleation
A
behavior compared to bulk conditions, which can be attractive for discovery and production of different solid-state forms that cannot be produced easily via bulk nucleation.[142, 145]
26
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Figure 8. Schematic illustration of a membrane assisted crystallization process.
Membranes have also been combined with preferential crystallization for chiral separations.[146,
U
147] Enantioseparation of conglomerate forming systems with high efficiency has been
N
demonstrated by using two compartments that are coupled via exchange of the mother liquor (see
A
Figure 9).[148, 149] Each compartment is seeded with crystals of one type of enantiomer at the
M
start of the batch. Supersaturation is generated by cooling and is controlled to avoid primary
D
nucleation. Consequently, both seed crystals will grow and consume the corresponding enantiomer
TE
in the solution. Mother liquor needs to be exchanged between both compartments to avoid a high supersaturation of the enantiomer that is not present in solid form in a compartment. Membranes
EP
can act as an permeable barrier for liquid exchange as demonstrated by Svang-Ariyaskul et al.[147] for the case of preferential crystallization of DL-glutamic acid utilizing two crystallization
CC
compartments and an aluminum oxide membrane. Besides simply using a membrane to prevent
A
transport of crystals between both compartments, membranes can also help to extent preferential crystallization to enantioseparation of a racemic compound by taking advantage of the chiral separation function. Unlike conglomerates, a racemic compound forming system cannot be separated directly by preferential crystallization alone. A possible way for separation is using a hybrid process, which couples preferential crystallization with an enantiomeric enrichment step
27
(see Figure 10).[150] The application of an enantioselective membrane for enrichment in such hybrid process has been demonstrated by Gou et al.[151] A liquid membrane was combined with preferential crystallization for chiral separation of mandelic acid racemic solution. The results
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showed that enantiomeric excesses in at least the range of 10-20% can be achieved by using
M
A
N
U
membranes.
D
Figure 9. Schematic illustration of simultaneously preferential crystallization in two coupled
A
CC
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compartments with mother liquid exchange by using a membrane.[147]
Figure 10. Hybrid process of enantiomeric enrichment with preferential crystallization for enantioseparation of a racemic compound.
28
2.3.1.2. Integration of chromatography and crystallization The combination of chromatography and crystallization is another attractive hybrid separation
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technique, in particular for the enantiomeric enrichment in a hybrid enantioseparation process as illustrated in Figure 10. A simulated moving bed (SMB) is a continuous chromatographic process, which is of interest to be combined with preferential crystallization to achieve chiral separation for racemic compounds.[152-155] The general working principle of SMB-chromatography is illustrated in Figure 11. The chiral separation can be realized in a countercurrent moving bed
U
chromatography, where the stationary phase moves in the opposite direction of the mobile phase
N
(Figure 11a). The less retained enantiomer will move with the fluid phase, while the more retained
A
enantiomer moves with the stationary phase. As a consequence, racemic mixtures can be separated
M
and concentrated enantiomers will be collected at both ends of the chromatographic column. Instead of moving the stationary phase, The SMB process simulates the movement of the stationary
D
phase by rotating the ports for injecting and removing materials in the same direction with the fluid
TE
flow (Figure 11b). This operation enables the use of simple equipment for continuous chiral
EP
separation, which consists of a series of conventionally used stationary chromatography columns separated by valves and ports for inlets and outlets. Subsequently, the enantiomeric enriched
A
CC
mixture will be further separated by preferential crystallization to obtain the pure enantiomer.
29
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A
Figure 11. a) Schematic illustration of the working principle of a countercurrent moving bed
M
chromatography to achieve enantioseparation; b) Technical implementation to simulate a countercurrent moving bed condition by rotating inlets and outlets in the SMB-chromatography
TE
D
process.[156]
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2.3.2. Process integration
Tablets are the most common dosage form for administration of APIs due to typical advantages
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such as low cost, high dose precision, good stability, and convenient administration.[157] The formation of aggregates by granulation is usually required to avoid demixing of powders and to
A
improve the powder flowability and compactability before tableting.[158] Usually crystallization and agglomeration are separate unit operations, in contrast, so-called spherical crystallization[159, 160] has been developed as an interesting PI method that integrates crystallization and agglomeration into a single processing step. Such integration can reduce the processing time,
30
energy consumption and equipment cost. Various methods have been investigated for the fabrication of spherical crystal agglomerates, which have been described in review papers and are summarized in Figure 12.[161-163] The conventionally used methods are: spherical
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agglomeration,[159] quasi-emulsion solvent diffusion,[164] crystallo-co-agglomeration[165] and
D
M
A
N
U
ammonia diffusion system.[166]
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Figure 12. Schematic illustration of spherical crystallization methods. 1) Spherical agglomeration;
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system.
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2) Quasi-emulsion solvent diffusion; 3) Crystallo-co-agglomeration; 4) Ammonia diffusion
1) Spherical agglomeration
A
Three compounds are required for spherical agglomeration: a solvent, an antisolvent and a bridging liquid. Crystallization takes place and leads to random agglomerates when API solution is poured into an antisolvent (see Figure 12). Then a bridging liquid (e.g. chloroform[160, 167]) is added in a controlled manner to bridge and bind crystals to form spherical agglomerates.
31
2) Quasi-emulsion solvent diffusion In the quasi-emulsion solvent diffusion process, API solution is dispersed into an antisolvent to
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form a quasi-emulsion under agitation. The word “quasi” is used because the two solvents have a degree of miscibility and the formed emulsion is not stable. Driven by diffusion, solvent exchange takes place, which decreases the API solubility in the droplet and leads to crystallization. The remaining solvent in the droplet acts as bridging liquid to assist the formation of spherical
U
agglomerates.
N
3) Crystallo-co-agglomeration
A
Crystallo-co-agglomeration is a modified version of the spherical agglomeration method in which
M
an API is crystallized and agglomerated with excipients[168, 169] or another API[170] (see Figure 12). This method enables the agglomeration of poorly compressible API crystals by introducing
TE
D
excipients and by designing agglomerates that contain more than one API.
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4) Ammonia diffusion system
Some APIs are amphoteric in nature, which means that they have a low solubility in neutral and
CC
organic solvents, but are well soluble in acidic or alkaline solutions. In this respect, ammonia water (alkaline) serves as the solvent in an ammonia diffusion system. Similarly to the quasi-emulsion
A
solvent diffusion method, diffusion happens after dispersion of the API solution in an antisolvent. In particular, ammonia diffuses out of a droplet and the antisolvent diffuses into the droplet, which provokes crystallization. The remaining ammonia water serves as bridging liquid to assist the formation of spherical agglomerates.
32
For APIs with low aqueous solubility, the production of small and uniform crystals is of great importance to enhance the bioavailability in case of oral administration or inhalation therapy.[171]
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Milling techniques, such as jet milling[172] or wet milling,[173] have long been a standard approach for size reduction if crystals cannot be produced in the desired size range directly. Recent studies have shown that process intensification can be achieved by integrating wet milling and crystallization using a recycle loop.[174-177] Comparing to the conventional sequential operation, the integration of crystallization and wet milling can help to reduce the number of unit operations,
U
improve the chemical and physical stability of the product, and enhance the safety by reducing
N
API dust exposure.[177] This integrated process enables the efficient production of small crystals,
A
because large crystals formed in the crystallizer can be broken by wet milling in the recycle loop.
M
In addition, the wet milling device can also act as a nuclei generator as the high shearing intensity can significantly increase primary and secondary nucleation rates. Such nuclei generator is an
D
attractive alternative to seeding, which requires the introduction of foreign material that has to be
TE
tightly regulated.[176, 178] The combination of wet milling with a continuous MSMPRC has
EP
recently been investigated by Yang et al.[177] In particular, two integration possibilities were studied: upstream as a continuous in-situ seed generator and downstream within a recycle loop as
CC
a continuous size reduction method. The results showed that both configurations could help to produce small crystals with a narrow size distribution and lead to a higher yield compared to a
A
single MSMPRC due to the enhanced nucleation kinetics. Moreover, the use of wet milling as a nuclei generator can also significantly reduce the start-up duration.
2.4 Energy domain
33
The use of external fields is one of the most studied PI domains with applications to crystallization. Crystallization process performance can be influenced significantly by changes in local conditions such as an increase in local supersaturation, which may trigger a nucleation event. External fields
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provide a tool to manipulate process conditions on a local scale, which is one of the reasons why this PI domain has been investigated so heavily. Furthermore, with the increasing importance of crystallization of large biomolecules for biopharmaceutical applications, external fields are also of interest to directly manipulate large biomolecules to better control biopharmaceutical crystallization. In general, much evidence exists for sensitivity of numerous crystallization systems
U
with respect to the properties of external fields such that they can be used to manipulate the process,
N
but consensus on the mechanistic principles is usually not present. This section aims to provide an
A
overview of the external fields that are commonly applied to crystallization, which include
M
ultrasound, electric fields, magnetic fields, microwave fields and laser (see Table 2).
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D
Table 2. An overview on the commonly applied external fields for crystallization
CC
Laser
EP
External fields
A
Microwave
Ultrasound
Effects on crystallization
Ref
Accelerated nucleation Polymorph control Spatial control of nucleation
[179-182] [183, 184] [181]
Rapid solvent evaporation Facilitate rapid temperature control
[185-188] [189]
Accelerated nucleation and size reduction Inhibited nucleation
[190-198]
[194, 198-203]
34
Magnetic
Orientate crystal direction Polymorph control Crystal quality improvement Polymorphs separation
[204-206] [207-210] [211, 212] [213, 214] [215]
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Electric (AC/DC)
Accelerated nucleation Inhibited nucleation Crystal quality improvement Electrochemically induced crystallization In-situ particle separation
2.4.1. Ultrasound
[216, 217] [218] [219, 220] [221]
U
The potential of ultrasound to discharge metastable systems, such as a supersaturated solution, was
N
already reported in 1927.[222] Dedicated work on the application of ultrasound to crystallization
A
systems demonstrated the ability to produce smaller and more uniform crystals decades ago.
M
Hem[223] reviewed the possible mechanisms of ultrasound-assisted crystallization of this earlier
D
work and concluded that a heterogeneous nucleation mechanism was supported by the strongest
TE
evidence at that time compared to any mechanism related to cavitation pressure. The possibility to make smaller and more uniform crystals is obviously important for pharmaceutical applications to
EP
potentially enhance dissolution rates and to improve product quality, respectively. This importance combined with the complexity of both the crystallization process itself and ultrasonics have
A
CC
triggered a substantial amount of work on so-called sonocrystallization in the recent decades.
Ultrasound can enhance crystallization by reducing the induction time and decreasing the crystal mean size, which has been demonstrated for many applications.[190-198] However, ultrasound may also inhibit crystallization depending on the operating conditions and system properties.[194, 198-203] The mechanism for enhancement of crystallization kinetics has been subject of debate
35
for over half a century. Ultrasonic waves can create imploding cavities in solution, enhance mixing, increase mass transfer and provide heat. All of these effects can influence various crystallization kinetics. For example, Thompson and Doraiswamy[224] demonstrated experimentally how
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ultrasound increased solubility, which was attributed to the formation of hot spots bringing the solvent in a supercritical state. Ultrasonic waves improve mixing and thus product quality is likely to improve in case of reactive and anti-solvent crystallization.[190] Furthermore, the increased shear can break agglomerates.[190, 192, 199, 225] Guo et al.[192, 226] attributed the enhancement of nucleation in an ultrasonic field to an increased diffusion coefficient. Furthermore, Guo et
U
al.[191] also considered heterogeneous nucleation induced by the surface area of the tiny bubbles
N
as a possible mechanism. Dodds et al.[227] used a classical homogeneous nucleation model as a
A
basis to describe a segregation mechanism based on the attachment of molecules to clusters and
M
aggregation between clusters driven by pressure gradients in the presence of cavitation. Virone et al.[196] also used a classical primary nucleation model as a basis for a mechanistic explanation of
D
the increased nucleation rate. They proposed that the local increase in pressure due to a bubble
TE
implosion would significantly increase the driving force for primary nucleation. Finally, in a
EP
number of papers, Schembecker and co-workers considered the enhanced heterogeneous nucleation rate due to the surface of the bubbles that provides an interface for nucleation as main
CC
mechanism.[228-231] The elegance of their work is that control experiments were done in which similar conditions were created, i.e., a large number of small bubbles were created from gassing,
A
in absence of any ultrasound, and similar effects were observed, which provides strong evidence for an enhanced heterogeneous nucleation mechanism.
36
The unique abilities of ultrasound to manipulate a crystallization process has led to various dedicated applications. For example, the manufacture of pulmonary drugs in dry powder form is challenging due to the strict requirements for particle size and shape.[232] Currently, milling is
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used to break big crystals into smaller fragments such that the particles can be deposited efficiently in the lungs via inhalation. Milling processes have various disadvantages such as a loss of yield, complicated process behaviour, and high shear forces that affect the surface properties of the crystalline particles. Therefore, producing API crystals with the desired product quality attributes can significantly simply the process by avoiding milling.[233] Abbas et al.[202] used the ability
U
of ultrasound to reduce the mean crystal size to produce crystalline particles that are suitable for
N
pulmonary drug delivery with a simple process based on ultrasound. Dhumal et al.[201]
A
demonstrated that ultrasound enabled the manufacture of high-quality particles of salbutamol
M
sulphate for inhalation, which is an API used to treat diseases such as asthma and chronic obstructive pulmonary disease. Furthermore, they developed an ultrasound-based crystallization
D
method for lactose crystals for inhalation, which was also superior compared to a conventional
EP
TE
process.[200] Such process for lactose was further developed at a large scale.[234]
Biopharmaceuticals are an important growing class of products within pharmaceutical industry.
CC
Crystallization is of interest as a separation and purification technology. However, the nucleation of large biomolecules such as proteins is notoriously difficult. Ultrasound can potentially achieve
A
intensification of protein crystallization, as induction times can be reduced. Kakinouchi et al.[198] demonstrated that the time needed for crystallization of lysozyme could either be enhanced or reduced depending on the application time of ultrasound, which suggests that ultrasound can also disrupt nucleation clusters when used for a long period. Crespo et al.[235] showed that the
37
metastable zone of lysozyme nucleation could be reduced by using ultrasound, which led to higher quality protein crystals. Furthermore, audible sound with a lower frequency compared to
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ultrasound was also found to enhance the crystallization rate of various proteins.[236]
The scale-up of ultrasound-based crystallization processes is arguably one of the greatest challenges for applications of this PI method in pharmaceutical industry. Although a number of studies on pilot-scale exist,[194, 203, 233] the vast majority of literature reports involve studies conducted on a lab-scale. The difficulty for scale-up of sonocrystallization is caused by at least
U
two main reasons. First, the complexity of sonocrystallization severely limits the possibility to
N
develop first-principle process models that have predictive capabilities over several order of
A
magnitude in production scale. Second, the penetration depth of ultrasound in solution is limited
M
to several centimetres only due to dissipation.[203] Therefore, the effect of ultrasound may completely diminish when translated directly to a larger scale. The scale-up problem of ultrasound
D
is especially profound when operating the crystallization process in batch mode, which is the
TE
traditional mode of operation in pharmaceutical industry. In a batch process, by definition, all
EP
material is processed at the same time. Therefore, irradiation of the complete process volume with ultrasound may only affect a small portion. Indeed it has been demonstrated that the use of
CC
ultrasound within a small part of a batch crystallization at pilot-scale to generate the initial crystal population may be insufficient and conventional methods such as seeding can give a superior
A
process performance, despite the more elaborative operational procedures that are needed for seeding.[194] However, the current trend in pharmaceutical industry toward continuous manufacturing provides new opportunities for application of sonocrystallization on a production scale. Continuous processing has an inherent advantage for scale-dependent PI methods in the
38
sense that not all material has to be processed at the same time. Therefore, systems with flow cells are promising for effective application of ultrasound in the pharmaceutical industry, as has been demonstrated by several studies.[237-241] Finally, the production volumes of biopharmaceuticals
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are often low, which reduces uncertainty from scale-up for this class of pharmaceuticals.
2.4.2 Electric field
The application of electric fields in crystallization of biopharmaceuticals has been extensively investigated in various forms in the past two decades. Approaches in which a protein solution stays
U
either in direct or indirect contact with a direct current (DC) or alternating current (AC) electric
N
field have been investigated.[205, 208, 212, 242-244] In general, electric fields provide an ability
A
to control protein crystallization kinetically with enhanced or reduced nucleation rates and
M
spatially by controlling the orientation and nucleation location of crystals. An extensive review on the impacts of an electric field on protein nucleation and growth has been provided recently by
TE
D
Nanev.[245]
EP
Driven by the motivation of obtaining high-quality crystals, Aubry’s group conducted the first study on electric-field-assisted protein crystallization, where lysozyme crystallization occurred in
CC
a sitting or hanging drop subject to a strong external DC electric field.[211, 212] It was found that with the applied electric field, fewer crystals were formed, but the crystals had a larger size, which
A
indicates a reduction in the nucleation rate. The crystals tended to nucleate near the cathode side of the droplet surface. They attributed this preferred nucleation location to the enhanced local supersaturation as a result of the concentration gradient between the electrodes formed by the
39
electric field. The crystal quality improved by the electric field, which was also confirmed by a recent work of Rubin et al. using X-ray diffraction analysis.[246]
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In addition to adjusting the electric field strength and frequency, the distribution of the electric field strength can be shaped flexibly by using electrodes of different materials and shapes and by varying the spatial arrangement of the electrodes. Nanev and Penkova studied lysozyme crystallization in a custom-made glass cell and observed preferred orientation of crystals along the c-axis with an external DC electric field at very low temperature.[242] They also showed that the
U
electric field can be augmented with an ultrasonic field to enhance the nucleation rate while
N
orienting the crystals. Besides lysozyme, the nucleation rate of ferritin and apoferritin could also
A
be varied with the applied electric field.[247] Moreno and Sazaki used two parallel platinum
M
electrodes to create a weak internal DC electric field (typically 4 mV/cm) over a lysozyme solution and a lysozyme gel. Compared to the strong electric fields used in the earlier studies (in the order
D
of several kV/cm), they found that the weak electric field could also influence crystallization by
TE
reducing the induction time with fewer crystals, but with a larger size.[208] Later, they explored
EP
the potential of using multiple electrodes with different geometries and showed that crystallization results were more reproducible at a controlled potential.[248] Veesler’s group investigated the
CC
influence of a large electric field and field gradient on crystallization of lysozyme and bovine pancreatic trypsin inhibitor (BPTI), and demonstrated the feasibility to spatially and temporally
A
control the nucleation process.[206, 249] For example, three successive nucleation waves of BPTI were triggered at the anode by adjusting the applied voltage.
40
To eliminate the Faradaic reactions at internal electrodes at high DC voltages, the application of AC electric fields has also been investigated for protein crystallization. Hou and Chang showed that a non-uniform AC electric field can reduce the number of nucleation sites and enhance the
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crystal quality.[250] Furthermore, it was concluded that the dielectrophoretic force may concentrate the crystals towards the electric field strength minima. Koizumi’s group conducted a series of experimental and theoretical investigations to interpret how the AC electric fields can influence protein crystallization. It was revealed that the increased or decreased nucleation rate of lysozyme by the AC electric fields with various frequency was a result of the difference between
N
U
the electrical permittivity of the liquid and solid phases.[209, 210, 244]
A
With the advantage of good optical transparency and high electrical conductivity, indium tin oxide
M
(ITO) has become a popular material to fabricate the electrodes used in crystallization experiments. Several devices have been designed for better control over nucleation rate and crystal quality using
D
ITO electrodes.[205, 251, 252] Li and Lakerveld[205] tested various patterns for a bottom
TE
electrode in a microfluidic device with a parallel-plate configuration and examined the influence
EP
of non-uniform AC electric fields on lysozyme and insulin crystallization. The nucleation rate was found to depend not only on the electric field properties but also on the shape and surface area of
CC
the bottom electrode while the nucleation location was influenced by the ITO layer as a template and also by the non-uniform electric field. For instance, the preference for protein nucleation on
A
the ITO surface in the absence of an electric field was weakened by an electric field of 1 MHz, pointing to a negative dielectrophoretic response of lysozyme, as the edged glass surface provided an electric-field minimum. Finally, the distribution of different solid phases can also be controlled by varying the electric field frequency.[253]
41
Besides the main application for electric fields for large biomolecules such as proteins, electric fields can also assist the crystallization of small organic molecules. At least two possible types of
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applications have been approached: electrochemically induced crystallization (EIC) and crystal separation. The EIC approach mainly takes advantage of the pH-dependent solubility profile of acidic or basic organic molecules, i.e., their free forms commonly have a lower solubility than the salt forms in aqueous solution. Electrolysis of water is used to locally shift the pH to create supersaturation for crystallization.[213, 214] In general, a non-uniform electric field can induce
U
dielectrophoretic and possibly electrophoretic forces, which have been used for particle
N
manipulation in various applications.[254] Recently, Li et al. demonstrated the successful
A
application of this concept for crystal separation. In particular, they crystalized and collected
M
phenazine and caffeine crystals at different electrodes under strong DC electric fields with purities
TE
2.4.3 Other fields
D
greater than 91%.[215]
EP
Microwave fields are generally believed to intensify chemical processes due to two effects: thermal effects or non-thermal effects.[255] The former effect is based on the notion that microwaves
CC
enable heating of fluid orders of magnitude faster than conventional heating. Moreover, microwave heating is volumetric and does not need any heat transfer surface, which favours
A
heating with smaller temperature gradients. Special effects related to mass transfer have also been reported to enable applications such as microwave-enhanced extraction[256] and microwaveenhanced molecular diffusion in polymeric materials.[257] Microwave irradiation has been used for crystallization by taking advantage of its thermal effect in two directions: microwave-assisted
42
evaporative crystallization and microwave-assisted temperature control for crystallization. Microwaves can provide rapid heating to enable exceptionally fast solvent evaporation,[185] which favours fast supersaturation generation and thus the production of crystals with reduced size.
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Microwave-accelerated evaporation can also be combined with silver nanoparticles that act as nucleation sites for amino acids crystals with selective morphology such as for acetaminophen,[186] glycine,[187] arginine.[188] Temperature control is important for crystallization and practical challenges can exist when a crystallizer is equipped with conventional actuation for both heating and cooling (e.g., under temperature cycling operation). Any change
U
between heating and cooling fluids will prolong the processing time and may introduce significant
N
time delays due to temperature control when heating-cooling cycles are used. Microwave heating
A
can intensify such temperature control by decoupling the actuation for heating and cooling and by
M
exploiting the exceptionally fast heating rate when using microwaves, which can lead to a significantly reduced batch time when temperature cycling is used, for example for fines
TE
D
destruction.[189]
EP
Magnetic fields have been applied to assist crystallization of metallic alloys,[258] inorganic salts, [259] and proteins.[260] An orientation effect on crystallization can be seen when using magnetic
CC
fields. For example, a magnetic field can favour the crystallization of calcium carbonate in aragonite form instead of calcite or vaterite.[218] A possible explanation for this phenomenon is
A
that the electrically charged nuclei would interact with the magnetic field. The resulting Lorentz force can modify the preferential surface for crystal growth.[261] As the aragonite form is needlelike and less adhesive to equipment walls, the magnetic field can be applied to relieve the scaling problem in water-treatment devices.[262] Macromolecules such as proteins also show sensitivity
43
to a magnetic field during crystallization. Lysozyme is the most commonly used model compound for studying the influence of magnetic fields on protein crystallization. The tetragonal form of a lysozyme crystal will grow with the c-axis aligned in the direction of magnetic field, which is due
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to the diamagnetic anisotropy of the peptide group in the amino acid sequence.[216] Sazaki et al. reported that this alignment of lysozyme crystals may be further enhanced by coupling magnetic fields with electric fields.[217] Magnetic fields have also been superimposed to gravitation to adjust the apparent gravitational force in a crystallization environment. Ramachandran and Leslie[219] used magnetic fields to counter the gravitation and mimicked the microgravity
U
environment of space for crystallization. The results demonstrated that crystal quality could be
N
improved with the reduced density-induced convection during crystal growth. Improvement in
A
crystal quality and alignment of crystals in parallel to the magnetic field were also observed for
M
other biomolecules such as monomeric sarcosine oxidase, acylphosphatase and nucleoside diphosphate kinase when the applied magnetic field was sufficiently strong to cancel out the
D
gravitational force of the solution.[220] Atkinson et al.[221] used magnetic levitation to separate
TE
mixtures of crystal polymorphs by taking advantage of the density difference between different
EP
polymorphs. This technique allows for fast separation of polymorphs that have a density difference
CC
larger than 0.001 g/cm-3.
Finally, laser is another promising external field for assisting crystallization, which is mainly used
A
to enhance the nucleation rate in supersaturated solutions. Several mechanisms have been proposed to understand the acceleration of nucleation under different types of laser irradiation, which can be categorized into photochemical and non-photochemical effects. Photochemical reactions can be triggered by a laser beam with short wavelength. As experimentally demonstrated by the
44
Okutsu’s research group, ultraviolet laser irradiation can induce photodimerization of anthracene and benzophenone to produce dipara-anthracene and benzopinacol crystals.[263, 264] They also showed in their later work for lysozyme crystallization that continuous ultraviolet laser irradiation
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could give rise to lysozyme radical intermediates, which improved the attractive interaction between molecules and enhanced nucleation.[179, 180] One important non-photochemical effect is the generation of cavitation bubbles by a laser, which can create a high supersaturation locally[181] and provide a surface for heterogeneous nucleation similarly as ultrasound can do.[182] Furthermore, Garetz et al. also demonstrated that the oscillating electric field of the laser
U
light can help to align and organize clusters as a source for nucleation, therefore, can reduce the
N
induction time for nucleation and enable control over the polymorphic form.[183, 184] Several
A
experimental results have shown that the intensity of the laser plays a more pronounced role than
M
wavelength in non-photochemical effects.[265] [266]
D
3. Conclusion and perspective
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This paper provides a systematic review of PI approaches for pharmaceutical crystallization.
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Following the framework proposed by Van Gerven and Stankiewicz,[11] the PI methods are categorized into four domains (i.e. space, time, function, energy) and are all illustrated with several
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examples. The list of examples is not exhaustive, which stresses the significant amount of literature that exists on this topic. Furthermore, examples often point to significant opportunities to intensify
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pharmaceutical crystallization processes. However, despite this vast body of literature and demonstrated opportunities, applications for PI of pharmaceutical crystallization at an industrial scale can only be found occasionally in open literature. A common argument for this apparent slow adoption rate is the traditional conservative and highly regulated business environment within the
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pharmaceutical industry. Nevertheless, the current business environment (e.g., increased competition, a changing mindset, strong regulatory support for innovation) and rapid development of new technological innovations provide a favourable ecosystem for the further adoption of PI for
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pharmaceutical crystallization. Part of those technological innovations have been addressed in this review paper, i.e., specific technological innovations that share at least one of the fundamental characteristics of PI. Furthermore, those methods often rely on enabling technologies such as PAT and continuous processing, which are increasingly adopted. Finally, much of the work reviewed in this paper is very recent, which indicates the strong current interest in the topic for future
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development.
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In general, the levels of maturity of the reviewed PI approaches for pharmaceutical crystallization
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differ. For example, technologies that can be used for screening of crystallization conditions (mainly in the structure domain) are readily available. However, the readiness of PI approaches in
D
the structure domain for manufacturing varies. For example, approaches that inherently rely on a
TE
large surface-to-volume ratio are likely not suitable for manufacturing (e.g., nanopatterns),
EP
whereas other approaches are readily available including the required equipment (e.g., various plug-flow crystallizers, emulsion crystallization, encapsulation). In the function domain,
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particularly some of the methods that integrate crystallization with downstream unit operations of pharmaceutical processes are mature and readily available, whereas hybrid separation methods
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such as membrane-assisted crystallization have been widely studied, but examples beyond laboratory scale in pharmaceutical industry are practically absent. This lack of industrial applications may be attributed to concerns regarding process robustness and the potential build-up of impurities, which is an important concern for pharmaceutical processes. The PI approaches in
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the time and energy domain offer many new opportunities for pharmaceutical crystallization. For example, continuous pharmaceutical crystallization (time domain) is growing rapidly both as a method itself and as an enabling technology for PI approaches in the energy domain. PI approaches
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in the energy domain often need a large surface-to-volume ratio for energy transfer and work better when processing smaller volumes per unit of time, which are both inherently enhanced by continuous processing compared to batch-wise processing. Furthermore, PAT has been a key enabling technology for PI approaches in the time domain, which are now widely available (e.g., when using temperature cycling). Hybrid chromatography is particularly interesting for chiral
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separations, because of synergistic advantages with crystallization, robustness, and the importance
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of chiral separations in pharmaceutical processes. In conclusion, it is clear that a broad window of
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opportunities currently exists for adopting and extending PI approaches for pharmaceutical
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crystallization due to a favourable combination of economical, regulatory, and technological
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[251] G. Gil-Alvaradejo, R.R. Ruiz-Arellano, C. Owen, A. Rodríguez-Romero, E. RudinoPinera, M.K. Antwi, V. Stojanoff, A. Moreno, Novel protein crystal growth electrochemical cell for applications in x-ray diffraction and atomic force microscopy, Cryst. Growth Des. 11 (2011) 3917-3922. [252] E. Flores-Hernández, V. Stojanoff, R. Arreguín-Espinosa, A. Moreno, N. Sánchez-Puig, An electrically assisted device for protein crystallization in a vapor-diffusion setup, J. Appl. Crystallogr. 46 (2013) 832-834. [253] Y. Tomita, H. Koizumi, S. Uda, K. Fujiwara, J. Nozawa, Control of Gibbs free energy relationship between hen egg white lysozyme polymorphs under application of an external alternating current electric field, J. Appl. Crystallogr. 45 (2012) 207-212. [254] Á.V. Delgado, F. Carrique, R. Roa, E. Ruiz-Reina, Recent developments in electrokinetics of salt-free concentrated suspensions, Curr. Opin. Colloid Interface Sci. 24 (2016) 32-43. [255] S.A. Galema, Microwave chemistry, Chem. Soc. Rev. 26 (1997) 233-238. [256] J. Gujar, S. Wagh, V. Gaikar, Experimental and modeling studies on microwave-assisted extraction of thymol from seeds of Trachyspermum ammi (TA), Sep. Purif. Technol. 70 (2010) 257-264. [257] Y. Nakai, H. Yoshimizu, Y. Tsujita, Enhanced gas permeability of cellulose acetate membranes under microwave irradiation, J. Membr. Sci. 256 (2005) 72-77. [258] A.a. Mikelson, Y.K. Karklin, Control of crystallization processes by means of magnetic fields, J. Cryst. Growth 52 (1981) 524-529. [259] H.L. Madsen, Influence of magnetic field on the precipitation of some inorganic salts, J. Cryst. Growth 152 (1995) 94-100. [260] S. Surade, T. Ochi, D. Nietlispach, D. Chirgadze, A. Moreno, Investigations into protein crystallization in the presence of a strong magnetic field, Cryst. Growth Des. 10 (2009) 691-699. [261] J. Donaldson, S. Grimes, Lifting the scales from our pipes, New Sci. 117 (1988) 43-46. [262] S. Koce, H. Eražić, P.J. McHuiness, J. Stražišar, The influence of the magnetic field on the crystallisation form of calcium carbonate and the testing of a magnetic water-treatment device, J. Magn. Magn. Mater. 236 (2001) 71-76. [263] T. Okutsu, K. Isomura, N. Kakinuma, H. Horiuchi, M. Unno, H. Matsumoto, H. Hiratsuka, Laser-induced morphology control and epitaxy of dipara-anthracene produced from the photochemical reaction of anthracene, Crystal growth & design 5 (2005) 461-465. [264] T. Okutsu, K. Nakamura, H. Haneda, H. Hiratsuka, Laser-induced crystal growth and morphology control of benzopinacol produced from benzophenone in ethanol/water mixed solution, Cryst. Growth Des. 4 (2004) 113-115. [265] R. Kacker, S. Dhingra, D. Irimia, M. Ghatkesar, A. Stankiewicz, H.J. Kramer, H.B. Eral, Multi-parameter investigation of laser induced nucleation of supersaturated aqueous KCl solutions, Cryst. Growth Des. (2017). [266] R. Murai, H.Y. Yoshikawa, H. Hasenaka, Y. Takahashi, M. Maruyama, S. Sugiyama, H. Adachi, K. Takano, H. Matsumura, S. Murakami, Influence of energy and wavelength on femtosecond laser-induced nucleation of protein, Chem. Phys. Lett. 510 (2011) 139-142.
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S0255-2701(18)30055-2 https://doi.org/10.1016/j.cep.2018.03.018 CEP 7228
To appear in:
Chemical Engineering and Processing
Received date: Revised date: Accepted date:
16-1-2018 17-3-2018 17-3-2018
Please cite this article as: Wang J, Li F, Lakerveld R, Process Intensification for Pharmaceutical Crystallization, Chemical Engineering and Processing (2010), https://doi.org/10.1016/j.cep.2018.03.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Crystallization
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Process Intensification for Pharmaceutical
Jiayuan Wang, Fei Li, Richard Lakerveld*
Department of Chemical and Biological Engineering, The Hong Kong University of Science and
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Technology, Clear Water Bay, Hong Kong
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Email: [email protected]
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Graphical abstract
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Highlights A systematic review on process intensification for pharmaceutical crystallization Principles and examples of process intensification methods for crystallization Perspectives on the opportunities for intensifying pharmaceutical crystallization
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ABSTRACT
Process intensification (PI) provides great opportunities to drastically improve the performance of
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chemical processes within many branches of chemical industry including the pharmaceutical
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industry. Crystallization is an important purification and separation technology within many
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pharmaceutical processes. This paper provides a systematic review on the recent developments of
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PI approaches that are applicable to pharmaceutical crystallization. The various approaches are categorized according to the four fundamental PI domains (space, time, function, energy) that have
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been proposed in literature. Each approach is illustrated with examples from literature with an
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emphasis on the opportunities to intensify pharmaceutical crystallization processes. Finally, some
provided.
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thoughts on the level of maturity for industrial implementation of the various approaches are
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KEYWORDS
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Process Intensification, Pharmaceutical Crystallization, Crystallization, Review
1. Introduction
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Pharmaceutical industry is a trillion dollar industry that produces high value-added products with stringent specifications for quality attributes. Traditionally, the use of methods for process intensification (PI) with step changes in performance has been complicated by the highly regulated
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environment of pharmaceutical industry and a typical business model focusing on molecule discovery and minimizing time-to-market to enjoy long patent protection. Consequently, any process innovations that might be subject to a long approval period are usually avoided. Therefore, the drug production is usually carried out according to a licensed recipe developed at the end of the research and development (R&D) phase even if the process efficiency could be improved
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significantly via methods for process intensification during commercial manufacturing. However,
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in recent years, pharmaceutical industry is challenged by the need for more efficient manufacturing
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processes driven by:
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1. increased competition from the generic market due to patent expirations of many drugs;[1] 2. increased cost of R&D for new drugs;[2]
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3. the growing demand for “greener” products and processes;[3]
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4. a changing mindset within the industry[4] and new regulatory incentives.[5-7]
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Therefore, there is currently an attractive window of opportunities to adopt innovations to the pharmaceutical industry. The systematic use of PI methods can be an important blueprint for such
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change.
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Crystallization is an important unit operation within many pharmaceutical processes for the separation and purification of intermediate compounds and active pharmaceutical ingredients (APIs). In comparison to processes delivering a liquid product, design and control of crystallization processes is complicated by stringent product requirements related to the intrinsic quality attributes
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of the crystalline phase. In particular, besides purity, other properties such as crystal size distribution, shape, and solid-state form should also be taken into consideration, as they have a significant impact on downstream processing (e.g. filtration, drying, milling, tableting) and final
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product performance (e.g., bioavailability). Pharmaceutical crystallization is traditionally not among the frontrunners of PI, nevertheless, step changes in performance of crystallization processes are also desirable in view of the general drivers of innovation in the pharmaceutical industry to meet future challenges. However, although review articles on the challenges and progress of pharmaceutical crystallization exist,[8, 9] a dedicated review on the opportunities of
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PI methods that can be applied to pharmaceutical crystallization is, to the best of our knowledge,
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currently lacking in literature, despite the significant recent development and understanding of PI
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methods that can be applied to pharmaceutical crystallization. Therefore, this paper aims to provide
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a systematic overview of the recent developments of those PI methods that can be applied to
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pharmaceutical crystallization.
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Several definitions have been proposed for the scope of PI based on different perspectives.[10-14]
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Van Gerven and Stankiewicz[11] provide a comprehensive and fundamental vision of PI. Instead of proposing a new definition for PI, they discuss and categorize the underlying principles,
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approaches and application scales of PI. This review paper will follow the framework proposed by Van Gerven and Stankiewicz[11] to present a systematic overview of PI methods for
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pharmaceutical crystallization. In particular, the methods will be categorized into the proposed four domains (i.e., time, space, energy and function) to adopt a fundamental view of PI. This review is not intended to be an exhaustive list of the numerous examples of PI approaches that have been used for various crystallization systems. Instead, we aim to provide a systematic
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overview on how pharmaceutical crystallization can benefit from the use of PI approaches by using a fundamental framework and selected examples. Furthermore, we do not explicitly distinguish between examples applied to pharmaceutical systems or other applications in chemical industry,
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as often there is no strict barrier between different application areas. Instead, we focus on PI methods with potential performance improvements on throughput and product quality control, which are generally most important for pharmaceutical applications. Finally, some perspective on the current opportunities for the implementation of PI approaches for pharmaceutical
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crystallization are discussed.
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2. PI approaches applied to pharmaceutical crystallization
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Solution crystallization involves the formation of a crystalline solid state from a homogeneous
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solution. Supersaturation is the driving force for crystallization, which is defined by the ratio of the chemical potential of the solute in solution and the chemical potential of the solute in the
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crystalline state and is often approximated by the ratio of the solute concentration to the solubility.
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Important material attributes of crystals include the crystal size distribution, shape, purity and
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polymorphic form. These material attributes may be critical to final product performance (i.e., affect critical quality attributes (CQAs) such as stability and bioavailability) when the crystals are
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incorporated in the final product and process throughput (i.e., the amount of crystalline material produced per unit of time[15]) when the crystal attributes affect downstream processes (see Figure
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1).
Crystal attributes are determined by crystallization kinetics in a multicomponent, multiphase system, which are usually complicated due to interdependent physical phenomena. For example,
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crystal growth and various forms of nucleation depend differently and often in a non-linear way on supersaturation. Dissolution of crystals only occurs in an under-saturated solution. Furthermore, agglomeration may take place at high supersaturation due to fast and uncontrolled solid-phase
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formation. Fluid shear induces mixing of a homogeneous liquid phase and improves mass and heat transfer. However, crystal breakage and attrition can also be provoked in areas with high shear, which makes the production of large crystals difficult. In addition, agglomeration is typically insignificant at conditions of either very low or high shear forces due to the competing interplay between the crystal collision rate, which is needed for the formation of agglomerates, and breakage
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of agglomerates. In this respect, one could argue that ultimately any PI approach applied to
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pharmaceutical crystallization needs to improve the independent control over these crystallization
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phenomena, thus, providing opportunities to improve the process flexibility, throughput and
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product quality control.[16] Such improvement would also align well with the concept of quality-
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pharmaceutical industry.
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by-design (QbD),[17, 18] which is currently one of the main regulatory incentives for
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This paper is structured according to the four fundamental PI domains with applications to pharmaceutical crystallization as illustrated in Figure 1. The classification has been developed
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based on the dominant features or intentions of the PI methods developed for crystallization,
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although some of the methods contain elements of several of the PI domains.
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Figure 1. An overview of process intensification for pharmaceutical crystallization.
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2.1 Space domain
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Spatial inhomogeneity complicates control and operation of chemical processes. Therefore, several PI approaches have been developed based on the general strategy to tightly control or
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restrict the processing space such that predictable operating conditions can be created for optimized process design and operation. Predictable operating conditions on a local scale are also
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important for crystallization processes, as the various crystallization phenomena that shape the final product quality have a different and often non-linear dependency on the solution properties.
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Crystallization from a bulk solution is usually difficult to predict and control due to spatial gradients in concentration, temperature, and momentum. Moreover, the spatial distribution of crystals within a crystallizer is often not uniform, which further complicates prediction and control. For example, large crystals tend to accumulate at the bottom of an agitated crystallization vessel.
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Finally, even if spatial gradients in solution properties and the dispersed phase could be well predicted, operation under inhomogeneous conditions remains undesirable since the differences in processing history of the crystals will lead to a non-uniform final product quality. PI approaches
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have been developed in the “space domain” to improve control over processing conditions that are relevant for crystallization. In particular, the PI approaches for crystallization in the space domain can be divided into two main directions: miniaturization and structurization as discussed below.
2.1.1. Miniaturization
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Miniaturization refers to crystallization in a confined space. Compared to crystallization in a bulk
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space, a confined space can create well-defined solution properties as a function of spatial
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coordinates and offers different crystallization behaviour mainly due to inherent volume effects
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and various surface effects. With respect to volume effects, due to the stochastic variability of nucleation, a significantly wider metastable zone may be present with suppressed homogeneous
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primary nucleation at a miniaturized scale.[19] The rapid depletion of supersaturation in a confined
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space due to the physical barriers limit crystal growth, which obviously favours the production of
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small crystals. However, besides crystal size, several studies have also shown that confining the processing volume for crystallization can also affect the polymorphic form of the produced
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crystals.[20-22] Such volume-dependent polymorphic preference has been attributed to the critical nucleus size according to the classical nucleation theory applied to a confined volume.[21]
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Confining crystal growth within pores that have a dimensions at or near the critical nucleus size could lead to stabilization of metastable polymorphs. In terms of surface effects, the miniaturized crystallization space offers a large surface-to-volume ratio, which offers opportunities to exploit
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heterogeneous nucleation to control crystal formation. Three popular approaches for miniaturization are summarized in Table 1 and discussed next.
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Table 1. Examples of enabling technologies for confining the crystallization conditions via miniaturization. Enabling technologies
Objectives
1. Production of small crystals 2. Drug encapsulation and delivery 3. Screening of crystallization conditions
[[23], [24]] [[25-27]] [[28-30]]
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Emulsion crystallization
References
[[31-33]] [34-36]
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1. Crystallization condition screening 2. Control of polymorphic form
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Crystallization on patterned surfaces
1. Drug encapsulation and delivery
[[37-41]]
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Crystallization inside porous materials
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An emulsion is a mixture of at least two immiscible liquids in which one liquid phase is dispersed in a continuous phase of the other liquid. Droplets with a uniform and controllable size from micro
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to nano-meter scale can be obtained during emulsification by using mechanical energy from intensive mixing[42, 43] or by using chemical energy from phase-transition phenomena.[44, 45] Microfluidic devices have also been used to produce emulsions with precise control over droplet size via confinement.[46-48] Emulsion crystallization can be used to produce crystals with a
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uniform and small size. For example, Shekunov et al.[23] crystallized cholesterol acetate from oilin-water emulsions with supersaturation created by supercritical CO2 extraction. The produced particles had a uniform size around 200 nm and were highly crystalline. Trotta et al.[24]
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crystallized griseofulvin from an emulsion using the solvent diffusion method to produce crystals with a size smaller than 100 nm and a low polydispersity. Emulsions, in particular of the oil-inwater type, have also been used for encapsulation and delivery of crystalline hydrophobic APIs to increase the bioavailability.[25] The manufacture of solid lipid nanoparticles loaded with a crystalline API for parental administration from an emulsion is an example of an application of
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such encapsulation.[49, 50] In general, each droplet of the dispersed phase can function as a tiny
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independent crystallizer, which also makes an emulsion system, in particular within microfluidic
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devices, a suitable platform for screening of crystallization conditions and solid-state form.[28-30]
Patterned surfaces can act as an array of tiny wells for crystallization. Each well behaves as an
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isolated crystallizer due to the solid barriers between the wells. The size and shape of the wells can
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be designed and fabricated flexibly via a range of standard lithographic techniques. For example,
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photolithography[51, 52] utilizes UV light to transfer the designed patterns from a mask onto a layer of photoresist material with typical resolutions of up to 300 nm. A higher resolution can also
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be achieved when using electron-beam[53, 54] or a self-assembled blockpolymer substrate.[55] Besides, other methods such as nano-imprint lithography,[56] interference lithography,[57] nano-
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sphere lithography[58] have also been used to fabricate periodic patterns on substrates. In general, the material type, roughness and the curvature (or angle) of a well can have a significant impact on the nucleation kinetics. For example, Diao et al.[35] crystallized aspirin on different polymeric substrates and found that only some polymers were able to induce nucleation under the tested
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conditions. In another work,[34] they studied the influence of surface shape on nucleation kinetics. The results demonstrated that an angular shape can better promote nucleation in a confined space compared to a round shape, as angles in the pore may enhance the orientation of the solute during
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nucleus formation. More recently, Stojaković et al.[36] investigated the heterogeneous nucleation of paracetamol on surfaces with imprinted nanopatterns and found that the nucleation rate varied with the angle of the nanopattern. Optimal results were obtained when the angle matched the intrinsic angle of the paracetamol crystal. Many approaches are available for confining crystallization processes. Similar as when using an emulsion for crystallization, a patterned surface
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can enable high-throughput screening of crystallization conditions with little consumption of
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valuable material.[31, 32] For example, Yang et al.[31] demonstrated a new approach to map the
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attainable polymorphic form of glycine crystals as a function of temperature on a patterned
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polydimethylsiloxane (PDMS) chip with 1330 round wells (~100 μm diameter) per 1 cm2. Zhou et al.[33] probed crystallization conditions for four different proteins on a patterned PDMS patch
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with the total volume of a single droplet of only around 20 nL.
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Porous materials offer another possibility to confine crystallization. Various porous materials such as porous glasses,[59] MCM-41 silica matrix,[60] and alginate gel[61] have been applied for
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crystallization. Confined crystallization of APIs in porous matrices provides opportunities to enhance the bioavailability due to a decrease in the crystal size and potential stabilization of
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metastable polymorphs or amorphous solid states.[22, 62] The use of biocompatible porous materials further enhances the valorisation of this PI approach into real pharmaceutical processes since downstream formulation processes can be simplified. Lee et al.[37] used porous mannitol to confine tadalafil crystallization and obtained an average crystal size below 1 μm. Their in vitro
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release tests confirmed the expected improvement of the dissolution performance. Speybroeck et al.[38] used mesoporous silicate SBA-15 for encapsulating ten different poorly soluble APIs. All the SBA-15 formulations showed enhanced dissolution performance and a high stability after
and carriers for encapsulating and delivering APIs.[39-41]
2.1.2. Structurization
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storage for six months. Finally, various biodegradable polymers have also been used as excipients
The various crystallization phenomena as well as heat and mass transfer rates that shape the final
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product quality and process performance depend on the mixing characteristics of any multiphase
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crystallizer. In the early 1980s, Tavare[63] already reviewed the topic and made a distinction
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between two mixing mechanisms: micromixing at the molecular level and macromixing at the
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macroscopic level, which is related to the residence time distribution of crystals in suspension when continuous crystallizers are used. Mixing is particularly important when the supersaturation
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is generated rapidly, for example by a reaction between different compounds (i.e., so-called
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precipitation or reactive crystallization) or by the mixing of a feed stream with a miscible solvent
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that drastically reduces solubility (i.e., antisolvent crystallization). A lack of rapid mixing can lead to a high supersaturation locally, which affects crystal morphology, purity and size distribution
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often in an unpredictable way.[64-66] Mahajan and Kirwan[67] crystallized L-asparagine monohydrate from aqueous solution using 2-propanol as antisolvent in a device that was designed
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for rapid mixing. They found that crystals with a broader size distribution and a larger mean size were produced when poor mixing was present (i.e., when the induction time was shorter than the characteristic mixing time). Due to the possible large density difference between a solid and a liquid phase, a suspension density distribution may exist in the vertical direction.[68, 69]
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Sufficiently strong macromixing is required to approach ideal homogeneous suspension condition, so that no classification occurs when withdrawing product (e.g., in a continuous flow mode) and
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that all crystals have the same processing history leading to a uniform product.[70]
Many PI methods have been applied to intensify the mixing for crystallization, which are usually based on the introduction of certain structures within the crystallizer. Several recent examples are based on tubular crystallizers. Small tube diameters and low flow rates lead to laminar flow conditions. When sufficient mixing can be provided in radial direction, but not in axial direction
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(i.e., plug-flow conditions), a narrow residence time distribution can be achieved, which favours
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the production of crystals with a uniform product quality.[71-73] Auxiliary structures are often
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necessary to achieve such plug-flow conditions and to avoid classification within the tube or
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clogging.[74] Simply applying a higher velocity to approach more turbulent flow is often not desirable, because a prohibitive long tube would be required to achieve the long residence times
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that are often needed for pharmaceutical applications.
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Figure 2. Examples of the use of structures to intensify mixing in a tubular crystallizer. a)
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oscillatory baffled crystallizer;[75] b) Kenics type static mixer; c) Segmented flow.[76]
The use of oscillatory flow for crystallization is a well-developed technology to intensify the
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mixing.[75, 77, 78] The oscillatory baffled crystallizer is a tubular crystallizer with spatial orifice
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baffles (see Figure 2a). The crystallizer configuration employs a piston to oscillate the motion of the flow along the tube, which leads to the generation and cessation of eddies around baffles.
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Consequently, uniform mixing can be achieved between baffles owing to the strong radial motion.[75] Care should be taken on selecting oscillation amplitude and frequency as the oscillation can introduce axial back mixing and broaden the residence time distribution.[79] Moreover, high shearing from the oscillation flow can also induce much (usually undesired) secondary nucleation.[75] Static mixers have also been used as a PI method for improving the
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mixing in a tube under laminar flow conditions.[80] Static mixers are based on well-defined structures to redistribute the fluid mainly in the radial direction (see Figure 2b). Comparing to the oscillation flow, axial mixing can be reduced by using static mixers, thus, the real residence time
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distribution can better approach plug-flow conditions. Static mixers are commonly used only at the entrance to generate homogeneous supersaturation before crystallization or precipitation via rapid mixing. Alvarez and Myerson[81] demonstrated the use of a static mixer along the entire length of a tubular crystallizer for crystallization of flufenamic acid and L-glutamic acid. Such configuration facilitates dosage of antisolvent via multiple points distributed along the length of
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the crystallizer to produce crystals with a controllable size. The use of segmented flow is another
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example for enabling favourable plug-flow conditions in a tubular crystallizer at low volumetric
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flow rates. The solution (or slurry) is divided into small liquid/slurry segments that are separated
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by a gas or an immiscible liquid.[76, 82-84] The segmented structure avoids back mixing as each segment acts as a small independent crystallizer. Moreover, internal circulation in a segment is
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induced as the segment moves along the tube (see Figure 2c),[85, 86] which makes mixing possible
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without using any internal structures. Similarly, the application of an inert phase to induce mixing
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can also be found in air-lift crystallizers, where the mixing is induced by sparging air bubbles in a column (i.e., riser), which creates a density difference with any column in open connection to the
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riser inducing liquid circulation.[87, 88] Both the segmented flow and the air-lift mechanism
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provide mild and uniform mixing conditions, which can help to supress secondary nucleation.
2.2 Time domain
PI approaches for chemical processes in the time domain in general follow two possible strategies: manipulations of process time scales or dynamic states. In particular, the switch from batch to
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continuous mode is an important application of PI in the time domain for pharmaceutical crystallization, which aligns with the current paradigm shift for the manufacture of pharmaceuticals. Furthermore, periodic operation has also been exploited for crystallization
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processes to create a desired dynamic profile of states. For example, temperature cycling has been applied to control various critical material attributes (CMAs) of crystals such as size distribution, morphology, polymorphic form and chirality. A periodic flow pattern has been demonstrated to provide better suspension mixing and flexibility to manipulate a process residence time.
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2.2.1. Continuous operation
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Pharmaceutical manufacturing is historically dominated by batch-wise processing. However, in
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recent years, the interest in continuous manufacturing to improve efficiency and to enable better
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product-quality control has increased significantly.[89-91] In comparison to batch-wise processing, the potential advantages of continuous processing include smaller inventories,
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elimination of batch-to-batch variability, simplified process control, and reduced costs.[92, 93]
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Continuous processing also enables better integration of all processing equipment within an end-
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to-end process minimizing requirements for storage of intermediate compounds. For example, Mascia et al.[89] described a fully integrated pilot plant of an end-to-end continuous
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pharmaceutical process, which could produce tablets with aliskiren hemifumarate at a rate of around 100 g/h starting from an advanced chemical intermediate. The overall residence time of the
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process was strongly reduced from 300 hours for the batch process to 47 hours for the continuous process. Adamo et al.[90] showed for a different application that further reduction in footprint, processing time, and a high degree of modularization can be achieved. They developed an integrated and re-configurable continuous pharmaceutical manufacturing process with the size of
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a refrigerator that could produce sufficient product to supply hundreds to thousands of doses of four basic drugs per day. Such a flexible and compact manufacturing process has a great potential for on-demand production of pharmaceuticals to adjust locally to fluctuating market demands and,
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ultimately, to align with modern concepts of personalized medicine. Product quality in the pharmaceutical industry is traditionally controlled by strictly following batch recipes and validated by off-line testing. However, under the initiative of regulatory authorities, a QbD approach[94, 95] for pharmaceutical development has been recommended. QbD involves the definition of the target product profile, identification of critical quality attributes, and the design of a manufacturing
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process with appropriate control strategy to ensure that a target product performance is
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achieved.[94] The recent advances in process analytical technologies (PAT) have enabled
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important progress in the ability to measure material attributes in-situ and in real time,[96] which
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allows for effective feedback control methods to be developed.[97] The ability to operate near steady-state conditions and the availability of PAT for real-time control provide new opportunities
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robustness and flexibility.
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to align the operation of a continuous process with QbD principles to improve the process
Crystallization is a key unit operation for the separation and purification of many intermediate
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compounds and APIs in pharmaceutical processes. The paradigm shift towards continuous manufacturing in the pharmaceutical industry has, therefore, renewed the interest in continuous
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crystallization.[98] Two basic types of design for continuous crystallization have been studied: a single or multistage mixed suspension mixed product removal crystallizer (MSMPRC) and a plug flow crystallizer (PFC) (Figure 3).[9] The MSMPRC provides a robust operation, as intensive mixing can easily be achieved mechanically and the surface-to-volume ratio is small, which
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reduces fouling. Moreover, existing equipment traditionally used for batch crystallization can be utilized to realize continuous crystallization with an MSMPRC. However, the residence time distribution in a single MSMPRC is broad, which leads to a different processing history for each
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crystal and, correspondingly a non-uniform product quality. MSMPRCs can be connected sequentially to obtain a narrower residence time distribution at the expense of increased equipment costs. The use of multiple MSMPRCs in sequence also provide more degrees of freedom for design and operation such as a targeted supersaturation profile over the sequence of crystallizers.[99] The PFC offers theoretically a narrow residence time distribution and typically has a higher efficiency
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than the MSMPRC of the same volume, as the latter operates at outlet conditions. The PFC also
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allows for easy process scale-up via parallelization and dedicated feed distribution systems.[100]
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The supersaturation profile along the tube can be manipulated by distributed antisolvent addition
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or temperature control in different segments of the tube. The choice between an MSMPRC and a PFC depends on the crystallization kinetics. In general, an MSMPRC may be better used when a
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long residence time is needed due to the practical problem associated to long tubular crystallizers
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while a PFC is preferred when shorter residence times are allowed for pharmaceutical applications
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due to the superior attainable product quality that can be obtained from a tubular crystallizer. The continuous crystallization using both designs can be further combined with other technologies that
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especially work well in continuous-flow mode, such as membranes or mother liquid recycling to
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reduce waste and increase crystal yields.[101, 102]
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MSMPRC
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PFC
Figure 3. Basic configurations for multistage MSMPRCs (upper diagram) and PFC with
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antisolvent addition and temperature control (lower diagram).
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2.2.2. Periodic operation
Temperature cycling is a commonly used periodic operation strategy for crystallization, which
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employs alternating heating and cooling of the crystal suspension (see Figure 4).[103] The solution
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becomes undersaturated during the heating cycle (C to B), which leads to the (partial) dissolution
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of existing crystals and an increase in the solute concentration. Next, supersaturation is created during the cooling cycle (B to C), which causes the remaining crystals to grow and possibly new
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nuclei to appear (i.e., primary or secondary nucleation). These successive dissolutionrecrystallization cycles can be regarded as an accelerated ripening process. In particular, crystals
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are exposed to varying conditions such that metastable states can be converted to thermodynamically favoured states. Temperature cycling has been successfully used as a strategy to control various crystal quality attributes, such as crystal size distribution,[104] morphology,[105] polymorphism[106] and chirality.[107]
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Figure 4. Schematic illustration of the temperature cycling mechanism.
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Controlling a crystal size distribution is a typical motivation for temperature cycling. Small
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crystals have a larger surface-to-volume ratio and dissolve faster than big crystals, because the
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molecule packing on the surface is energetically less stable than the ordered packing within the
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crystal lattice. Consequently, fines can be removed to support the growth of larger crystals via controlled temperature cycling, which could also be seen as an intensified form of Ostwald
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ripening.[108] Since fines are usually undesired, their potential destruction via temperature cycling has become a popular technique to produce large crystals with a narrow size distribution. For
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example, Saleemi et al.[104] crystallized paracetamol from isopropanol with a narrow unimodal size distribution using temperature cycling. In addition, the temperature cycling was implemented
A
in an automated fashion to effectively dissolve fines. Such direct nucleation control relies on the ability to measure the number of fines with PAT, which, for example, can be achieved by the use of focused beam reflectance measurements.[104] In addition to potential improvements of the
20
crystals size distribution, temperature cycling may also help to reduce fouling and favours longterm continuous operation.[109]
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Crystal shape can also be modified via temperature cycling, [105, 110, 111] which is conventionally done by altering solvents[112, 113] or by adding growth inhibitors.[114, 115] By taking advantage of the difference between the relative dissolution and growth rates of the different crystal faces, crystals with a large attainable region on the shape can be formed using sequential growth and dissolution cycles.[116] A popular model used for analyzing the crystal shape
U
evolution has been proposed by Snyder and Doherty,[117] which is based on the changing of
N
perpendicular distances of crystal faces that are governed by a set of linear ordinary differential
A
equations. A stable steady-state exists for growth conditions, while an unstable steady-state exists
M
for dissolution, which can be demonstrated by an eigenvalue analysis. These two steady-state points can be used to construct a theoretical attainable region of crystal shape to be obtained by
D
temperature cycling.[116] The target crystal shape within the attainable region can be obtained by
EP
TE
applying feedback control as demonstrated recently by Eisenschmidt et al.[118]
Temperature cycling can also be used to promote crystallization of the most stable polymorph, as
CC
different polymorphic forms have different physical properties (e.g., solubility as a function of temperature). The mechanism of such temperature-cycling strategy can be understood via a
A
solubility diagram of a crystal that exhibits two polymorphic forms (see Figure 5).[119] In this example, form II is more stable and, consequently, has a lower solubility than form I. The transformation of crystals of both form I and II to crystals of only form II can be realized by applying the illustrated temperature cycling trajectory. Crystals of form I will dissolve during the
21
heating cycle and the additional supersaturation will preferentially be used for the growth of crystals of form II. Feedback control strategies can be applied to polymorphic systems due to the availability of PAT tools. For example, Simone et al.[106] developed an active polymorphic
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feedback control (APFC) strategy enabled by Raman and ATR-UV/vis spectroscopy to monitor
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D
M
A
N
U
the polymorphic composition and solute concentration, respectively.
Figure 5. A schematic illustration of a temperature cycling profile for obtaining crystals of a more
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stable polymorphic form (i.e., form II). [119]
Another purpose of temperature cycling can be to obtain pure enantiomers from racemic
A
conglomerates. The principle of such deracemization process is based on Viedma ripening, which traditionally uses grinding to induce the chiral symmetry breaking.[120] Viedma ripening is an elegant process based on a complicated interplay between various physical phenomena. A possible mechanism proposed to understand Viedma ripening is illustrated in Figure 6, which involves four main phenomena.[121-123] Attrition by grinding produces clusters of R and S and molecules from
22
the bulk crystals continuously, while the reincorporation of these chiral clusters and molecules into large crystals of the same enantiomeric form takes place. Because the reincorporation occurs at a higher rate for the enantiomer that is present in excess in the solid phase, the solution will become
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enriched with the opposite enantiomer, which shifts the racemisation reaction to the side of the solid-excessive enantiomer. Meanwhile, Ostwald ripening ensures that large crystals can keep growing at the expense of smaller crystals. As a consequence, an initially small enantiomeric excess can be amplified due to this autocatalytic effect, which over time transforms the conglomerate completely into one of the enantiomers. Similar as for grinding, temperature cycling
U
can also provoke the required dissolution-growth cycles to enable the deracemization process. The
N
use of programmed heating-cooling profiles for successful producing enantiomers from
A
conglomerates of a chiral compound and a salt form has been demonstrated experimentally by
A
CC
EP
TE
D
M
Suwannasang et al.[107] and Li et al.,[124] respectively.
Figure 6. Schematic illustration of a proposed mechanism of Viedma ripening.[121]
23
Crystallization processes can also be intensified by operating flows in a periodic fashion. The oscillatory baffled crystallizer is one typical example of such periodic flow as described earlier. Another example is based on operating a periodic flow of a single or multistage MSMPRC.[125,
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126] Instead of feeding and withdrawing materials at a constant flow rate, as is commonly done when operating an MSMPRC in continuous-flow mode, periodic transfer of material is applied (see Figure 7). Due to the possibility of using a high flowrate, fouling and blockage in the transfer line can be prevented by washing out. Such periodic flow operation can also be regarded as a combination of batch and continuous operation, which gives more flexibility to design the mean
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TE
D
M
A
N
U
residence time of crystals.
Figure 7. Profiles of inlet and outlet flowrates of a continuously and periodically operated stirred-
A
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tank crystallizer.
2.3 Function domain
Executing multiple processing functions in a single physical space is a classical PI strategy. If synergistic effects exist, then the different functions can lead to a better performance compared to when executing the functions separately. Traditional examples include the combination of an
24
equilibrium reaction with a separation leading to reactive distillation,[127] which enables a shift of the reaction equilibrium to the product side. A similar effect can be obtained with membrane reactors.[128] Besides synergistic effects, combining different functions also offers the potential
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to improve the process time and cost efficiency by reducing the equipment costs. Crystallization is a separation and purification method, which, like any separation technology, has kinetic and thermodynamic limitations. Therefore, combining crystallization and other separation techniques is potentially a promising strategy to enable synergistic effects leading to an overall improvement of the separation system performance. Such combination of different separation technologies into
U
an integrated separation system is also known as a hybrid separation process. Typical examples
N
for hybrid separation processes include the combination of crystallization with membranes or with
A
chromatography, which are both discussed in more detail below. Finally, methods for integration
M
of crystallization with downstream processes are discussed, which offer new opportunities to
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2.3.1. Hybrid separation
D
simplify a pharmaceutical manufacturing process and to achieve a better product performance.
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2.3.1.1. Membrane-assisted crystallization Membranes are an attractive separation technology due to the simple operation and flexibility,
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potentially high efficiency and selectivity for specific compounds, low energy requirements, and easy control and scale up.[129, 130] Membranes are standard solutions for many processes such
A
as desalination[131, 132] and reactive separation.[133] Membranes have also been combined with crystallization.[134-136] One main function of membranes when combined with crystallization is solvent removal to generate supersaturation. The solvent can be selectively removed using reverse osmosis[137, 138] or membrane distillation.[139] The former uses a dense membrane over which
25
a high pressure is applied against the osmotic pressure to generate sufficient driving force for solvent permeation. The latter uses a porous membrane to support a vapor-liquid interface. Consequently, heat needs to be supplied to evaporate solvent. Membranes achieve the same
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process function as evaporation. However, membranes offer flexibility to intensify and design the surface area that is available for solvent removal, which can be exploited to manipulate supersaturation generation. Moreover, membranes, in particular reverse osmosis membranes, enable solvent removal with lower energy requirements compared to evaporation, as no liquidvapor phase transition is required.[138, 140] In a solvent removal application, the membrane
U
module is typically installed within a circulation loop that operates at higher temperature, thus
N
below saturated conditions (see Figure 8).[134, 138] Therefore, crystallization in principle only
A
happens in the crystallizer and severe membrane fouling is avoided. Furthermore, if some
M
classification device is used, the membrane circulation loop can also act as a fines destruction loop. The decoupling between crystallization and membrane conditions can improve operational
D
flexibility and give better control over crystallization phenomena.[136, 141] Instead of solvent
TE
removal, the selective transport function of membranes has also been used recently for the
EP
separation of impurities[101] and solvent/antisolvent.[142] The combination of a membrane surface in contact with a solution of high concentration may promote nucleation.[143, 144]
CC
Although nucleation on the membrane or within its pores usually prevents long-term operation, the reduced induction time and different nucleation conditions can lead to different nucleation
A
behavior compared to bulk conditions, which can be attractive for discovery and production of different solid-state forms that cannot be produced easily via bulk nucleation.[142, 145]
26
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Figure 8. Schematic illustration of a membrane assisted crystallization process.
Membranes have also been combined with preferential crystallization for chiral separations.[146,
U
147] Enantioseparation of conglomerate forming systems with high efficiency has been
N
demonstrated by using two compartments that are coupled via exchange of the mother liquor (see
A
Figure 9).[148, 149] Each compartment is seeded with crystals of one type of enantiomer at the
M
start of the batch. Supersaturation is generated by cooling and is controlled to avoid primary
D
nucleation. Consequently, both seed crystals will grow and consume the corresponding enantiomer
TE
in the solution. Mother liquor needs to be exchanged between both compartments to avoid a high supersaturation of the enantiomer that is not present in solid form in a compartment. Membranes
EP
can act as an permeable barrier for liquid exchange as demonstrated by Svang-Ariyaskul et al.[147] for the case of preferential crystallization of DL-glutamic acid utilizing two crystallization
CC
compartments and an aluminum oxide membrane. Besides simply using a membrane to prevent
A
transport of crystals between both compartments, membranes can also help to extent preferential crystallization to enantioseparation of a racemic compound by taking advantage of the chiral separation function. Unlike conglomerates, a racemic compound forming system cannot be separated directly by preferential crystallization alone. A possible way for separation is using a hybrid process, which couples preferential crystallization with an enantiomeric enrichment step
27
(see Figure 10).[150] The application of an enantioselective membrane for enrichment in such hybrid process has been demonstrated by Gou et al.[151] A liquid membrane was combined with preferential crystallization for chiral separation of mandelic acid racemic solution. The results
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showed that enantiomeric excesses in at least the range of 10-20% can be achieved by using
M
A
N
U
membranes.
D
Figure 9. Schematic illustration of simultaneously preferential crystallization in two coupled
A
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compartments with mother liquid exchange by using a membrane.[147]
Figure 10. Hybrid process of enantiomeric enrichment with preferential crystallization for enantioseparation of a racemic compound.
28
2.3.1.2. Integration of chromatography and crystallization The combination of chromatography and crystallization is another attractive hybrid separation
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technique, in particular for the enantiomeric enrichment in a hybrid enantioseparation process as illustrated in Figure 10. A simulated moving bed (SMB) is a continuous chromatographic process, which is of interest to be combined with preferential crystallization to achieve chiral separation for racemic compounds.[152-155] The general working principle of SMB-chromatography is illustrated in Figure 11. The chiral separation can be realized in a countercurrent moving bed
U
chromatography, where the stationary phase moves in the opposite direction of the mobile phase
N
(Figure 11a). The less retained enantiomer will move with the fluid phase, while the more retained
A
enantiomer moves with the stationary phase. As a consequence, racemic mixtures can be separated
M
and concentrated enantiomers will be collected at both ends of the chromatographic column. Instead of moving the stationary phase, The SMB process simulates the movement of the stationary
D
phase by rotating the ports for injecting and removing materials in the same direction with the fluid
TE
flow (Figure 11b). This operation enables the use of simple equipment for continuous chiral
EP
separation, which consists of a series of conventionally used stationary chromatography columns separated by valves and ports for inlets and outlets. Subsequently, the enantiomeric enriched
A
CC
mixture will be further separated by preferential crystallization to obtain the pure enantiomer.
29
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A
Figure 11. a) Schematic illustration of the working principle of a countercurrent moving bed
M
chromatography to achieve enantioseparation; b) Technical implementation to simulate a countercurrent moving bed condition by rotating inlets and outlets in the SMB-chromatography
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process.[156]
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2.3.2. Process integration
Tablets are the most common dosage form for administration of APIs due to typical advantages
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such as low cost, high dose precision, good stability, and convenient administration.[157] The formation of aggregates by granulation is usually required to avoid demixing of powders and to
A
improve the powder flowability and compactability before tableting.[158] Usually crystallization and agglomeration are separate unit operations, in contrast, so-called spherical crystallization[159, 160] has been developed as an interesting PI method that integrates crystallization and agglomeration into a single processing step. Such integration can reduce the processing time,
30
energy consumption and equipment cost. Various methods have been investigated for the fabrication of spherical crystal agglomerates, which have been described in review papers and are summarized in Figure 12.[161-163] The conventionally used methods are: spherical
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agglomeration,[159] quasi-emulsion solvent diffusion,[164] crystallo-co-agglomeration[165] and
D
M
A
N
U
ammonia diffusion system.[166]
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Figure 12. Schematic illustration of spherical crystallization methods. 1) Spherical agglomeration;
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system.
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2) Quasi-emulsion solvent diffusion; 3) Crystallo-co-agglomeration; 4) Ammonia diffusion
1) Spherical agglomeration
A
Three compounds are required for spherical agglomeration: a solvent, an antisolvent and a bridging liquid. Crystallization takes place and leads to random agglomerates when API solution is poured into an antisolvent (see Figure 12). Then a bridging liquid (e.g. chloroform[160, 167]) is added in a controlled manner to bridge and bind crystals to form spherical agglomerates.
31
2) Quasi-emulsion solvent diffusion In the quasi-emulsion solvent diffusion process, API solution is dispersed into an antisolvent to
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form a quasi-emulsion under agitation. The word “quasi” is used because the two solvents have a degree of miscibility and the formed emulsion is not stable. Driven by diffusion, solvent exchange takes place, which decreases the API solubility in the droplet and leads to crystallization. The remaining solvent in the droplet acts as bridging liquid to assist the formation of spherical
U
agglomerates.
N
3) Crystallo-co-agglomeration
A
Crystallo-co-agglomeration is a modified version of the spherical agglomeration method in which
M
an API is crystallized and agglomerated with excipients[168, 169] or another API[170] (see Figure 12). This method enables the agglomeration of poorly compressible API crystals by introducing
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D
excipients and by designing agglomerates that contain more than one API.
EP
4) Ammonia diffusion system
Some APIs are amphoteric in nature, which means that they have a low solubility in neutral and
CC
organic solvents, but are well soluble in acidic or alkaline solutions. In this respect, ammonia water (alkaline) serves as the solvent in an ammonia diffusion system. Similarly to the quasi-emulsion
A
solvent diffusion method, diffusion happens after dispersion of the API solution in an antisolvent. In particular, ammonia diffuses out of a droplet and the antisolvent diffuses into the droplet, which provokes crystallization. The remaining ammonia water serves as bridging liquid to assist the formation of spherical agglomerates.
32
For APIs with low aqueous solubility, the production of small and uniform crystals is of great importance to enhance the bioavailability in case of oral administration or inhalation therapy.[171]
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Milling techniques, such as jet milling[172] or wet milling,[173] have long been a standard approach for size reduction if crystals cannot be produced in the desired size range directly. Recent studies have shown that process intensification can be achieved by integrating wet milling and crystallization using a recycle loop.[174-177] Comparing to the conventional sequential operation, the integration of crystallization and wet milling can help to reduce the number of unit operations,
U
improve the chemical and physical stability of the product, and enhance the safety by reducing
N
API dust exposure.[177] This integrated process enables the efficient production of small crystals,
A
because large crystals formed in the crystallizer can be broken by wet milling in the recycle loop.
M
In addition, the wet milling device can also act as a nuclei generator as the high shearing intensity can significantly increase primary and secondary nucleation rates. Such nuclei generator is an
D
attractive alternative to seeding, which requires the introduction of foreign material that has to be
TE
tightly regulated.[176, 178] The combination of wet milling with a continuous MSMPRC has
EP
recently been investigated by Yang et al.[177] In particular, two integration possibilities were studied: upstream as a continuous in-situ seed generator and downstream within a recycle loop as
CC
a continuous size reduction method. The results showed that both configurations could help to produce small crystals with a narrow size distribution and lead to a higher yield compared to a
A
single MSMPRC due to the enhanced nucleation kinetics. Moreover, the use of wet milling as a nuclei generator can also significantly reduce the start-up duration.
2.4 Energy domain
33
The use of external fields is one of the most studied PI domains with applications to crystallization. Crystallization process performance can be influenced significantly by changes in local conditions such as an increase in local supersaturation, which may trigger a nucleation event. External fields
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provide a tool to manipulate process conditions on a local scale, which is one of the reasons why this PI domain has been investigated so heavily. Furthermore, with the increasing importance of crystallization of large biomolecules for biopharmaceutical applications, external fields are also of interest to directly manipulate large biomolecules to better control biopharmaceutical crystallization. In general, much evidence exists for sensitivity of numerous crystallization systems
U
with respect to the properties of external fields such that they can be used to manipulate the process,
N
but consensus on the mechanistic principles is usually not present. This section aims to provide an
A
overview of the external fields that are commonly applied to crystallization, which include
M
ultrasound, electric fields, magnetic fields, microwave fields and laser (see Table 2).
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D
Table 2. An overview on the commonly applied external fields for crystallization
CC
Laser
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External fields
A
Microwave
Ultrasound
Effects on crystallization
Ref
Accelerated nucleation Polymorph control Spatial control of nucleation
[179-182] [183, 184] [181]
Rapid solvent evaporation Facilitate rapid temperature control
[185-188] [189]
Accelerated nucleation and size reduction Inhibited nucleation
[190-198]
[194, 198-203]
34
Magnetic
Orientate crystal direction Polymorph control Crystal quality improvement Polymorphs separation
[204-206] [207-210] [211, 212] [213, 214] [215]
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Electric (AC/DC)
Accelerated nucleation Inhibited nucleation Crystal quality improvement Electrochemically induced crystallization In-situ particle separation
2.4.1. Ultrasound
[216, 217] [218] [219, 220] [221]
U
The potential of ultrasound to discharge metastable systems, such as a supersaturated solution, was
N
already reported in 1927.[222] Dedicated work on the application of ultrasound to crystallization
A
systems demonstrated the ability to produce smaller and more uniform crystals decades ago.
M
Hem[223] reviewed the possible mechanisms of ultrasound-assisted crystallization of this earlier
D
work and concluded that a heterogeneous nucleation mechanism was supported by the strongest
TE
evidence at that time compared to any mechanism related to cavitation pressure. The possibility to make smaller and more uniform crystals is obviously important for pharmaceutical applications to
EP
potentially enhance dissolution rates and to improve product quality, respectively. This importance combined with the complexity of both the crystallization process itself and ultrasonics have
A
CC
triggered a substantial amount of work on so-called sonocrystallization in the recent decades.
Ultrasound can enhance crystallization by reducing the induction time and decreasing the crystal mean size, which has been demonstrated for many applications.[190-198] However, ultrasound may also inhibit crystallization depending on the operating conditions and system properties.[194, 198-203] The mechanism for enhancement of crystallization kinetics has been subject of debate
35
for over half a century. Ultrasonic waves can create imploding cavities in solution, enhance mixing, increase mass transfer and provide heat. All of these effects can influence various crystallization kinetics. For example, Thompson and Doraiswamy[224] demonstrated experimentally how
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ultrasound increased solubility, which was attributed to the formation of hot spots bringing the solvent in a supercritical state. Ultrasonic waves improve mixing and thus product quality is likely to improve in case of reactive and anti-solvent crystallization.[190] Furthermore, the increased shear can break agglomerates.[190, 192, 199, 225] Guo et al.[192, 226] attributed the enhancement of nucleation in an ultrasonic field to an increased diffusion coefficient. Furthermore, Guo et
U
al.[191] also considered heterogeneous nucleation induced by the surface area of the tiny bubbles
N
as a possible mechanism. Dodds et al.[227] used a classical homogeneous nucleation model as a
A
basis to describe a segregation mechanism based on the attachment of molecules to clusters and
M
aggregation between clusters driven by pressure gradients in the presence of cavitation. Virone et al.[196] also used a classical primary nucleation model as a basis for a mechanistic explanation of
D
the increased nucleation rate. They proposed that the local increase in pressure due to a bubble
TE
implosion would significantly increase the driving force for primary nucleation. Finally, in a
EP
number of papers, Schembecker and co-workers considered the enhanced heterogeneous nucleation rate due to the surface of the bubbles that provides an interface for nucleation as main
CC
mechanism.[228-231] The elegance of their work is that control experiments were done in which similar conditions were created, i.e., a large number of small bubbles were created from gassing,
A
in absence of any ultrasound, and similar effects were observed, which provides strong evidence for an enhanced heterogeneous nucleation mechanism.
36
The unique abilities of ultrasound to manipulate a crystallization process has led to various dedicated applications. For example, the manufacture of pulmonary drugs in dry powder form is challenging due to the strict requirements for particle size and shape.[232] Currently, milling is
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used to break big crystals into smaller fragments such that the particles can be deposited efficiently in the lungs via inhalation. Milling processes have various disadvantages such as a loss of yield, complicated process behaviour, and high shear forces that affect the surface properties of the crystalline particles. Therefore, producing API crystals with the desired product quality attributes can significantly simply the process by avoiding milling.[233] Abbas et al.[202] used the ability
U
of ultrasound to reduce the mean crystal size to produce crystalline particles that are suitable for
N
pulmonary drug delivery with a simple process based on ultrasound. Dhumal et al.[201]
A
demonstrated that ultrasound enabled the manufacture of high-quality particles of salbutamol
M
sulphate for inhalation, which is an API used to treat diseases such as asthma and chronic obstructive pulmonary disease. Furthermore, they developed an ultrasound-based crystallization
D
method for lactose crystals for inhalation, which was also superior compared to a conventional
EP
TE
process.[200] Such process for lactose was further developed at a large scale.[234]
Biopharmaceuticals are an important growing class of products within pharmaceutical industry.
CC
Crystallization is of interest as a separation and purification technology. However, the nucleation of large biomolecules such as proteins is notoriously difficult. Ultrasound can potentially achieve
A
intensification of protein crystallization, as induction times can be reduced. Kakinouchi et al.[198] demonstrated that the time needed for crystallization of lysozyme could either be enhanced or reduced depending on the application time of ultrasound, which suggests that ultrasound can also disrupt nucleation clusters when used for a long period. Crespo et al.[235] showed that the
37
metastable zone of lysozyme nucleation could be reduced by using ultrasound, which led to higher quality protein crystals. Furthermore, audible sound with a lower frequency compared to
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ultrasound was also found to enhance the crystallization rate of various proteins.[236]
The scale-up of ultrasound-based crystallization processes is arguably one of the greatest challenges for applications of this PI method in pharmaceutical industry. Although a number of studies on pilot-scale exist,[194, 203, 233] the vast majority of literature reports involve studies conducted on a lab-scale. The difficulty for scale-up of sonocrystallization is caused by at least
U
two main reasons. First, the complexity of sonocrystallization severely limits the possibility to
N
develop first-principle process models that have predictive capabilities over several order of
A
magnitude in production scale. Second, the penetration depth of ultrasound in solution is limited
M
to several centimetres only due to dissipation.[203] Therefore, the effect of ultrasound may completely diminish when translated directly to a larger scale. The scale-up problem of ultrasound
D
is especially profound when operating the crystallization process in batch mode, which is the
TE
traditional mode of operation in pharmaceutical industry. In a batch process, by definition, all
EP
material is processed at the same time. Therefore, irradiation of the complete process volume with ultrasound may only affect a small portion. Indeed it has been demonstrated that the use of
CC
ultrasound within a small part of a batch crystallization at pilot-scale to generate the initial crystal population may be insufficient and conventional methods such as seeding can give a superior
A
process performance, despite the more elaborative operational procedures that are needed for seeding.[194] However, the current trend in pharmaceutical industry toward continuous manufacturing provides new opportunities for application of sonocrystallization on a production scale. Continuous processing has an inherent advantage for scale-dependent PI methods in the
38
sense that not all material has to be processed at the same time. Therefore, systems with flow cells are promising for effective application of ultrasound in the pharmaceutical industry, as has been demonstrated by several studies.[237-241] Finally, the production volumes of biopharmaceuticals
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are often low, which reduces uncertainty from scale-up for this class of pharmaceuticals.
2.4.2 Electric field
The application of electric fields in crystallization of biopharmaceuticals has been extensively investigated in various forms in the past two decades. Approaches in which a protein solution stays
U
either in direct or indirect contact with a direct current (DC) or alternating current (AC) electric
N
field have been investigated.[205, 208, 212, 242-244] In general, electric fields provide an ability
A
to control protein crystallization kinetically with enhanced or reduced nucleation rates and
M
spatially by controlling the orientation and nucleation location of crystals. An extensive review on the impacts of an electric field on protein nucleation and growth has been provided recently by
TE
D
Nanev.[245]
EP
Driven by the motivation of obtaining high-quality crystals, Aubry’s group conducted the first study on electric-field-assisted protein crystallization, where lysozyme crystallization occurred in
CC
a sitting or hanging drop subject to a strong external DC electric field.[211, 212] It was found that with the applied electric field, fewer crystals were formed, but the crystals had a larger size, which
A
indicates a reduction in the nucleation rate. The crystals tended to nucleate near the cathode side of the droplet surface. They attributed this preferred nucleation location to the enhanced local supersaturation as a result of the concentration gradient between the electrodes formed by the
39
electric field. The crystal quality improved by the electric field, which was also confirmed by a recent work of Rubin et al. using X-ray diffraction analysis.[246]
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In addition to adjusting the electric field strength and frequency, the distribution of the electric field strength can be shaped flexibly by using electrodes of different materials and shapes and by varying the spatial arrangement of the electrodes. Nanev and Penkova studied lysozyme crystallization in a custom-made glass cell and observed preferred orientation of crystals along the c-axis with an external DC electric field at very low temperature.[242] They also showed that the
U
electric field can be augmented with an ultrasonic field to enhance the nucleation rate while
N
orienting the crystals. Besides lysozyme, the nucleation rate of ferritin and apoferritin could also
A
be varied with the applied electric field.[247] Moreno and Sazaki used two parallel platinum
M
electrodes to create a weak internal DC electric field (typically 4 mV/cm) over a lysozyme solution and a lysozyme gel. Compared to the strong electric fields used in the earlier studies (in the order
D
of several kV/cm), they found that the weak electric field could also influence crystallization by
TE
reducing the induction time with fewer crystals, but with a larger size.[208] Later, they explored
EP
the potential of using multiple electrodes with different geometries and showed that crystallization results were more reproducible at a controlled potential.[248] Veesler’s group investigated the
CC
influence of a large electric field and field gradient on crystallization of lysozyme and bovine pancreatic trypsin inhibitor (BPTI), and demonstrated the feasibility to spatially and temporally
A
control the nucleation process.[206, 249] For example, three successive nucleation waves of BPTI were triggered at the anode by adjusting the applied voltage.
40
To eliminate the Faradaic reactions at internal electrodes at high DC voltages, the application of AC electric fields has also been investigated for protein crystallization. Hou and Chang showed that a non-uniform AC electric field can reduce the number of nucleation sites and enhance the
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crystal quality.[250] Furthermore, it was concluded that the dielectrophoretic force may concentrate the crystals towards the electric field strength minima. Koizumi’s group conducted a series of experimental and theoretical investigations to interpret how the AC electric fields can influence protein crystallization. It was revealed that the increased or decreased nucleation rate of lysozyme by the AC electric fields with various frequency was a result of the difference between
N
U
the electrical permittivity of the liquid and solid phases.[209, 210, 244]
A
With the advantage of good optical transparency and high electrical conductivity, indium tin oxide
M
(ITO) has become a popular material to fabricate the electrodes used in crystallization experiments. Several devices have been designed for better control over nucleation rate and crystal quality using
D
ITO electrodes.[205, 251, 252] Li and Lakerveld[205] tested various patterns for a bottom
TE
electrode in a microfluidic device with a parallel-plate configuration and examined the influence
EP
of non-uniform AC electric fields on lysozyme and insulin crystallization. The nucleation rate was found to depend not only on the electric field properties but also on the shape and surface area of
CC
the bottom electrode while the nucleation location was influenced by the ITO layer as a template and also by the non-uniform electric field. For instance, the preference for protein nucleation on
A
the ITO surface in the absence of an electric field was weakened by an electric field of 1 MHz, pointing to a negative dielectrophoretic response of lysozyme, as the edged glass surface provided an electric-field minimum. Finally, the distribution of different solid phases can also be controlled by varying the electric field frequency.[253]
41
Besides the main application for electric fields for large biomolecules such as proteins, electric fields can also assist the crystallization of small organic molecules. At least two possible types of
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applications have been approached: electrochemically induced crystallization (EIC) and crystal separation. The EIC approach mainly takes advantage of the pH-dependent solubility profile of acidic or basic organic molecules, i.e., their free forms commonly have a lower solubility than the salt forms in aqueous solution. Electrolysis of water is used to locally shift the pH to create supersaturation for crystallization.[213, 214] In general, a non-uniform electric field can induce
U
dielectrophoretic and possibly electrophoretic forces, which have been used for particle
N
manipulation in various applications.[254] Recently, Li et al. demonstrated the successful
A
application of this concept for crystal separation. In particular, they crystalized and collected
M
phenazine and caffeine crystals at different electrodes under strong DC electric fields with purities
TE
2.4.3 Other fields
D
greater than 91%.[215]
EP
Microwave fields are generally believed to intensify chemical processes due to two effects: thermal effects or non-thermal effects.[255] The former effect is based on the notion that microwaves
CC
enable heating of fluid orders of magnitude faster than conventional heating. Moreover, microwave heating is volumetric and does not need any heat transfer surface, which favours
A
heating with smaller temperature gradients. Special effects related to mass transfer have also been reported to enable applications such as microwave-enhanced extraction[256] and microwaveenhanced molecular diffusion in polymeric materials.[257] Microwave irradiation has been used for crystallization by taking advantage of its thermal effect in two directions: microwave-assisted
42
evaporative crystallization and microwave-assisted temperature control for crystallization. Microwaves can provide rapid heating to enable exceptionally fast solvent evaporation,[185] which favours fast supersaturation generation and thus the production of crystals with reduced size.
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Microwave-accelerated evaporation can also be combined with silver nanoparticles that act as nucleation sites for amino acids crystals with selective morphology such as for acetaminophen,[186] glycine,[187] arginine.[188] Temperature control is important for crystallization and practical challenges can exist when a crystallizer is equipped with conventional actuation for both heating and cooling (e.g., under temperature cycling operation). Any change
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between heating and cooling fluids will prolong the processing time and may introduce significant
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time delays due to temperature control when heating-cooling cycles are used. Microwave heating
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can intensify such temperature control by decoupling the actuation for heating and cooling and by
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exploiting the exceptionally fast heating rate when using microwaves, which can lead to a significantly reduced batch time when temperature cycling is used, for example for fines
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destruction.[189]
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Magnetic fields have been applied to assist crystallization of metallic alloys,[258] inorganic salts, [259] and proteins.[260] An orientation effect on crystallization can be seen when using magnetic
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fields. For example, a magnetic field can favour the crystallization of calcium carbonate in aragonite form instead of calcite or vaterite.[218] A possible explanation for this phenomenon is
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that the electrically charged nuclei would interact with the magnetic field. The resulting Lorentz force can modify the preferential surface for crystal growth.[261] As the aragonite form is needlelike and less adhesive to equipment walls, the magnetic field can be applied to relieve the scaling problem in water-treatment devices.[262] Macromolecules such as proteins also show sensitivity
43
to a magnetic field during crystallization. Lysozyme is the most commonly used model compound for studying the influence of magnetic fields on protein crystallization. The tetragonal form of a lysozyme crystal will grow with the c-axis aligned in the direction of magnetic field, which is due
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to the diamagnetic anisotropy of the peptide group in the amino acid sequence.[216] Sazaki et al. reported that this alignment of lysozyme crystals may be further enhanced by coupling magnetic fields with electric fields.[217] Magnetic fields have also been superimposed to gravitation to adjust the apparent gravitational force in a crystallization environment. Ramachandran and Leslie[219] used magnetic fields to counter the gravitation and mimicked the microgravity
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environment of space for crystallization. The results demonstrated that crystal quality could be
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improved with the reduced density-induced convection during crystal growth. Improvement in
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crystal quality and alignment of crystals in parallel to the magnetic field were also observed for
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other biomolecules such as monomeric sarcosine oxidase, acylphosphatase and nucleoside diphosphate kinase when the applied magnetic field was sufficiently strong to cancel out the
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gravitational force of the solution.[220] Atkinson et al.[221] used magnetic levitation to separate
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mixtures of crystal polymorphs by taking advantage of the density difference between different
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polymorphs. This technique allows for fast separation of polymorphs that have a density difference
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larger than 0.001 g/cm-3.
Finally, laser is another promising external field for assisting crystallization, which is mainly used
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to enhance the nucleation rate in supersaturated solutions. Several mechanisms have been proposed to understand the acceleration of nucleation under different types of laser irradiation, which can be categorized into photochemical and non-photochemical effects. Photochemical reactions can be triggered by a laser beam with short wavelength. As experimentally demonstrated by the
44
Okutsu’s research group, ultraviolet laser irradiation can induce photodimerization of anthracene and benzophenone to produce dipara-anthracene and benzopinacol crystals.[263, 264] They also showed in their later work for lysozyme crystallization that continuous ultraviolet laser irradiation
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could give rise to lysozyme radical intermediates, which improved the attractive interaction between molecules and enhanced nucleation.[179, 180] One important non-photochemical effect is the generation of cavitation bubbles by a laser, which can create a high supersaturation locally[181] and provide a surface for heterogeneous nucleation similarly as ultrasound can do.[182] Furthermore, Garetz et al. also demonstrated that the oscillating electric field of the laser
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light can help to align and organize clusters as a source for nucleation, therefore, can reduce the
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induction time for nucleation and enable control over the polymorphic form.[183, 184] Several
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experimental results have shown that the intensity of the laser plays a more pronounced role than
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wavelength in non-photochemical effects.[265] [266]
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3. Conclusion and perspective
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This paper provides a systematic review of PI approaches for pharmaceutical crystallization.
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Following the framework proposed by Van Gerven and Stankiewicz,[11] the PI methods are categorized into four domains (i.e. space, time, function, energy) and are all illustrated with several
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examples. The list of examples is not exhaustive, which stresses the significant amount of literature that exists on this topic. Furthermore, examples often point to significant opportunities to intensify
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pharmaceutical crystallization processes. However, despite this vast body of literature and demonstrated opportunities, applications for PI of pharmaceutical crystallization at an industrial scale can only be found occasionally in open literature. A common argument for this apparent slow adoption rate is the traditional conservative and highly regulated business environment within the
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pharmaceutical industry. Nevertheless, the current business environment (e.g., increased competition, a changing mindset, strong regulatory support for innovation) and rapid development of new technological innovations provide a favourable ecosystem for the further adoption of PI for
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pharmaceutical crystallization. Part of those technological innovations have been addressed in this review paper, i.e., specific technological innovations that share at least one of the fundamental characteristics of PI. Furthermore, those methods often rely on enabling technologies such as PAT and continuous processing, which are increasingly adopted. Finally, much of the work reviewed in this paper is very recent, which indicates the strong current interest in the topic for future
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development.
A
In general, the levels of maturity of the reviewed PI approaches for pharmaceutical crystallization
M
differ. For example, technologies that can be used for screening of crystallization conditions (mainly in the structure domain) are readily available. However, the readiness of PI approaches in
D
the structure domain for manufacturing varies. For example, approaches that inherently rely on a
TE
large surface-to-volume ratio are likely not suitable for manufacturing (e.g., nanopatterns),
EP
whereas other approaches are readily available including the required equipment (e.g., various plug-flow crystallizers, emulsion crystallization, encapsulation). In the function domain,
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particularly some of the methods that integrate crystallization with downstream unit operations of pharmaceutical processes are mature and readily available, whereas hybrid separation methods
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such as membrane-assisted crystallization have been widely studied, but examples beyond laboratory scale in pharmaceutical industry are practically absent. This lack of industrial applications may be attributed to concerns regarding process robustness and the potential build-up of impurities, which is an important concern for pharmaceutical processes. The PI approaches in
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the time and energy domain offer many new opportunities for pharmaceutical crystallization. For example, continuous pharmaceutical crystallization (time domain) is growing rapidly both as a method itself and as an enabling technology for PI approaches in the energy domain. PI approaches
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in the energy domain often need a large surface-to-volume ratio for energy transfer and work better when processing smaller volumes per unit of time, which are both inherently enhanced by continuous processing compared to batch-wise processing. Furthermore, PAT has been a key enabling technology for PI approaches in the time domain, which are now widely available (e.g., when using temperature cycling). Hybrid chromatography is particularly interesting for chiral
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separations, because of synergistic advantages with crystallization, robustness, and the importance
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of chiral separations in pharmaceutical processes. In conclusion, it is clear that a broad window of
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opportunities currently exists for adopting and extending PI approaches for pharmaceutical
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crystallization due to a favourable combination of economical, regulatory, and technological
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