Crystallization of
`Organic Compounds
`
`An Industrial Perspective
`
`Hsien-Hsin Tung
`Edward L. Paul
`
`Michael Midler
`
`James A. McCauley
`
`.
`
`WILEY
`
`A JOHN WILEY & SONS, INC., PUBLICATION
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`Library of Congress Cataloging-in-Publication Data:
`
`Crystallization of Organic Compounds: An Industrial Perspective/Hsien-Hsin Tung .
`p. cm.
`Includes bibliographical references and index.
`ISBN 978—0»47l—46780-9 (cloth)
`2. Pharmaceutical chemistry.
`1. Crystallization-—li-idustrial applications.
`I. Tung, Hsien—l-Isin, 1955-TPl56.C7I53 2009
`615’. l 9-—dc22
`
`.
`
`. [et al.].
`
`3. Pharmaceutical industry.
`
`2008042950
`
`
`
`
`
`
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`Printed in the United States of America
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`10987654321
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`Janssen Ex. 2042
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`106
`
`Chapter 5 Critical Issues in Crystallization Practice
`
`surtace ->
`
`Growthrateof[110]
`
`Supersaturation
`Figure 5-2 Comparison of the growth rate of hexamethylene tetramine crystals as a function of super-
`saturation in aqueous solution and in ethanol solution. (Reproduced with permission from Davey et al. 1982.)
`
`Experimentation is required to evaluate these effects. The most useful experiments utilize
`spiking with known impurities when they can be isolated for this use. However, as E
`often the case, the number and possibly the low concentration of impurities often make
`this impractical. An experimentally simpler method is to recrystallize the compound with
`and without spiking of the mother
`liquors obtained from the process
`isolation.
`Differences in nucleation and growth may readily be observed by comparing photomicro—
`graphs of the resulting crystals. Both size and shape can be expected to be affected. If no
`significant differences are observed, the impurities from the process may not cause an}
`nucleation or growth changes and the inherent properties of the compound may be assumed
`to prevail.
`Ideal steps in determining growth potential include the following:
`
`purification to the highest possible extent (using chromatography if necessary)
`
`selection of a solvent with solubility <50 gm/liter and some dependence on
`temperature
`
`preparation of a clear solution with low supersaturation
`
`aging of this solution with minimal or no mixing in the presence of some seeds, and
`or
`
`subjecting the solution to heat/cool cycles (some fines dissolve during each heating
`cycle, and some growth may occur on slow cooling)
`
`This procedure may show that growth is possible. A growth rate can then be determined by
`various methods, including the fluid bed method described in Chapter 4 using the crystals
`from the heat/cool experiments as seed.
`
`
`
`5.4 OILING OUT. AGGLOMERATION/AGGREGATION
`
`The most important property of a compound from a crystallization point of View may be ir-
`inherent growth characteristics. The critical question is: will it grow? A method to evalux
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`5.4 Oiling Out, Agglomeration/Aggregation
`
`107
`
`growth potential is outlined in the previous section. Additionally, in an actual crystallization
`operation, in order to be crystalline, nucleation must occur and the resulting nuclei are then
`assumed to grow to some limit in the nucleation phase. The question here is whether, after
`reaching this nucleation limit, fu11:her conditions of growth will or will not result in additional
`growth. While the authors have found that most compounds will continue to grow to some
`limit, depending on many process and inherent factors, there are some that do not exhibit
`significant growth beyond the 5— 10 micron range.
`A substantial-sized subgroup of those compounds which do not exhibit typical crystal
`growth, in which a repeated lattice grouping or crystal structure, is so difficult to achieve that
`the compound resembles a liquid as it emerges from solution. This is the phenomenon of
`oiling out, which is often accompanied by the additional complication of agglomeration/
`aggregation.
`It is perhaps helpful to begin this discussion with the consideration of oiling out since it
`may be the first event in the pathway of crystallization or, in extreme cases, the operation may
`end with an oil, gel, or intractable gum or tar (Bonnett et al. 2002).
`
`5.4.1 Oiling Out
`
`Oiling out can be a critical factor in crystallization by any of the methods of creating super~
`saturation and becomes increasingly possible under several conditions, including
`
`- high supersaturation
`
`0 rapid generation of supersaturation
`
`- high levels of impurities
`
`0 presence of crystallization inhibitors even at low levels
`- absence of seed
`
`-
`
`inadequate mixing (high local supersaturation)
`
`Oiling out is species dependent and may be more prevalent for low—melting compounds,
`although in many respects it resembles the solidification of high molecular weight eom—
`pounds such as polymers. As discussed in Chapter 2, oiling out can be considered as a spon-
`taneous phase split into two liquid phases. On a Gibbs free energy—composition diagram, it
`represents asystem in which the overall composition has exceeded the critical composition
`for spinodal decomposition.
`A mechanism for oiling out can be postulated as follows: When supersaturation is
`achieved rapidly such that the concentration is beyond the upper metastable limit—as can
`often be the case in a nucleation—based process—the substrate is forced to separate into a
`second phase by the creation of the resulting high solution concentration. However, crystal-
`lization is delayed by a slow crystallization rate. This combination may result in the creation
`of a nonstructured oil or possibly an amorphous solid. The rates of phase separation and
`nucleation are relative to each other such that “slow nucleation” implies only that nucleation
`was not fast enough to create discrete particles before oil separation.
`Transition of an oil or an amorphous solid or a crystal can then occur. However, this type
`of operation can be difficult to control, and scale-up is treacherous because the oil droplets
`may coalesce into masses and/or form gum balls and increase in size to intolerable levels.
`It should also be noted that the tendency to oil out and/or form an amorphous solid is
`generally increased for low—melting compounds because solvent association can effectively
`
`‘
`
`super-
`. al. 1982.)
`
`nts utilize
`‘ever, as is
`often make
`1 und with
`
`isolation.
`.
`1
`otornicro-
`i
`;-
`ted. lf no
`\' cause any
`be assumed
`
`‘ may be its
`to evaluate
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`108
`
`Chapter 5 Critical Issues in Crystallization Practice
`
`reduce the melting point below its expected value, leading to melting—oiling. High mole-
`cular weight compounds are also subject to oiling and/ or amorphous solid formation
`because of the increased complexity of molecular alignment in crystal formation. Oiling
`is, of course, also dependent on the solubility in the solvent and is particularly likely to
`occur on “reverse addition” of a solution to ar1 antisolvent. An additional factor may be
`mutual solubility of the substrate and a component of the solvent mixture, in which case
`the oil may be a transient solution of the solvent and the substrate in the two-liquid phase.
`three—component nonequilibrium mixture.
`Oiling out may be minimized or eliminated by control of supersaturation and seeding
`(Deneau and Steele 2005), as discussed below. Seeding has been proven to be essential to
`prevent oiling out in some systems because, although the oil may not be the thermodynami-
`cally stable phase, the transformation to crystals may be sufficiently slow and uncontrolled to
`cause severe processing problems, as discussed above.
`The initial formation of an oil, gel, gum, or amorphous, solid conforms with the Ostwald
`step rule discussed in Myerson (2001 , p. 39). This rule states that in any process, the state that
`is initially obtained is not the most stable state but rather the least stable state that is closest in
`terms of free energy change to the original one. It has been postulated that the initial state of
`crystallization processes is amorphous clusters and that the difference in time constants for
`the transformation to more stable crystalline states (nuclei) is a key determining factor in the
`course of the crystallization. It is difficult to distinguish between cluster formation, nuclea-
`tion, agglomeration, and growth in the early stages (Mersmann 2001, p. 235). The following
`possibilities can be recognized qualitatively as determined by the time constants and the
`physical chemistry of the specific compound and system:
`
`- Initial oil or gum that never transforms into a crystal and can agglomerate into large
`masses.
`
`- Initial oil or gum that transforms into an amorphous solid and stops at that point-
`never crystallizes—but can form agglomerates.
`
`
`
`-
`
`Initial oil or gum that transforms into crystals slowly enough that the amorphous form
`can be observed and can cause agglomeration before discrete crystals are obtained.
`
`- Crystals once formed—either slowly or so rapidly that the amorphous form virtually
`does not exist—can transform into stable crystals.
`
`0 Transformation may continue into more stable polymorphs—if they exist.
`
`- Transformation among polymorphs can be slow such that only the initial form is
`obtained or, at the other extreme, rapid so that the most stable form is the only one
`observed.
`
`As is well known, some compounds have never been crystallized, and phase separation
`results in a stable oil or an amorphous solid. The search for solvents and conditions, or the
`introduction of foreign particle seeds (e.g., by scratching a glass test tube) to induce
`crystal formation for a new compound, becomes a matter of trial and error. Combinatorial
`techniques continue to be developed that can aid in this evaluation. A critical factor for
`success may be removal of impurities to achieve a very high level of purity, because the
`effect of even very low levels of impurities on homogeneous nucleation will not be
`known at this stage.
`High supersaturation can lead to very small (nano-sized) particles and resultant agglom-
`eration and gel formation. This phenomenon has been discussed by Mersmann (2001.
`p. 295) and Mullin (2001, p. 317). Although difficult to define or predict, one mechanism
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`5.4 Oiling Out, Agglomeration/Aggregation
`
`109
`
`of phase separation leading to agglomeration may be a combination of gelling, to produce a
`colloidal system, followed by oiling out and nucleation in which the oil serves as a bridge
`between developing nuclei. Operation at high global or local supersaturation ratios is
`expected to promote this effect. Mixing can also be a key factor. Although increased
`mixing may result in breakup of agglomerates in some cases, it may also cause an increased
`rate of formation by impact between “particles.” The effect of mixing on agglomeration of
`particles smaller than the Kolmogoroff length scale has been termed by Smoluchowski
`(1918) “orthokinetic.” This would predominate in a stirred vessel. The other term used is
`“perikinetic,” pertaining to Brownian motion in a static fluid and when particles are in the
`submicron size range.
`
`5.4.2 Agglomeration and Aggregation
`
`The distinction between agglomeration and aggregation has been described differently by
`various authors. Both have received further study by several
`investigators,
`including
`(Myerson, 2001, pp. 110- 111, 146), Mullin (2001, pp. 3l6ff.), and Mersmann (2001,
`pp. 235ff., 527). In agreement with these authors, the differences between them are not
`significant and agglomeration will be the term used in this discussion.
`One mechanism for agglomerate growth is the collision of growing nuclei followed by
`“cementing” together from continuing growth between two or more crystals. Although sim-
`ultaneous collision of more than two particles is not statistically important, the addition of a
`large number of nuclei to an original two—crystal agglomerate can readily occur by ongoing
`collisions, leading to very large agglomerates. Aggregation is weak bonding of colloidal
`particles. Aggregates are relatively easily separated.
`Several investigators have developed models for the effectiveness of collisions that lead
`to agglomeration including Nyvlt et al. (1985) and Sohnel and Garside (1992). This complex
`interaction of hydrodynamics and crystallization physical chemistry is difficult to predict or
`describe but can be critical to the successful operation and scale—up of a crystallization pro-
`cess. In particular, for reactive crystallization in which high supersaturation levels are inher-
`ently present, agglomeration is very likely to occur as the precipitate forms. Careful control
`may be necessary to avoid extensive agglomeration, as outlined in Section 5.4.3. below and
`in Examples 10-1 and 10-2 for reactive crystallization.
`The difficulties that can result from agglomeration include
`
`- entrapment of solvent and/or impurities in the crystal mass
`- reduced effective surface area for true growth
`
`- subsequent breakup of agglomerates into small crystals that were captured during
`nucleation without an opportunity for growth
`
`0 difficulties in downstream processing because of these small crystals
`
`For these reasons, agglomeration is generally to be avoided. The use of additives (Myerson,
`2001, p. 146) may be considered for minimizing agglomeration. However,
`the use of
`additives in the pharmaceutical industry—particularly for final products—is generally not
`done for regulatory reasons barring extreme need.
`There are operations, however, which may intentionally generate agglomerates for a
`particular purpose. These operations are described as flocculation and/or coagulation.
`However, a discussion of the purposeful generation of these clusters is beyond the scope
`of this section.
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