Controlling the polymorphic form obtained

Crystal growth is a science and an art. The scientist s role in the crystal growth process is that of an assistant who helps molecules to crystallize. Most molecules, after all, are very good at growing crystals. The scientific challenge is to learn how to intervene in the process in order to improve the final product. (Etter 1991) 

I am very sorry, that to the many... difficulties which you meet with, and must therefore surmount, in the serious and effectual prosecution of Experimental Philosophy, I must add one discouragement more, which will perhaps as much surprise you as dishearten you and it is, that besides that you will find... many of the experiments published by Authors, or related to you by the persons you converse with, false or unsuccessful,. .. you will meet with several Observations and Experiments, which though communicated for true by Candid Authors or undistrusted Eye-witnesses, or perhaps recommended to you by your own experience, may upon further tried disappoint your expectation, either not at all succeeding constantly, or at least varying much from what you expected. 

Control nevertheless is important in science—tremendously so—not as an end but as a component of proof. The ability to control is the strongest possible demonstration of true understanding. Many doubted whether Becquerel, Curie, Bohr, Oppenheimer and the rest really understood what causes what inside the atom. But after July 16, 1945, when the day dawned prematurely to the northwest of Alamagordo, at White Sands, New Mexico, no one could possibly doubt any more, for the atom bomb was plainer than the sun. With a demonstrated abdity to control, the good scientist may sign off hke the mathematician at the end of a proof Quod erat demonstrandum. (Huber 1991) 

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This is clearly an area where the combination of thermodynamic, kinetic and structural information potentially can lead to successful strategies for controlling the polymorphic form obtained, in specific instances a metastable form, and as the means for obtaining these data become more sophisticated the approaches described here are sure to be developed and expanded (see also Section 3.7). 

In pharmaceutical applications the choice of polymorphic modification for formulation depends very much on the robustness of the crystallization process as well as the properties and characteristics of the preferred modification. Hence, considerable effort is expended in gaining control over the polymorphic form obtained under various conditions. As noted above, up to four polymorphic modifications and three monohydrates have been reported for cimetidine (SmithKline Beecham s Tagamet ) (Bavin et flZ.1979 Prodic-Kojic et al. 1979 Shibata etal. 1983 Hegedus and Gorog 1985). In experiments to selectively crystallize the A form in preference to the more stable B congener it was found that with isopropanol as a solvent, A crystallizes exclusively at high supersaturation, in the presence or absence of seeds (Sudo et al. 1991). 

The polymorphism can be inconvenient also for the processing, when small variations of the processing conditions can produce samples in different crystalline forms. This is, for instance, the case of s-PS, for which the crystalline form obtained by cooling from the melt (a and/or p) is dependent not only on the cooling rate but also on the crystalline form of the starting material, on the maximum temperature to which the melt is heated as well as on the time for which the melt is held at this maximum temperature (Sect. 3.1). This requires, in order to get reproducible manufacts, an extremely accurate control of the processing conditions, which is, of course, undesirable in thermoplastic materials. 

Sometimes the difference between success and failure of a pharmaceutical development projea will depend on obtaining an appropriate crystalline form of a compound. Properties such as mixability of the substance with other ingredients of a capsule, the rate of dissolution, or the stability will depend on the polymorph. Similarly, materials researchers may want to control the polymorph that is being produced. Understanding why and how compounds crystallize the way they do is an area of research to which computations can contribute. In Chapter 7, Drs. Paul Verwer and Frank J. J. Leusen discuss methods for predicting crystal polymorphs by computer simulation. 

The great number of papers and patents that appeared on this polymer in the last years are the main results of these studies. The principal objective of these studies was the crystallization behavior of SPS, the structure of the ordered forms, and the properties of SPS with the respect to the processing conditions. The possibility of controlling the conditions for obtaining controlled structures indeed is particularly interesting in view of the different physical properties that the various polymorphic structures show. 

Two new polymorphs of (2E)-2-cyano-3-[4-(diethylamino)phenyl]-prop-2-enethioamide and an acetone solvate were crystallized, and the structures compared to the known nonsolvated form [11]. One of the new forms was found to be considerably more stable than the others, and subsequently the other two new forms became vanishing polymorphs that could only be produced under strictly controlled conditions. The structures of all three polymorphs could be found using polymorph predictor, if the initial molecular structure was obtained from the X-ray data, the molecule held to be rigid during the energy minimization, and both VDW and Coulomb interactions taken into account. 

PVDF exhibits a complex crystalline polymorphism, which cannot be found in other known synthetic polymers. There are a total of four distinct crystalline forms alpha, beta, gamma, and delta. These are present in different proportions in the material, depending on a variety of factors that affect the development of the crystalline structure, such as pressure, intensity of the electric field, controlled melt crystallization, precipitation from different solvents, or seeding crystallization (e.g., surfactants). The alpha and beta forms are most common in practical situations. Generally, the alpha form is generated in normal melt processing the beta form develops under mechanical deformation of melt-fabricated specimens. The gamma form arises under special circumstances, and the delta form is obtained by distortion of... 

By making use of Volmer s equations some attempts have been made by Becker and Doring (1935), Stranski and Totomanov (1933), and Davey (1993) to explain the Rule in kinetic terms. In doing this, it becomes apparent that the situation is by no means as clear cut as Ostwald might have us believe. Figure 2.11 shows the three possible simultaneous solutions of the nucleation equations which indicate that by careful control of the occurrence domain there may be conditions in which the nucleation rates of two polymorphic forms are equal, and hence their appearance probabilities are nearly equal. Under such conditions we might expect the polymorphs to crystallize concomitantly (see Section 3.3). In other cases, there is a clearer distinction between kinetic and thermodynamic crystallization conditions, and that distinction may be utilized to selectively obtain or prevent the crystallization of a particular polymorph. 

Two-component (i.e. two molecules) systems also exhibit concomitant polymorphism, implying a balance for the equilibrium situations governing the formation of the isomeric complexes as well as the kinetic and thermodynamic factors associated with the crystallization processes. The often serendipitous nature of the discovery of concomitant polymorphs is also illustrated by an example of a hydrogen-bonded two-component system, pyromellitic acid 3-XIV and 2,4,6-trimethylpyridine 3-XV (Biradha and Zaworotko 1998). The first polymorph (A) was obtained by reacting 3-XIV with four equivalents of 3-XV in a methanolic solution. Using 3-XV as the solvent yielded a second polymorph (B) in 15 min. Modification A was found to have crystallized as well in the same reaction vessel after about 24 h. These two polymorphs are not readily distinguishable by their morphology. However, the authors point out that the experimental evidence indicates that Form B is the kinefically controlled one, while Form A is the thermodynamically preferred one. 

Experimental Procedure. A dispersion of fat crystals in oil was obtained by adding 5 mL of the preprepared oil solution (saturated by -PPP, as above), to a controlled amount of unlabeled PPP crystals (either 10 or 20 mg). TTie polymorphic form of the PPP crystals was determined to be P [from diff ential scanning calorimetry (DSC)]. The dispersion was gently agitated and the temperature controlled at the temperature of interest. At regular intervals, a sample (ISO pL) of the dispersion was removed and centrifuged. The clear upper phase of this sample was then analyzed by the detector, and so the residual -PPP in the oil at that time was measured. The method is further described in a [nevious pr r. 

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