Crystal polymorphism, control with

Spherical vaterite crystals were obtained with 4-mercaptobenzoic acid protected gold nanoparticles as the nucleation template by the carbonate diffusion method [51]. The crystallization of calcium carbonate in the absence of the 4-MBA capped gold nanoparticles resulted in calcite crystals. This indicates that the polymorphs of CaCOj were controlled by the acid-terminated gold nanoparticles. This result indicates that the rigid carboxylic acid structures can play a role in initiating the nucleation of vaterite as in the case of the G4.5 PAMAM dendrimer described above. 

Control of Crystal Polymorphism with the Assistance of "Tailor-Made" Auxiliaries... 

Acceptor species concentrations, equations, 400-401 Acentric materials biomimetic design, 454-455 synthesis approaches, 446 Ar-(2-Acetamido-4-nitrophenyl)pyrrolidene control of crystal polymorphism with assistance of auxiliary, 480-482 packing arrangements, 480,481-482/ Acetylenes, second- and third-order optical nonlinearities, 605-606 N-Acetyltyrosine, phase-matching loci for doubling, 355,356/, t Acid dimers, orientations, 454 Active polymer waveguides, applications, 111... 

Meeting crystal product specifications with a robust, repeatable process requires careful control and balancing of nucleation and growth kinetics. Careful structuring of the environment can dictate the fundamental mechanisms of nucleation and crystal growth and their resultant kinetics. Undesired polymorphs can be often minimized or eliminated by suitable control of rate processes. 

A dramatic example of the impact of crystal polymorphism on a drug formulation is that of ritonavir (Norvir ), used for the treatment of HIV patients. The problem arose in May of 1998, approximately two years after the launch of the drug, when researchers at the Abbott Laboratories became aware that after 240 production batches it was no longer possible to obtain ritonavir in the crystal form (Form I) approved by the FDA and required for the formulation of Norvir because of the sudden and unexpected appearance of a more stable and much less soluble crystal form (Form II, Fig. 3.3.17). The loss of control over the production process forced Abbott to withdraw the drug from the market for approximately one year until they learned how to replace the solid formulation with a gel capsule suspension with greater problems of stability and bioavailability. Subsequent investigations have led to the discovery of four other crystalline forms of ritonavir [33]. 

In the general case, if there are any other polymorphic forms with solubilities below that of Form n, the above-described process will continue between each successive pair of forms until the system finally contains only the most stable (the least soluble) form. The implication of this hypothesis is that, by controlling supersaturation and by harvesting crystals at an appropriate time, it should be possible to isolate the different polymorphic forms. Furthermore, the theory predicts that at equilibrium the product of any crystallization experiment must be the stable form, regardless of the solvent system. It is apparent, however. 

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. 

Polymorph control by solvent-drop grinding during co-crystallization of caffeine with glutaric acid. 

Sun Y, Xi H et al (2008a) Crystallization near glass transition transition from diffusion-controlled to diffusionless crystal growth studied with seven polymorphs. J Phys Chem B 112(18) 5594-5601 Sun Y, Xi H et al (2008b) Diffusionless crystal growth from glass has precursor in equilibrium liquid. J Phys Chem B 112(3) 661-664... 

Hiremath, R., Basile, J.A., Varney, S.W., Swift, J.A. (2005). Controlling molecular crystal polymorphism with self assembled monolayer templates. Journal of the American Chemical Society, Vol. 127, No. 51,18321-18327... 

By controlling the pH of the Ca -loaded polymer solution and thus the crystal polymorph (brushite and hydroxyapatite delicate mesoskeletons of interconnected calcium phosphate nanofibers with star-like, neuron-like, and... 

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