Crystallization case study

Manipulation of the Pharmacological Action of a Drug by Co-Crystallization Case Study of Insulin... 

Melt crystallization is carried out either with a suspension of crystals or an advanciag front (layer) of soHds, although a more complete categorization of melt crystallization is available (71). FoUowiag is a brief review of processes ia which melt crystallization is used a more complete review, including a worked out case study for system design, is available (69). 

The y-cut crystals showed little, if any, output signal under the same conditions for which the z-cut crystals were studied. In this case it should be observed that the y-cut crystals exhibit higher elastic limits and much higher piezoelectric polarizations than the z-cut crystals. These conditions result in much higher electric fields in the elastic region, and these fields are apparently sufficiently large that the crystals were completely conductive internally in the region between the elastic and plastic waves. 

Table 1. Dimensionless values of parameters in the Solutal Model for two cases studied here. The systems I and II are representative of the thermophysical properties of the succinonitrile-acetone systems with differing values of the dif-fusivity ratio Rm, temperature gradient G and capillary parameter F. System III corresponds to parameters for a Pb-Sb alloy with equal diffusivities in melt and crystal...

More subtle effects of preservatives on injectable formulations are possible. Formulation of insulin is an illustrative case study. Insulin is usually formulated as a multiple-dose vial, since individual dosage varies among patients. Preservation of zinc insulin with phenol causes physical instability of the suspension, whereas methyl-paraben does not. However, the presence of phenol is required for obtaining protamine insulin crystals [9]. 

Since one unit of 59 contains one molecule of 58 and two molecules of 2a, at least two of these units should take part in the photodimerization of 58. In other words, four molecules of 2a are concerned in each photodimerization of 58. It is not clear at present whether this has something to do with the relatively high enantioselectivity and efficiency of the photodimerization or not. In future, an X-ray crystal structural study of 59 is required to clarify this question. As in the case of 37, 58 exists as an equilibrium mixture of two flipping optical conformers. We may also learn from an X-ray analysis which optical conformer is included in 59. 

Case Studies Adsorption of Acetic Acid on Pt(111) Single Crystal Electrodes. Acetic acid is one of a very few organic compounds which is reversibly adsorbed on platinum at room temperature (20,25). We report below our radiochemical results on adsorption of this compound on Pt(111) and on polycrystalline Pt. 

Case study theophylline anhydrate and monohydrate The type of structural information that can be obtained from the study of the x-ray diffraction of single crystals will be illustrated through an exposition of studies conducted on the anhydrate and hydrate phases of theophylline (3,7-dihydro-l,3-dimethyl-LH-purine-2,6-dione). The unit cell parameters defining the two phases are fisted in Table 7.2, while the structure of this compound and a suitable atomic numbering system is located in Fig. 7.3. 

Whenever the solubility curve is crossed for the less stable Form II there is a risk that it will nucleate and contaminate the product. This situation is very probable when the solubility curves of the two polymorphs lie close together, as shown in Figure 21 of the Cimetidine case study. The addition of seed crystals of Form I, close to its solubility curve, and minimization of the supersaturation during the growth process is a good method of control in this instance. Solvent selection to extend the width of the Form II metastable zone would also be desired, as discussed in section 2.4.4. 

The non-random two-liquid segment activity coefficient model is a recent development of Chen and Song at Aspen Technology, Inc., [1], It is derived from the polymer NRTL model of Chen [26], which in turn is developed from the original NRTL model of Renon and Prausznitz [27]. The NRTL-SAC model is proposed in support of pharmaceutical and fine chemicals process and product design, for the qualitative tasks of solvent selection and the first approximation of phase equilibrium behavior in vapour liquid and liquid systems, where dissolved or solid phase pharmaceutical solutes are present. The application of NRTL-SAC is demonstrated here with a case study on the active pharmaceutical intermediate Cimetidine, and the design of a suitable crystallization process. 

Case Study - Solubility Modelling and Crystallization Process Design for Cimetidine... 

Cimetidine is known to crystallize in 5 polymorphic forms and 3 hydrated forms [11]. Solubility data is presented in this reference for Forms A, B and C. Form E was not known at the start of the study in reference [11] and Form D could not be crystallized, suggesting that it is less stable than the other forms. This is confirmed by melting point data which indicates the order of thermodynamic stability close to the melting temperature isEmelting point data for the evaluated forms are presented in Table 3. Form A is the commercially available Form and the desired product for this case study. 

For the purpose of this case study we will select Isopropyl alcohol as the crystallization solvent and assume that the NRTL-SAC solubility curve for Form A has been confirmed as reasonably accurate in the laboratory. If experimental solubility data is measured in IPA then it can be fitted to a more accurate (but non predictive) thermodynamic model such as NRTL or UNIQUAC at this point, taking care with analysis of the solid phase in equilibrium. As the activity coefficient model only relates to species in the liquid phase we can use the same model with each different set of AHm and Tm data to calculate the solubility of the other polymorphs of Cimetidine, as shown in Figure 21. True polymorphs only differ from each other in the solid phase and are otherwise chemically identical. 

NRTL-SAC has been demonstrated through the case study on Cimetidine as a valuable aid to solubility data assessment and targeted solvent selection for crystallization process design. The average model error is typically 0.5 Ln (x) [1] and is sufficient as a solvent screening tool. Methods that can deliver greater accuracy would increase the value and utility of these techniques. It is impressive in the case of Cimetidine that the NRTL-SAC correlation is capable of reasonable accuracy and predictive capability on the basis of just 2 fitted parameters. Further work to extend the solvent database and optimize the descriptive parameters will be beneficial, and are planned by the developers. 

Solvent design for crystallization of pharmaceutical products 4.4 CASE STUDIES... 

Case Study 1 Cooling Crystallization Solvent Design... 

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