Screening polymorph

Chen, S., et al., "The Cytochrome P450 2D6 (CYP2D6) Enzyme Polymorphism Screening Costs and Influence on Clinical Outcomes in Psychiatry," Clin. Pharmacol. Ther., 60, 522-534 (1996). 

Raman spectroscopy is emerging as a powerful analytical tool in the pharmaceutical industry, both in PAT and in qualitative and quantitative analyses of pharmaceuticals. Reviews of analyses of pharmaceuticals by Raman spectroscopy have been published.158 159 Applications include identification of raw materials, quantification of APIs in different formulations, polymorphic screening, and support of chemical development process scale-up. Recently published applications of Raman spectroscopy in high-throughput pharmaceutical analyses include determination of APIs in pharmaceutical liquids,160,161 suspensions,162 163 ointments,164 gel and patch formulations,165 and tablets and capsules.166-172... 

As discussed in section 2.4.4 the coordinating ability of a solvent will often affect the rate of nucleation and crystal growth differently between two polymorphs. This can be used as an effective means of process control and information on solvent effects can often be obtained from polymorph screening experiments. There are no theoretical methods available at the present time which accurately predict the effect of solvents on nucleation rates in the industrial environment. 

The case study of Ritonavir [19] is valuable in highlighting the potential consequence of a previously unknown polymorph appearing in a pharmaceutical product. It has made a far reaching impact on the industry and the thoroughness of polymorph screening. 

Polymorph screening experiments should be performed at the milligram scale, in 96 well plates, using protocols [9] that investigate the affects of ... 

The results of the polymorph screening step in combination with bioavailability studies, provide the information required by the clinical research team to nominate the desired crystal form of the API for long term manufacture and formulation. This form will usually be the most stable polymorph, where a number of forms have been identified, or a salt form if bioavailability is low or when there are formulation concerns regarding polymorph stability. In some cases it may be necessary to select an amorphous form or metastable polymorph because of crystallization difficulties, time constraints or bioavailability requirement. The nomination of a hydrate or solvate is generally avoided because of their relative instability and compositional variability such constraints are less of a concern for the earlier synthetic intermediates. 

If sufficient data is available from the polymorph screening step to identify solvent types which are likely to promote the formation of the desired polymorph then they can be included in the selection process at this point [12]. 

It is clear that kinetic effects must be utilized in the design of a process to make the commercially available Form A, because it is never the most thermodynamically stable form. Information from the literature and patents in reference [14] indicates that Form A can be successfully isolated from Acetonitrile, Acetone, Methyl isobutyl ketone, Toluene, the C2 to C4 alkenols, Ethanol, Methanol and Propan-2-ol. In these solvents it is likely that solvation is favourable to the nucleation rate of Form A or detrimental to crystal growth of the other forms, or both. For a new development compound there should be similar solvent interaction data available from polymorph screening experiments. 

Ab initio methods for polymorph, hydrate and solvate prediction are highly prized by the industry and good progress has been made in this field in recent years. This work is still a number of years from routine commercial application however, and polymorph screening experiments together with crystal structure determination, remain critical tasks for today s Pharmaceutical companies. 

Typical methods for generation of polymorphs include sublimation, crystallization from different solvents, vapor diffusion, thermal treatment, melt crystallization, and rapid precipitation. High-throughput screening methods have been reported for polymorph screening.50... 

Oh, K.T., Anis, A.H., and Bae, S.C. (2004) Pharmacoeconomic analysis of thiopurine methyltransferase polymorphism screening by polymerase chain reaction for treatment with azathioprine in Korea. Rheumatology (Oxford). 43,156-163. 

This chapter will review some of the key applications presented by protein microarrays. The use of profein microarrays sfems from works on gene expression arrays described earlier. However, rmlike ifs predecessors whose process formats (mutation detection, polymorphism screening, gene expression analysis, etc.) are essentially based upon solid-phase hybridization of nucleic acid complementary strands, the protein array may play different roles and comprise a variety of formafs. 

SNP/Polymorphism Screening Porf msics/paternity/military i d ... 

Crystal stmcture prediction by computer has made great steps forward in the last 10 years, with progress toward consistent success in blindfold tests. Fundamental uncertainties still remain, due to the unknown role of nucleation kinetics and to the neglect of temperature effects in the calculations. Success or failure still depends to some extent on hardly predictable factors and on the extent to which the experimental polymorph screening has been carried out. Presently, some of the best computational tools are not yet available to the general community of solid state scientists, being implemented in commercial, strictly copyrighted software. 

A basic, yet crucially important, application of powder XRD is in the identification ( fingerprinting ) of crystalline phases, based on the fact that different crystal structures give rise to distinct powder XRD patterns. Qualitative characterization of materials in this manner finds applications in many scientific disciplines (both academic and industrial), including quality control, polymorph screening, and the characterization of products from rapid throughput crystallization experiments [97, 98]. 

Pharmaceutical Polymorph screening, Unknown particle Tablet reconstruction,... 

Salt screening is often conducted in parallel to the polymorph screening in case a scalable crystallization process for the drug is not found. Chapter 11 in this book is devoted to this topic, and the reader is directed there for a detailed discussion. 

In an extraordinarily comprehensive review of polymorph screening procedures, it has been reported that during the conduct of 245 polymorph screens, about 90% of the systems studied exhibited multiple crystalline and noncrystalline forms, and about 50% exhibited polymorphism [38]. As to cocrystal screening, it was concluded that it is most efficient to use a combination of structural and physical property evaluation methods in conjunction with screening protocols similar to those used to detect new polymorphic forms. Data from 64 cocrystal screening studies were considered, and it was shown that cocrystals were found in 61% of the studied systems. 

Zhu Y, Spitz MR, Amos Cl, Lin J, Schabath MB, Wu X. An evolutionary perspective on single-nucleotide polymorphism screening in molecular cancer epidemiology. Cancer Res 2004 64 2251-2257. 

Livak, K.J., Marmaro, J. and Todd, J.A. (1995) Towards fully automated genome-wide polymorphism screening. Nature Genetics, 9 341-342. 

Fallin MD, Lasseter VK, Avramopoulos D, Nicodemus KK, Wolyniec PS, et al. 2005. Bipolar I disorder and schizophrenia A 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am J Hum Genet 77 918-936. 

In the early stage of preformulation, characterization of the drug molecule involves ionization constants and partition coefficient determinations, aqueous and nonaqueous kinetic and equilibrium solubility determination, pH solubility profile, chemical stability assessment, and salt and polymorph screening. Assessment of biopharmaceutics and toxicological screening are also essential... 

Crystallics, B. V. (Amsterdam) (2000). High throughput polymorph screening. Presented at 2nd International Symposium on Polymorphism and Crystallisation— Chemical Development Issues, Chester, UK. (Organized by Scientific Update, UK). [92]... 

The analysis also has implications for polymorph screening, where the emphasis in experimental design is commonly focused on solvent diversity. This is born from the pervasive assumption that polymorphic outcome is primarily governed by specific interactions between solute and solvent. While solvent diversity is certainly an important consideration, Threlfall s analysis shows that other factors such as supersaturation, concentration, cooling rate, nucleation temperature, and collection temperature should also receive adequate attention in experimental design for polymorph screening. 

Gu, C. Young, V. Grant, D. Polymorph screening influence of solvents on the rate of solvent-mediated polymorphic transformation. J. Pharm. Sci. 2001, 90 (11), 1878-1890. 

Romkes, M. Buch, S.C. Genotyping technologies application to biotransformation enzyme genetic polymorphism screening. Methods Mol. Biol. 2005, 291, 399-414. 

Trace amounts of impurities can lead to the formation of a new crystalline form or the preferential formation of another polymorph, as discussed for crystallization of abecarnil. For this reason it is wise to screen for polymorph formation using both highly purified final product and material of routine purity. The solids resulting from the removal of solvents from a final product extract may be appropriate for polymorph screening. 

Kim SK, Jun JB, El-Sohemy A, Bae SC (2006) Cost-effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 33 1266-1274... 

When improvements in the physical stability of a product are needed, choices must be based upon the nature of the problem and the desired goal. One of the first choices made is to use the most stable polymorph of the drug. This may involve an extensive polymorph screening effort to attempt to find the most stable polymorph. If the most stable polymorph is undesirable for some reason (e.g., solubility issues), then avoiding contamination of the desired polymorph with seeds of the most stable polymorph becomes very important. In a product that uses an amorphous form of a drug, it is critical to inhibit crystallization to avoid dramatic changes in stability and solubility. 

Gu CH, Young VJr, and Grant DJW. Polymorph Screening Influence of Solvents on the Rate of Solvent-Mediated Polymorphic Transformation. J Pharm Sci 2001 90 1878-1890. 

The rate and mechanisms by which crystallization occurs are determined by numerous thermodynamic, kinetic, and molecular recognition factors. (Nyvlt et al., 1985 Sohnel and Garside, 1992 Mersmann, 1995 Mullin, 2001 Myerson, 2002) These factors are summarized in Figure 1. The solvent plays a key role in crystallization as many of the factors depend directly on the solvent (Davey, 1982). Therefore, the intricate balance between thermodynamic, kinetic, and molecular recognition must be considered when designing experiments for polymorph screening, selection, and isolation. 

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