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Consistency checking: file format, valence, and structural integrity.
Removal of inorganics and separation of mixtures into individual components.
Removal of salts and counterions (the salts list is available in Additional file
Conversion of tautomers and mesomers to consistent representations. Examples include: nitro and azide mesomers, keto–enol tautomers, enamine–imine tautomers, enol-ketenes, etc. [37 (link)–39 ].
Neutralization of charged structures and removal of stereochemistry information.
Addition of explicit hydrogen atoms and aromatization of structures.
Removal of duplicates using InChIKey [40 ].
Original substances (left) and processed, linked chemical structures (right) indicating similarities and differences between the QSAR-Ready and MS-Ready workflows.
Example 3
The pulverized vicagrel salt was placed with pregelatinized starch, lactose, and sodium carboxymethyl starch in a fluidized bed, fluidized mixing is started for 10 min, and 5% hydroxypropyl methylcellulose is prepared as a binder. At an air inlet temperature of 80° C., the binder was sprayed while maintaining a bed temperature at 40-50° C. The formed particles were dried for 30 min while the bed temperature was maintained at 50-60° C., and were discharged. Sodium stearyl fumarate was added and mixed for 5 min, and the particles were filled into capsules.
Example 13
A solution of Varenicline free base (20.0 g) in methylene dichloride (100 mL) was stirred with the aqueous solution of Fumaric acid (13.18 g, 1.2 eq in 100 mL of water). The aqueous layer containing Varenicline fumarate salt was stirred with methylene dichloride to remove the nitrosamine impurity by solvent extraction. Thereafter, follow the general procedure for the isolation of Varenicline base from the aqueous layer. Yield: 14.0 g
Example 7
Approximately 10-20 mg of 1-(4-{[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-4-fluoro-piperidin-1-yl)-propenone were weighed into glass vials. 7 mL of FaSSIF medium (pH 6.5, prewarmed to 37° C.) were added and the suspension was shaken at 450 rpm at 37° C. After 30 min, 60 min and 120 min, 1 mL suspension was withdrawn and filtered through a 0.2 μm syringe filter. Clear filtrate was analysed by HPLC after suitable dilution to measure the amount of API dissolved.
Results from mini dissolution studies are summarised below.
While a number of embodiments of this invention are described herein, it is apparent that the basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the previously described embodiments rather than by the specific embodiments that have been represented by way of example.