Apparatuses and methods for creating and testing pre-formulations and systems for same

Abstract

The invention provides methods, apparatus, and systems for performing high-throughput preparation and screening of salts and polymorphs of drug candidates. The invention is directed towards enhancing the pre-formulation discovery process used for drug development. In particular, processes that determine suitable salts and processes that discover substantially every polymorph that can form from a particular drug candidate are provided. The processes are performed using several apparatuses that are specifically configured to carry-out various steps in a high-throughput characterization process. One such apparatus is configured for synthesizing a plurality of library members based on, for example, a library model generated by a computer system. Another apparatus may filter the synthesized solution to provide a substantially pure mixture that can be subjected to salt or polymorph testing. Yet another apparatus may be used to crystallize mixtures on a substrate such that the crystallized mixture can be screened by one or more screening devices.

1 - 96 . (canceled)  
     
     
         97 . A method for performing high throughput screening of drug candidate compounds, the method comprising: 
 preparing a first library of drug candidate solutions, the first library comprising a plurality of members, the preparing comprising combining at least one drug candidate and at least one solvent in each of the plurality of library members and heating the plurality of library members to form first drug candidate solutions;    sampling the first drug candidate solutions and determining a first concentration of drug candidate dissolved in each of the first drug candidate solutions;    daughtering the first library of drug candidate solutions to create a plurality of second libraries of drug candidate solutions, each of the plurality of second drug candidate solutions comprising a plurality of members, each second library member corresponding to a member of the first library of drug candidate solutions;    subjecting each of the plurality of second libraries to different crystallization conditions to produce drug candidate crystals, including subjecting a plurality of the second libraries to different crystallization methods selected from cooling, evaporation, precipitation or slurry methods, a first one of the second libraries being subjected to a cooling method to produce drug candidate crystals and supernatant in one or more members of the first one of the second libraries;    sampling the supernatants and determining a second concentration of the drug candidates in the supernatants;    screening drug candidate crystals produced during the subjecting to obtain crystal data for each of the drug candidate crystals; and    characterizing the drug candidates based on the crystal data and the first and second concentrations.    
     
     
         98 . The method of  claim 97 , further comprising: 
 filtering the members of the first library of drug candidate solutions before the daughtering.    
     
     
         99 . The method of  claim 98 , wherein: the filtering is performed in parallel.  
     
     
         100 . The method of  claim 97 , wherein: 
 characterizing the drug candidates comprises grouping the drug candidate crystals based on the crystal data.    
     
     
         101 . The method of  claim 97  wherein: 
 characterizing the drug candidates comprises determining solubilities of the drug candidates based on the first and second concentrations.    
     
     
         102 . The method of  claim 97 , wherein: 
 screening drug candidate crystals comprises screening the drug candidate crystals using at least two techniques selected from the group consisting of solubility, log P, melting point, birefringence, hygroscopicity, infrared spectroscopy, near infrared spectroscopy, Raman spectroscopy, X-ray diffraction, UV-Vis spectroscopy, nuclear magnetic resonance spectroscopy, gas chromatography, and liquid chromatography.    
     
     
         103 . The method of  claim 97 , wherein: 
 screening drug candidate crystals comprises screening each of the drug candidate crystals using Raman spectroscopy and X-ray diffraction techniques.    
     
     
         104 . The method of  claim 103 , wherein: 
 screening drug candidate crystals further comprises screening each of the drug candidate crystals using melting point, birefringence, and hygroscopicity techniques.    
     
     
         105 . The method of  claim 97 , wherein: 
 screening drug candidate crystals comprises screening each of the drug candidate crystals using birefringence and Raman spectroscopy techniques.    
     
     
         106 . The method of  claim 97 , wherein: 
 subjecting the second libraries to different crystallization conditions comprises subjecting the second libraries to one or more of different temperatures, pressures, times and humidities.    
     
     
         107 . The method of  claim 97 , wherein: 
 combining at least one drug candidate and at least one solvent in each of the plurality of library members comprises combining the same drug candidate with a different solvent in each of a plurality of library members.    
     
     
         108 . The method of  claim 97 , wherein: 
 combining at least one drug candidate and at least one solvent in each of the plurality of library members comprises combining at least one drug candidate with at least one solvent and at least one salt reactant in each of the plurality of library members, and allowing the at least one drug candidate and the at least one salt reactant to react to produce a plurality of different drug candidate salts.    
     
     
         109 . The method of  claim 97 , wherein: 
 characterizing the drug candidates comprises identifying one or more drug candidate polymorphs based on the crystal data.