The solid forms of an API can be a crystalline free form, salt, co-crystal or an amorphous form. Different solid forms may have varying physical and chemical properties, such as bioavailability, solubility, dissolution rate, and stability, which are important for the success of a drug candidate. To determine the best solid form for clinical study, it is necessary to have systematic solid form screening and selection. A comprehensive screening also optimizes patent protection and lifecycle management, which increases the long-term value of a drug.
The completeness of a polymorph screening study and the accuracy of its thermodynamic stability ranking have been the major challenges for researchers. In a standard screening, more than 200 experiments are performed with over 20 solvents to ensure the completeness of the polymorphs landscape. The stable forms are usually produced in slow crystallization or solvent-mediated transformation methods, while metastable forms tend to yield from rapid crystallization methods. XtalPi adopts a variety of crystallization methods, such as solvent evaporation, cooling, agitating slurry, vapor diffusion, rapid precipitation, melt-quench, and amorphous transformation, to conduct the polymorph screening experiments. The new forms are scaled up and thoroughly characterized, and competitive slurry experiments are used to determine the thermodynamic stability ranking between the identified solid forms.
In addition to providing efficient and comprehensive polymorph screening service, XtalPi also offers its cutting-edge crystal structure prediction (CSP) technology. This technology can generate thermodynamically stable virtual crystal structures and provide accurate energy ranking. The results can complement experimental polymorph screening by evaluating the completeness of the experimental research and assessing the risk of a missed stable form. XtalPi is the only company in the world that can provide innovative screening services and crystal structure prediction services together.
When the solubility or stability properties of the free-form API is undesired, a salt form can be considered as the solid form of API. In a systematic salt screening process, the solvent-mediated method is preferred, and more than 20 acid/alkaline counterions are tried to conduct reaction crystallization with the free-form. The resulting solid samples are characterized by a series of methods to determine the formation of a salt, the ratio of counterions, and the thermal properties. For the salt forms with desired properties, the scaled-up study and systematic characterization are carried out. Finally, the optimal salt form will be selected by a comprehensive evaluation of thermal properties, hygroscopicity, stability, and solubility, for subsequent research and development.
Co-crystal, a unique form differently from free and salt form, has attracted more and more attention from pharmaceutical companies in recent years. Different from the traditional experimental co-crystal screening process, XtalPi first conducts a virtual screening of hundreds of co-formers. By using a high-precision force field customized for molecular modeling and crystal structure prediction, the co-crystal formation propensity of different co-formers with the API can be predicted. Co-crystal screening experiments are then performed based on the recommendations by the virtual screening so that the success rate and efficiency of co-crystal screening can be improved. Various screening methods, such as ball milling, solution-mediated method, are adopted to investigate multiple experimental factors. The co-crystal form with desired properties can be further scaled up and characterized.