RESUMO
In recent years, high throughput (HT) screening has become the most widely used approach for early phase salt screening and selection in a drug discovery/development setting. The purpose of this study was to compare a rational approach for salt screening and selection to those results previously generated using a HT approach. The rational approach involved a much smaller number of initial trials (one salt synthesis attempt per counterion) that were selected based on a few strategic solubility determinations of the free form combined with a theoretical analysis of the ideal solvent solubility conditions for salt formation. Salt screening results for sertraline, tamoxifen, and trazodone using the rational approach were compared to those previously generated by HT screening. The rational approach produced similar results to HT screening, including identification of the commercially chosen salt forms, but with a fraction of the crystallization attempts. Moreover, the rational approach provided enough solid from the very initial crystallization of a salt for more thorough and reliable solid-state characterization and thus rapid decision-making. The crystallization techniques used in the rational approach mimic larger-scale process crystallization, allowing smoother technical transfer of the selected salt to the process chemist.
Assuntos
Cristalização/métodos , Preparações Farmacêuticas/química , Sais/química , Solventes/química , Difração de Raios X/métodos , Estabilidade de Medicamentos , Solubilidade , Tecnologia Farmacêutica/métodos , Fatores de TempoRESUMO
Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Descoberta de Drogas , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Área Sob a Curva , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , RatosRESUMO
Solution-mediated phase transformation (SMPT) has been used as a focused technique to rapidly identify the stable polymorph of a given substance. Despite ample precedence for acetonitrile being a good solvent for SMPT of sulfamerazine (SMZ), samples from specific lots of SMZ failed to convert from Form I to Form II after suspension for 2 weeks in acetonitrile. In these lots, an acetyl derivative of SMZ was identified and shown to impede transformation to the stable polymorph. The inhibitory effect of this impurity on polymorphic conversion was overcome with practical adjustments to experimental procedure, which hastened the kinetics of SMPT. The critical factors considered were (1) modifying the solvent to increase solubility, (2) minimizing the level of impurity in the slurries, (3) pre-treatment of the solid to quickly reach maximum supersaturation, and (4) temperatures that optimized kinetics as well as the free energy difference between enantiotropically related polymorphs.
Assuntos
Anti-Infecciosos/química , Contaminação de Medicamentos , Sulfamerazina/química , Acetonitrilas/química , Química Farmacêutica , Cristalização , Estabilidade de Medicamentos , Cinética , Modelos Químicos , Tamanho da Partícula , Solubilidade , Solventes/química , Propriedades de Superfície , Tecnologia Farmacêutica/métodos , TemperaturaRESUMO
The thermodynamically most stable polymorph under ambient conditions is almost without exception the most desirable crystalline form for development by a pharmaceutical company. It is, therefore, beneficial to discover and to characterize this polymorph at the earliest possible stage of development. A screen for discovering the stable polymorph of a pharmaceutical compound early in the drug discovery-development process is developed and described. In this screen, a small amount of compound is suspended in a diverse group of solvents for two weeks in an effort to crystallize the most stable polymorph. The solubility of the compound in each solvent utilized in the stable polymorph screen is also simultaneously determined using a simple gravimetric method. Ritonavir and an early development candidate (Pfizer compound A) are used as model compounds to demonstrate the utility of the screen for finding the stable polymorph early in the drug discovery-development process.