Industry White Paper: Contemporary Opportunities and Challenges in Characterizing Crystallinity in Amorphous Solid Dispersions.

Members of the IQ Consortium ″Working Group on Characterization on Amorphous Solid Dispersions″ shares here a perspective on the analytical challenges, and limitations of detecting low levels of crystalline drug substance in amorphous solid dispersions (ASDs) and associated drug products. These companies aim to employ highly sensitive commercially available analytical technologies to guide development, support control strategies, and enable registration of quality products. We hope to promote consistency in development and registration approaches and guide the industry in development of "characterization best practices" in the interest of providing high quality products for patients. The first half of this perspective highlights the unique challenges of analytical methodologies to monitor crystalline drug substance in ASDs and their associated drug products. Challenges around use of limit tests, analyte spiking experiments, and method robustness are also underscored. The latter half describes the merits and limitations of the diverse analytical "toolbox" (such as XRPD, NIR and DSC), which can be readily applied during development and, in some cases, considered for potential application and validation in the commercial QC setting when necessary.

Study and characterization of crystalline hydrate/polymorph forms of 5,11-dihydro-11-ethyl-5-methyl-8-(2-(1-oxido-4-quinolinyl)ethyl-6H-dipyrido(3,2-B:2',3'-E)(1,4)diazepin-6-one by solid-state NMR and solution NMR.

A novel inhibitor of reverse transcriptase was studied by solid-state NMR. Three phases of the compound were examined which included the dihydrate and two anhydrous polymorphs (Form I and Form III). By correlating (1)H and (13)C solution NMR with the solid-state (13)C NMR CP/MAS and CPPI spectral editing experiments, comparative (13)C assignments were made for each phase. Polymorphs of Form I and Form III and the dihydrate were easily distinguished based upon chemical shift patterns of the carbon resonances. The (1)H spin-lattice relaxation times were also measured for each phase which provided information on the mobility and relative crystallinity. The (13)C ssNMR spectrum of Form I showed the presence of a minor component identified as the dihydrate. Weight/percent quantitation of major and minor components in Form I was obtained from integrated intensities of a 50:50 mixture containing weighed amounts of Form I and the pure dihydrate. Comparison of the ssNMR and X-ray powder diffraction techniques is discussed.

Drug-excipient complexation in lipid based delivery systems: an investigation of the Tipranavir-1,3-dioctanolyglycerol complex.

This report describes the solubility properties of a poorly soluble drug-excipient complex in a lipid based formulation. Tipranavir (TPV) was used as the model drug and 1,3-dioctanoylglycerol (DOG) as the excipient. The TPV-DOG complex was prepared by dissolving TPV and DOG in ethanol at 60 degrees C followed by evaporation of ethanol. The formation of the complex with a 4:1 TPV-to-DOG molar ratio was confirmed by XRPD, DSC, and NMR. At 25 degrees C, total solubility of TPV decreased with increasing DOG concentration. The solubility properties of the TPV-DOG complex can be described by two simultaneous equilibria: a liquid-solid phase equilibrium of the complex and a species equilibrium among the various species in the liquid phase. A model equation was derived accordingly with two parameters, the intrinsic solubility of the complex (S(o)), and the solution complex constant (K(41)). The model was in good agreement with experimental results. The values of S(o) and K(41) are 0.0186 +/- 0.0025 (M) and 21.97 +/- 7.19 (1/M(4)), respectively. The equation can successfully predict the concentrations of total and free TPV as a function of DOG in the formulation. The approach developed provides a useful tool for rationale selection of excipients and their levels to avoid drug precipitation in lipid based formulations.