Amorphous Dissolution Research Articles

Dissolution and Growth Kinetics and the Rate-Controlling Step in Transformation of Amorphous to Crystalline Phase Using Antisolvent Crystallization

The kinetics of the formation of amorphous disodium guanosine 5′-monophosphate and its transformation to the heptahydrate phase were studied under various operating conditions using in situ Raman and focused beam reflectance measurement (FBRM). Supersaturation, solvent composition, feed concentration, addition rate, and viscosity were shown to affect the rate-determining steps of the transformation. The rate-controlling mechanisms in the overall kinetics have been confirmed. The observation of the slurry viscosity of the suspension of the amorphous phase shows the option to observe the phase transformation. The transformation process was affected by the dissolution, growth, and supersaturation in which the rate-controlling step was divided into two sections, such as the initial and later sections of the transformation. The overall rate constants were determined by combining the constants of the dissolution rate and the growth rates of each section. In situ Raman spectroscopy examination of the concentration of solution and solids can determine the rate-limiting processes during the transformation. The zero-order, first-order, and surface reaction equations as kinetic equations are highlighted and compared for the dissolution of the amorphous solids and the growth of the heptahydrate crystals. The dissolution of the amorphous (metastable form) and the growth of the heptahydrate (stable form) were found to be best fitted to the zero-order kinetic model. In particular, the variation of particle size distribution over time can give the rate-determining steps. These results suggest that the data measured by Raman spectroscopy and FBRM can be successfully coupled into a dissolution and growth model to further grasp and interpret the phase transformation. A dissolution rate-controlling step was dominated by a pattern in which both supersaturation and amorphous dissolution decreased simultaneously, and the growth rate-controlling step was shown in a pattern in which either supersaturation or amorphous dissolution was constant. Furthermore, the growth of heptahydrate crystals at a viscosity of the suspension with the amorphous solids below 70 cp and the dissolution of the amorphous solids above it can be used as the key determinant. Using the method developed and the kinetic constants obtained in this work, it is possible to create an appropriate control strategy to produce the desired form in the final product.

Comparison of induction methods for supersaturation: Amorphous dissolution versus solvent shift

Simple solvent shift is often used to induce supersaturation and investigate precipitation kinetics in early drug development as a substitute for amorphous dissolution. This study develops and compares a small-scale non-sink amorphous dissolution method to a solvent shift method as induction methods for supersaturation of the model drugs albendazole, felodipine and tadalafil with respect to the maximum dissolved drug concentration, and the solid form of the precipitate. The study also investigates the effect of pre-dispersed precipitation inhibitors (hydroxypropyl methyl cellulose (HPMC) or polyvinylpyrrolidone (PVP)) on tadalafil supersaturation induced by both amorphous dissolution and solvent shift with respect to maximum dissolved drug concentration, precipitation rate and solid form of the precipitate. The maximum drug concentrations achieved through solvent shift were 15.9, 208 and 108 µg/mL for albendazole, felodipine and tadalafil, respectively. Pre-dispersing 0.1% (w/v) HPMC or PVP, increased the maximum concentration by solvent shift of tadalafil to 180 µg/mL, for both polymers. Dissolution of up to 90 mg albendazole, 120 mg felodipine and 8.9 mg tadalafil could yield a maximum dissolved drug concentration of 76.1%, 87.9% and 102.5%, respectively, of the corresponding solvent shift maximum concentration. The maximum concentration achieved through amorphous dissolution of tadalafil with HPMC or PVP present in the dissolution medium was 87.1% and 88.7%, respectively of the solvent shift maximum concentration. Dissolution of 2 mg amorphous tadalafil with and without pre-dispersed polymer gave the same rank order of onset of precipitation as for the solvent shift method. The solid form of precipitate was the same for albendazole, felodipine, tadalafil and tadalafil with PVP for both methods. For tadalafil with HPMC, the precipitate was amorphous following solvent shift, but crystalline after amorphous dissolution. Overall, this study shows that the maximum concentration achievable through amorphous dissolution can be estimated when performing solvent shift and the precipitation inhibition of excipients assessed via solvent shift can be used to predict the effect on precipitation using amorphous dissolution.

Elucidating spray-dried dispersion dissolution mechanisms with focused beam reflectance measurement: contribution of polymer chemistry and particle properties to performance

Amorphous spray-dried dispersions (SDDs) are a key enabling technology for oral solid dosage formulations, used to improve dissolution behaviour and clinical exposure of poorly soluble active pharmaceutical ingredients (APIs). Appropriate assessment of amorphous dissolution mechanisms is an ongoing challenge. Here we outline the novel application using focused beam reflectance measurement (FBRM) to analyse particle populations orthogonal to USP 2 dissolution. The relative impact of polymer substitution and particle attributes on 25% BMS-708163/HPMC-AS SDD dissolution was assessed. Dissolution mechanisms for SDDs were categorized into erosion versus disintegration. Beyond an initial mixing period, FBRM particle counts diminish slowly and particles are detectable until the point where API dissolution is complete. There is correlation between FBRM particle count decay rate, representing loss of SDD particles in the dissolution media, and UV dissolution rate, measuring dissolved API. For the SDD formulation examined, the degree of succinoyl substitution for HPMC-AS, SDD particle size and surface area all had an impact on dissolution. These data indicate the SDD displayed an erosion mechanism and that FBRM is capturing a rate-limiting step. From this screening tool, the mechanistic understanding and measured impact of polymer chemistry and particle properties can inform a risk-assessment and control strategy for this compound.