Modeling Physical Stability of Amorphous Solids Based on Temperature and Moisture Stresses

Abstract

Isothermal microcalorimetry was utilized to monitor the crystallization process of amorphous ritonavir (RTV) and its hydroxypropylmethylcellulose acetate succinate-based amorphous solid dispersion under various stressed conditions. An empirical model was developed: ln(τ)=ln(A)+EaRT-b⋅wc, where τ is the crystallization induction period, A is a pre-exponential factor, Ea is the apparent activation energy, b is the moisture sensitivity parameter, and wc is water content. To minimize the propagation of errors associated with the estimates, a nonlinear approach was used to calculate mean estimates and confidence intervals. The physical stability of neat amorphous RTV and RTV in hydroxypropylmethylcellulose acetate succinate solid dispersions was found to be mainly governed by the nucleation kinetic process. The impact of polymers and moisture on the crystallization process can be quantitatively described by Ea and b in this Arrhenius-type model. The good agreement between the measured values under some less stressful test conditions and those predicted, reflected by the slope and R(2) of the correlation plot of these 2 sets of data on a natural logarithm scale, indicates its predictability of long-term physical stability of amorphous RTV in solid dispersions. To further improve the model, more understanding of the impact of temperature and moisture on the amorphous physical stability and fundamentals regarding nucleation and crystallization is needed.

Kinetic Modeling of Accelerated Stability Testing Enabled by Second Harmonic Generation Microscopy

“…Ritonavir is an active ingredient in many successful anti-HIV formulations with extensively studied crystallization kinetics. , Given the rich phase behavior of ritonavir, a substantial body of literature has accumulated for modeling crystallization of amorphous ritonavir, both as a pure compound and as an amorphous formulation. In a recent study centered on crystallization of ritonavir and formulations containing amorphous ritonavir, Zhu et al performed a series of stability experiments to develop predictive models for ritonavir crystallization behaviors, as a case study. The kinetic modeling was performed based on determination of the induction time, corresponding to the minimum time required to detect onset of crystallization.…”

Crystallization Risk Assessment of Amorphous Solid Dispersions by Physical Shelf-Life Modeling: A Practical Approach

“…A reported fitting function can be used to estimate the corresponding water content w water in the fenofibrate tablets from any given environmental relative humidity RH As shown in eq , pure water has a very low T g,water of −138 °C, and hence an increasing content of absorbed water leads to decreasing T g . Lowering T g in turn accelerates the molecular movement in the ASD and leads to faster API crystallization …”

“…37 Lowering T g in turn accelerates the molecular movement in the ASD and leads to faster API crystallization. 20 Combining eqs 2 and 3, a direct correlation between the wet-T g and the relative humidity RH was obtained as a function T g (RH). In fact, it was aimed to correlate moisture sorption and wet-T g .…”

“…18 As discussed in our prior study, it is possible to monitor the crystal growth in ASDs even at elevated environmental stress using TRS. 18 A first attempt to extrapolate the crystal growth kinetics using the augmentation of the approach by Genton and Kesselring 19 introduced by Zhang et al, 20 which links the natural logarithm of the rate constant for crystal growth to the water content in the ASD, has been presented in our previous study. 21 Linking the crystal growth with the molecular mobility in glasses as published by Suryanarayanan et al, 22−24 Greco et al, 25 Paluch et al, 26−28 and others, in this work, an approach is presented that correlates the crystal growth rate with the ratio of T g of the humid ASD and the storage temperature above T g .…”

Coamorphous Active Pharmaceutical Ingredient–Small Molecule Mixtures: Considerations in the Choice of Coformers for Enhancing Dissolution and Oral Bioavailability

“…21 Similarly, a 90:10 w/w ritonavir-HPMCAS dispersion remained physically stable for up to 18 months at 30 C/57% relative humidity (RH). 22 To date, most studies with coamorphous systems reporting the extent of solid-state stability upon storage have observed physical stability for days, weeks, and months. For example, a 1:1 molar ratio of coamorphous sulfathiazoleetartaric acid remained stable for 28 days at room temperature and 10% RH, 23 a 1:1 molar ratio of lurasidone hydrochlorideesaccharin remained stable for 60 days at 25 C/60% RH, 24 and a 1:1 molar ratio of repaglinide-saccharin remained stable for 3 months at 40 C/75% RH.…”