Exploring the Complexity of Processing-Induced Dehydration during Hot Melt Extrusion Using In-Line Raman Spectroscopy

Abstract

The specific aim in this study was to understand the effect of critical process parameters on the solid form composition of model drug compounds during hot melt extrusion using in-line Raman spectroscopy combined with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) modeling for semi-quantitative kinetic profiling. It was observed that the hydrate and anhydrate solid forms of two model drugs in the melts of nitrofurantoin (NF):polyethylene oxide (PEO) and piroxicam (PRX):PEO could be resolved from a MCR-ALS model without an external calibration dataset. Based on this model, the influence of two critical process parameters (shear and temperature) on the solid form composition could be evaluated in a real-time mode and the kinetics of complex transformation pathways could be explored. Additionally, the dehydration pathways of NF monohydrate and PRX monohydrate in molten PEO could be derived. It can be concluded that dehydration of both hydrates in PEO occurs via competing mechanisms—a solution-mediated transformation pathway and a solid–solid transformation, and that the balance between these mechanisms is determined by the combined effect of both temperature and shear. Another important observation was that the water released from these hydrate compounds has a detectable effect on the rheological characteristics of this mixture.

Material-Sparing Feasibility Screening for Hot Melt Extrusion

“…However, as no mixing or mechanical stress is applied and API-specific degradation is not evaluated, selection of HME temperatures using only these results is likely to incorrectly predict degradation under extrusion conditions, as demonstrated by analysis of unmixed samples herein. Additionally, degradation can be complex when considering the shear and other stresses induced by the extrusion process [ 13 , 46 , 65 , 66 ]. This is where the value of the feasibility screening using the MiniMixer comes into play, as it generates a sample emulating the HME conditions that can be analyzed for both API degradation and loading.…”

“…While great for studying and optimizing the extrusion processing window for scale-up, they are not necessarily ideal as a starting point when the temperature processing range and achievable API loadings have yet to be defined. For this reason, micro compounders are commonly used for HME feasibility screening [ 17 , 30 , 44 , 45 , 46 , 47 , 48 , 49 ]. They have conical screws that send material into a recirculating chamber, allowing time, temperature and shear (via rpm) to be studied as independent variables.…”

Controlling desolvation through polymer-assisted grinding

“…Interestingly, the released water remained in the molten polymer during heating and had a plasticizing effect on the drug-polymer mixture. 9 Mechanochemistry [10][11][12][13] is well established in providing suitable conditions for obtaining different solid forms of the same molecule or molecular system. [13][14][15][16] However, its application specifically for desolvation processes is not yet widely studied.…”

Monitoring the Isothermal Dehydration of Crystalline Hydrates Using Low-Frequency Raman Spectroscopy

“…42 MCR has been successfully applied in solid-state transformation studies using powder X-ray powder diffraction 43 and RS. 44 In the present study, we set out to utilize both the low-and mid-frequency regions as well as computational simulations to better understand the dehydration of crystalline hydrates. The simultaneous access to the low-and mid-frequency regions (LFR and MFR) was made feasible using a custom built Raman instrument.…”

“…This allows for both qualitative and quantitative analyses . MCR has been successfully applied in solid-state transformation studies using powder X-ray powder diffraction and RS …”