Stability Of Amorphous Solid Dispersions Research Articles

Development of stable amorphous solid dispersion and quantification of crystalline fraction of lopinavir by spectroscopic-chemometric methods

This study aimed to improve the dissolution of the poorly soluble drug lopinavir (LPV) by preparing amorphous solid dispersions (ASDs) using solvent evaporation method. The ASD formulations were prepared with ternary mixtures of LPV, Eudragit® E100, and microcrystalline cellulose (MCC) at various weight ratios. The ASDs were subjected to solid-state characterization and in vitro drug dissolution testing. Chemometric models based on near infrared spectroscopy (NIR) and NIR-hyperspectroscopy (NIR-H) data were developed using the partial least squares (PLS) regression and externally validated to estimate the percent of the crystalline LPV in the ASD. Initially, the solid-state characterization data of ASDs showed transformation of the drug from crystalline to amorphous. Negligible fraction of crystalline LPV was present in the ASD (3%). Compared to pure LPV, ASDs showed faster and higher drug dissolution (<2% vs. 60.3–73.5%) in the first 15 min of testing. The ASD was stable against crystallization during stability testing at 40 °C/75% for a month. In conclusion, the prepared ASD was stable against devitrification and enhance the dissolution of LPV.

Investigating crystallization tendency, miscibility, and molecular interactions of drug–polymer systems for the development of amorphous solid dispersions

Crystallization tendencies, thermal analysis [i.e. glass transition temperature (T g)], crystallinity, and melting point depression, along with theoretical calculations such as solubility parameter, of five different drugs [i.e. curcumin (CUR), indomethacin (IND), flutamide (FLU), dipyridamole (DIP), and griseofulvin (GRI)] in the absence and presence of four different polymers in various drug–polymer ratios were determined and analyzed. Physical states of the drug in the solid dispersions (SDs) and their stability were characterized by X-ray diffraction and modulated differential scanning calorimetry. Infrared (IR) and Raman were used in selected systems (i.e. CUR, DIP, and GRI systems) to explore the role of drug–polymer interactions in the amorphization of SDs. The crystallization tendencies of pure drugs were categorized as low (CUR, IND), moderate (FLU), and high (DIP, GRI). In the presence of selected polymers, the crystallization tendency of the drugs changed, though a high polymer concentration was required for high crystallization-tendency drugs [i.e. DIP and GRI (>50% w/w)]. Polymers showing a greater effect on the crystallization tendency of drugs were found to have higher drug–polymer miscibility and stronger molecular interactions. Drug–polymer systems selected from the investigation of physical mixtures formed stable amorphous solid dispersions (ASD). Furthermore, the rank order of the crystallization tendency of drug–polymer systems correlated well with those on miscibility and molecular interactions. Those rank orders also correlated well with the stability of prepared/reported SDs. Hence, the developed approach has significant potential to be a rational screening method for the development of amorphous SDs.

How Does the Addition of Kollidon®VA64 Inhibit the Recrystallization and Improve Ezetimibe Dissolution from Amorphous Solid Dispersions?

Amorphization serves as a strategy for the improvement of poor dissolution characteristics of many drug compounds. However, in many formulations the content of polymeric stabilizer is high, which is undesirable from the perspective of future applications. Thus, studying the composition-dependent stability of amorphous solid dispersions seems to be demanded. In this paper, we describe the amorphization of ezetimibe, a lipid-lowering drug, in the spray drying process and investigate the effect of polyvinylpyrrolidone-co-poly(vinyl acetate) (PVP/VA) content on the physical stability and dissolution characteristics of the drug. Fully amorphous systems were obtained when the concentration of the polymer in solid dispersion was as low as 20%. The amorphization led to the dissolution enhancement by even 70%, with a noticeable sudden increase at around 40% of PVP/VA content and very small variations for systems having 66–90% PVP/VA. It was also correlated to wettability characteristics of solid dispersions, which may suggest that in the vicinity of 40% of the polymer content, the behavior of the system becomes independent of the PVP/VA content.

Thermal Stability of Amorphous Solid Dispersions.

Amorphous solid dispersion drug delivery systems (ASD DDS) were proved to be efficient for the enhancement of solubility and bioavailability of poorly water-soluble drugs. One of the major keys for successful preparation of ASD is the selection of appropriate excipients, mostly polymers, which have a crucial role in improving drug solubility and its physical stability. Even though, excipients should be chemically inert, there is some evidence that polymers can affect the thermal stability of active pharmaceutical ingredients (API). The thermal stability of a drug is closely related to the shelf-life of pharmaceutical products and therefore it is a matter of high pharmaceutical relevance. An overview of thermal stability of amorphous solids is provided in this paper. Evaluation of thermal stability of amorphous solid dispersion is perceived from the physicochemical perspective, from a kinetic (motions) and thermodynamic (energy) point of view, focusing on activation energy and fragility, as well all other relevant parameters for ASD design, with a glance on computational kinetic analysis of solid-state decomposition.

An Investigation into the Use of Mesoporous Silica for Improving Physical Stability of Amorphous Solid Dispersion with High Drug Loading

An Investigation into the Use of Mesoporous Silica for Improving Physical Stability of Amorphous Solid Dispersion with High Drug Loading

A review on the physical stability of amorphous solid dispersion

Solid dispersions in water-soluble carriers have piqued researchers&#39; interest as a way to boost the dissolution rate, and thus the bioavailability, of a variety of hydrophobic drugs. Despite its many benefits, strong dispersion has a number of significant disadvantages. One of the most serious issues is the physical stability of the drug&#39;s high-energy amorphous state. Since solid dispersion aids in improving dissolution and solubility, the drug in an amorphous state can crystallise over time. This review focuses on the factors that aid in the improvement of solid dispersion&#39;s physical stability. The consequences of a better understanding of physical stability are addressed, with a focus on optimising the carrier-to-drug ratio, carrier selection, and the estimation of the glass transition temperature of the drug. The medication and the carrier, as well as the physical changes in solid dispersions that lead to crystallisation.

Use of Ibuprofen Dimer as an Incidental Indicator of Stability in Amorphous Solid Dispersions

Attaining a high drug load while maintaining stability of amorphous solid dispersions (ASD) is one of the critical formulation challenges during the developmental phase. We propose here that early detection of the ibuprofen dimer can be used as an indirect indicator of potential physical destabilization of the ASD. Conventional approaches to determine stability involve exposure of prepared ASDs to different stress conditions in order to observe drug recrystallization. The approaches are time- consuming and often considered as a limiting factor for the use of ASD. Here, Attenuated Total Reflection Fourier Transform Infrared spectroscopy (ATR-FTIR) has been used as a tool to detect ibuprofen dimer in an ibuprofen and hydroxypropyl methylcellulose (HPMC) ASD prepared using hot melt extrusion (HME). X-ray diffractometry (XRD), Differential Scanning Calorimetry (DSC) and Raman spectrometry were used to support our hypothesis. Presence of ibuprofen dimer in the ASD was found to correlate well with the solid-state stability of ASDs. This indirect approach was further confirmed by exposing extrudates of different ibuprofen concentration to various stress conditions. XRD, DSC and Raman spectrometry were used to confirm solid state stability of the ASD by providing an ortho-analytical approach. Results confirmed that 15%w/w drug loading of ibuprofen was the maximum drug concentration able to produce a stable ASD with absence of ibuprofen dimer.

Solvent influence on the phase behavior and glass transition of Amorphous Solid Dispersions

Understanding the long-term stability of amorphous solid dispersions (ASDs) is important for their successful approval for market. ASD stability does not only depend on the interplay between the active pharmaceutical ingredient (API) and the polymer in the final formulation but may already be disadvantageously influenced by process steps during the production (e.g. selection of inappropriate solvent for spray drying). Residual solvent can affect the API solubility in the polymer, molecular mobility (by influencing the glass-transition temperature) and induce liquid-liquid phase separation. Enhanced mobility in the ASD due to residual solvent can promote recrystallization in ASDs.The removal of residual solvent can be expensive, time-consuming, and usually requires secondary drying procedures to fulfil the regulatory requirements. The aim of this work is to predict the API solubility in polymer-solvent mixtures, solvent influence on the glass transition, and the occurrence of liquid-liquid phase separation of solvent-loaded ASDs using the thermodynamic model PC-SAFT and to experimentally validate these predictions. ASDs containing the APIs ritonavir or naproxen and the polymers poly(vinylpyrrolidone), poly (vinylpyrrolidone-co-vinyl acetate), or hydroxypropyl methylcellulose acetate succinate were spray-dried using the solvents acetone, ethanol, and dichloromethane. API solubility, sorption behavior, liquid-liquid phase separation and glass transition in the ternary API/polymer/solvent mixtures were predicted based on the binary phase behavior between API/solvent, API/polymer, and polymer/solvent and successfully validated experimentally using dynamic vapor sorption (DVS), and Raman spectroscopy. Thus, the presented methodology allows for an in-silico selection of appropriate solvent systems for solvent-based ASD preparation based on a limited amount of experimental data for binary systems only.

A Mechanistic Model for Predicting the Physical Stability of Amorphous Solid Dispersions.

In this paper, we establish a mechanistic model for the prediction of amorphous solid dispersion (ASD) stability. The novel approach incorporates fundamental physical parameters, principally supersaturation, diffusivity, and interfacial energy, to model crystallization in ASDs accounting for both kinetic and thermodynamic drivers. API dependent decoupling coefficients were also considered which allowed dynamic mechanical analysis to probe molecular mobility, with viscosity measurements, across an exceptionally broad range of temperatures to support ASD stability simulations. ASDs are multicomponent systems in which the amorphous form of active pharmaceutical ingredients (APIs) are molecularly dispersed within a carrier. This gives rise to a transiently supersaturated API solution upon dissolution which increases the driving force for oral absorption and results in increased bioavailability as compared to that of the crystalline API. A major shortcoming of ASDs, however, is that there is the potential for amorphous APIs to revert to their more stable crystalline form during storage, despite the use of polymer carriers to stabilize formulations and limit recrystallization. Hot melt extrusion (HME) has been employed as the preparation method for ASDs used in this study as it is well-suited for the formation of uniform dispersions. The ASDs were stored under controlled temperature conditions, in the absence of humidity, to determine recrystallization kinetics. Our mechanistic model, considering both crystal nucleation and growth processes, describes temporal ASD stability through a system of coupled differential equations that connect the physiochemical properties of the ASD system to drug recrystallization. The model and prolonged time scale of crystallization observed highlight the importance of considering both thermodynamic and kinetic factors in the preparation of stable ASDs. Experimental observations were found to be in good agreement with predictions of the model confirming its utility in predicting the temporal physical stability of amorphous solid dispersions through a mechanistic lens.

Molecular Dynamics and Physical Stability of Ibuprofen in Binary Mixtures with an Acetylated Derivative of Maltose.

In this paper, we explore the strategy increasingly used to improve the bioavailability of poorly water-soluble crystalline drugs by formulating their amorphous solid dispersions. We focus on the potential application of a low molecular weight excipient octaacetyl-maltose (acMAL) to prepare physically stable amorphous solid dispersions with ibuprofen (IBU) aimed at enhancing water solubility of the drug compared to that of its crystalline counterpart. We thoroughly investigate global and local molecular dynamics, thermal properties, and physical stability of the IBU+acMAL binary systems by using broadband dielectric spectroscopy and differential scanning calorimetry as well as test their water solubility and dissolution rate. The obtained results are extensively discussed by analyzing several factors considered to affect the physical stability of amorphous systems, including those related to the global mobility, such as plasticization/antiplasticization effects, the activation energy, fragility parameter, and the number of dynamically correlated molecules as well as specific intermolecular interactions like hydrogen bonds, supporting the latter by density functional theory calculations. The observations made for the IBU+acMAL binary systems and drawn recommendations give a better insight into our understanding of molecular mechanisms governing the physical stability of amorphous solid dispersions.

Mechanodegradation of Polymers: A Limiting Factor of Mechanochemical Activation in the Production of Amorphous Solid Dispersions by Cryomilling.

In this study, we report on the influence of mechanochemical activation on the chemical stability of amorphous solid dispersions made up of indomethacin and hydroxypropyl methyl cellulose (HPMC), poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone vinylacetate) (PVPVA), or Soluplus. In agreement with our recently published work, all applied carriers were found to be prone to polymer degradation. Covalent bonds within the polymers were cleaved and mechanoradicals were generated. Furthermore, decomposition of indomethacin was also observed but occurred only in the presence of polymers. Hence, it is proposed that the generated mechanoradicals from the polymers are responsible for the chemical degradation of indomethacin. Our study also strongly suggests the existence of a critical polymer- and process-dependent molecular weight limit "M∞", below which only limited mechanodegradation takes place since the lower-molecular-weight polymer PVP K12PF had a less profound influence on the degradation of indomethacin in comparison to PVP K25.

Compression-Induced Phase Transitions of Bicalutamide.

The formation of solid dispersions with the amorphous drug dispersed in the polymeric matrix improves the dissolution characteristics of poorly soluble drugs. Although they provide an improved absorption after oral administration, the recrystallization, which can occur upon absorption of moisture or during solidification and other formulation stages, serves as a major challenge. This work aims at understanding the amorphization-recrystallization changes of bicalutamide. Amorphous solid dispersions with poly(vinylpyrrolidone-co-vinyl acetate) (PVP/VA) were obtained by either ball milling or spray drying. The applied processes led to drug amorphization as confirmed using X-ray diffraction and differential scanning calorimetry. Due to a high propensity towards mechanical activation, the changes of the crystal structure of physical blends of active pharmaceutical ingredient (API) and polymer upon pressure were also examined. The compression led to drug amorphization or transition from form I to form II polymorph, depending on the composition and applied force. The formation of hydrogen bonds confirmed using infrared spectroscopy and high miscibility of drug and polymer determined using non-isothermal dielectric measurements contributed to the high stability of amorphous solid dispersions. They exhibited improved wettability and dissolution enhanced by 2.5- to 11-fold in comparison with the crystalline drug. The drug remained amorphous upon compression when the content of PVP/VA in solid dispersions exceeded 20% or 33%, in the case of spray-dried and milled systems, respectively.

Amorphous solid dispersion of nisoldipine by solvent evaporation technique: preparation, characterization, in vitro, in vivo evaluation, and scale up feasibility study.

The present study was designed to determine the applicability of a newly derived dimensionless number precipitation parameter, "supersaturation holding capacity (SHC)" in development of amorphous solid dispersion (ASD) of a rapidly crystallizing drug, nisoldipine. Also, ASD preparation from lab scale formulation technique to scalable spray drying technique followed by oral bioavailability study was demonstrated. Solution state screening of polymers was performed by determining nucleation induction time (tin) and SHC. With screened polymers, lab scale ASDs of nisoldipine were prepared using rotary evaporation (solvent evaporation) method, and the optimized stable ASDs were scaled up by spray drying. The ASDs were characterized by DSC, PXRD, and FTIR for amorphous nature and evaluated for apparent solubility, dissolution, and solid-state stability improvement. The spray dried ASDs were additionally evaluated for micrometric properties and oral bioavailability study.PVP grades demonstrated superior crystal growth inhibition properties (with 2-4-fold enhancements in SHC). ASDs prepared by both lab scale and scale-up technique using PVP stabilized the amorphous nisoldipine via antiplasticization effect that maintained the stability under accelerated stability conditions (40°C/75% RH) for 6months. Additionally, FTIR study confirmed the role of intermolecular interactions in amorphous state stabilization of PVP-based solid dispersions. PVP-based spray dried ASDs improved the apparent solubility 4-fold for PVP K17 and more than 3-fold for remaining spray dried ASDs. The enhanced solubility was translated to improved dissolution of the drug when compared with crystalline and amorphous form complementing the outcome of the solution state study. The spray dried ASD showed 2.3 and > 3-fold the improvement in Cmax and AUC (0-24h) respectively when compared with crystalline nisoldipine during oral bioavailability study which highlights the significance of SHC parameter of polymers. The spray dried ASD has shown improved micromeritics properties then crystalline nisoldipine in terms of flow behavior.This unique study provides a rational strategy for selection of appropriate polymer in development of ASDs that can tackle both precipitation during dissolution and amorphous state stabilization in solid state and also considers the SHC in scale-up study. Graphical abstract.

Crystallization tendency of APIs possessing different thermal and glass related properties in amorphous solid dispersions.

The correlation between glass forming ability (GFA) and several thermophysical or physicochemical properties of APIs with the formation and the physical stability of amorphous solid dispersions (ASDs) was evaluated in the present study. Eight poorly water-soluble APIs belonging in different GFA classes (i.e. a) GFA Class I: Carbamazepine, CBZ, b) GFA Class II: Agomelatine, AGO, Aprepitant, APT, Rivaroxaban, RIV, and c) GFA Class III: Indomethacin, IND, Pioglitazone, PIO, Piroxixam, PIR, and Simvastatin, SIM) were tested, in addition to six commonly used matrix-carriers (namely povidone, PVP, hydroxypropyl cellulose, HPC-SL, copovidone, coPVP, Soluplus®, SOL, and gelatin) in order to prepared ASDs via film casting approach. Results using polarized light microscopy (PLM) showed a similar drug crystallization tendency from ASDs independently of their GFA classification, glass stability or glass fragility. X-ray diffraction analysis verified the formation and the physical stability of ASD (independently of GFA class) when a suitable matrix-carrier was selected (i.e. SOL for AGO, RIV and SIM, PVP for APT, CBZ and IND, coPVP for PIO and gelatin for PIR). Further attempts to correlate some physicochemical properties (i.e. component's binding affinity and miscibility) with the formation and the crystallization tendency of the prepared ASDs showed no apparent correlation in regards to the different drug GFA classes. Finally, the evaluation of molecular interactions via FTIR analysis also failed to adequately distinguish the differences in regards to the formation and the physical stability of the prepared systems.

Stable amorphous solid dispersions of fenofibrate using hot melt extrusion technology: Effect of formulation and process parameters for a low glass transition temperature drug

Development of stable amorphous solid dispersions (ASDs) for a low glass transition temperature (Tg) drug is a challenging task. The physico-chemical properties of the drug and excipients play a critical role in developing stable ASDs. In this study, ASDs of poorly soluble fenofibrate, a drug with a low Tg, were formulated using hydroxy propyl methylcellulose acetate succinate (HPMCAS) via hot melt extrusion (HME). The feasible processing conditions were established at varying drug loads and processing temperatures. The prepared ASDs were characterized for crystallinity using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Fourier transform-infrared spectroscopy was performed to study the potential interactions. DSC and PXRD studies confirmed the amorphous state of fenofibrate in the prepared ASDs. A discriminative in vitro dissolution method was established to study the impact of HPMCAS grades on dissolution profile. The dissolution parameters such as dissolution efficiency, initial dissolution rate and mean dissolution rate, suggested improved dissolution characteristics compared to pure fenofibrate. Accelerated stability studies at 40 °C/75% RH showed preservation of the amorphous nature of fenofibrate in formulations with 15% drug load and in vitro drug release studies indicated similar release profiles (f2 >50). This study provides an insight into the formulation and processing of ASDs for poorly soluble drugs with low Tg.

Solvent-free Hot Melt Extrusion Technique in Improving Mesalamine Release for Better Management of Inflammatory Bowel Disease

Abstract: Background: Poor oral bioavailability of mesalamine (Mes) is due to extensive metabolism in the intestinal epithelial cells in addition to the liver. Purpose: Improved mesalamine release by Hot-Melt Extrusion (HME) technique could be utilized for better management of Inflammatory Bowel Disease (IBD). Methods: Mes and hydrophilic polymers like Eudragit- EPO, KollidonVA-64 and PEG 6000 were hot-melt extruded using a co-rotating twin-screw laboratory extruder. Results: The minor shifting with significantly reduced intensity and disappearance of peak in the Differential Scanning Calorimetry (DSC) thermogram could be attributed to some solid–solid interaction and not necessarily any incompatibility. Fourier-Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM) confirmed the transformation of individual drug crystal into accumulations of small crystallites due to partial or almost complete amorphization. Continuous manufacturing of stable amorphous solid dispersion by solvent-free drug loading Hot-melt extrusion technique has been found feasible in improving drug release compared to mesalamine alone in simulated gastric fluid (f1= 0.3 to 11.1 and f2 = 26 to 49). Conclusion: Melt dispersion samples have exhibited significantly improved mesalamine release and could be utilized for better management of Inflammatory Bowel Disease (IBD). Key words: Hot-melt extrusion, Solvent-free drug loading, Mesalamine, Feret diameter, Improving Release.

Myth or Truth: The Glass Forming Ability Class III Drugs Will Always Form Single-Phase Homogenous Amorphous Solid Dispersion Formulations.

The physical stability of amorphous solid dispersions (ASD) of active pharmaceutical ingredients (APIs) of high glass forming ability (GFA class III) is generally expected to be high among the scientific community. In this study, the ASD of ten-selected class III APIs with the two polymers, PVPVA 64 and HPMC-E5, have been prepared by spray-drying, film-casting, and their amorphicity at T0 was investigated by modulated differential scanning calorimetry and powder X-ray diffraction. It was witnessed that only five out of ten APIs form good quality amorphous solid dispersions with no phase separation and zero crystalline content, immediately after the preparation and drying process. Hence, it was further established that the classification of an API as GFA class III does not guarantee the formulation of single phase amorphous solid dispersions.

Crosslinking: An avenue to develop stable amorphous solid dispersion with high drug loading and tailored physical stability

Influence of crosslinking (crosslinker concentration and crosslinking condition) on molecular mobility and physical stability of ketoconazole (KTZ) solid dispersions was investigated over a wide temperature range in the supercooled state. Amorphous solid dispersions (ASDs) with very high drug loading (95% w/w) were prepared by thermal crosslinking. As the crosslinker concentration increased (from 0.25–1.0% w/w), there was a progressive decrease in molecular mobility as evident from both the longer α-relaxation time, and higher viscosity values. Consequently, there was progressive enhancement in physical stability (crystallization inhibition). At 1.0% w/w crosslinker concentration, when compared with the drug alone, there was ~4 orders of magnitude increase in both viscosity and α-relaxation times. Elevating the crosslinking temperature, by increasing the crosslinking density, provided a second avenue to enhance physical stability. Hence, crosslinking density offers a simple method to enhance physical stability and control drug release. We have formulated ASDs: (i) with very high drug loading (95% w/w), and (ii) pronounced stability even when exposed to elevated temperatures and water vapor pressure. Also, during dissolution study, the degree of supersaturation in the dissolution medium generated by the crosslinked systems gradually increased and maintained the supersaturation for a longer period.

Use of Terahertz-Raman Spectroscopy to Determine Solubility of the Crystalline Active Pharmaceutical Ingredient in Polymeric Matrices during Hot Melt Extrusion

Polymer-based amorphous solid dispersions (ASDs) comprise one of the most promising formulation strategies devised to improve the oral bioavailability of poorly water-soluble drugs. Exploitation of such systems in marketed products has been limited because of poor understanding of physical stability. The internal disordered structure and increased free energy provide a thermodynamic driving force for phase separation and recrystallization, which can compromise therapeutic efficacy and limit product shelf life. A primary concern in the development of stable ASDs is the solubility of the drug in the polymeric carrier, but there is a scarcity of reliable analytical techniques for its determination. In this work, terahertz (THz) Raman spectroscopy was introduced as a novel empirical approach to determine the saturated solubility of crystalline active pharmaceutical ingredient (API) in polymeric matrices directly during hot melt extrusion. The solubility of a model compound, paracetamol, in two polymer systems, Affinisol 15LV (HPMC) and Plasdone S630 (copovidone), was determined by monitoring the API structural phase transitions from crystalline to amorphous as an excess of crystalline drug dissolved in the polymeric matrix. THz-Raman results enabled construction of solubility phase diagrams and highlighted significant differences in the solubilization capacity of the two polymer systems. The maximum stable API-load was 20 wt % for Affinisol 15LV and 40 wt % for Plasdone S630. Differential scanning calorimetry and XRPD studies corroborated these results. This approach has demonstrated a novel capability to provide real-time API–polymer phase equilibria data in a manufacturing relevant environment and promising potential to predict solid-state solubility and physical stability of ASDs.

Effects of Surfactants on Itraconazole-Hydroxypropyl Methylcellulose Acetate Succinate Solid Dispersion Prepared by Hot Melt Extrusion. II: Rheological Analysis and Extrudability Testing

Although hydroxypropyl methylcellulose acetate succinate (HPMCAS) has been widely used as a carrier for amorphous solid dispersion of poorly water-soluble drugs, its application has mostly been limited to spray drying, and the solvent-free method of hot melt extrusion has rarely been used. This is on account of the high temperature (≥170°C) required for extrusion where the polymer and even a drug may degrade. In part 1 of this series of papers, we demonstrated that HPMCAS is miscible with surfactants such as, poloxamer 188, poloxamer 407 and d-alpha tocopheryl polyethylene glycol 1000 succinate, which may also serve as plasticizers (Solanki et al., J Pharm Sci. 2019; 108 (4):1453-1465). The present investigation was undertaken to determine plasticization effects of the surfactants and a model drug, itraconazole, in reducing melt extrusion temperatures of HPMCAS. The determination of complex viscosity as functions of temperature and also as functions of angular frequency at certain fixed temperatures showed that the surfactants and the drug greatly reduce viscosity of HPMCAS by their plasticization effects. Surfactants and drug also had synergistic effects in reducing viscosity. The torque analysis during melt extrusion demonstrated that these additives greatly enhanced extrudability of HPMCAS. Surfactant-drug-polymer mixtures were successfully extruded as stable amorphous solid dispersions at 130°C, which is much lower than the minimum extrusion temperature of 170°C for neat HPMCAS.