Hot-melt Extrusion Process Research Articles

Melt Processing Virus-Like Particle-Based Vaccine Candidates into Biodegradable Polymer Implants.

Melt processing is an emerging production method to efficiently encapsulate proteins into polymeric devices for sustained release. In the context of vaccines, melt processing is well-suited to develop vaccine delivery devices that are stable outside the cold chain and can generate protective immunity from a single dose. We have demonstrated the compatibility of bacteriophage Qβ virus-like particles (VLPs) with hot-melt extrusion (HME) and have leveraged this technology to develop a single-dose vaccine candidate for vaccination against human papillomavirus (HPV). Here, we detail the methods for chemically conjugating an HPV peptide epitope from the L2 minor capsid protein to Qβ VLPs to generate HPV-Qβ particles. We outline techniques used to characterize HPV-Qβ particles, and we elaborate on the process to encapsulate HPV-Qβ into biodegradable poly(lactic-co-glycolic acid) (PLGA) implants and discuss methods for the materials characterization of the HPV-Qβ/polymer melts. The methods described could be adapted to other disease targets, i.e., by conjugation of a different peptide epitope, or transferred to other VLP systems suited for conjugation, immune response, or stability during processing. Such VLPs are ideally suited for use in HME, a mature, scalable, continuous, and solvent-free process which can be adapted to mold devices, therefore allowing the processing of the melts into various geometries, such as subcutaneous implants, or self-administrable microneedle patches.

Optimization of Hot-Melt Extrusion Processing for the Synthesis of Ionic Cocrystals

Optimization of Hot-Melt Extrusion Processing for the Synthesis of Ionic Cocrystals

Facile fabrication of an extended-release tablet of Ticagrelor using three dimensional printing technology.

The objective of the study was to fabricate tailored extended-release tablets of blood thinner Ticagrelor as once-daily dosing using additive manufacturing for better compliance in heart failure therapy. The solid work design of the tablet was printed using hot melt extrusion (HME) based 3D printing by optimized mixture of Eudragit RS-100, plasticizer and drug for producing extrudable and printable filaments. FTIR and TGA results showed no covalent interaction among ingredients and no decomposition during HME process, respectively. Friability, weight variation, assay and content uniformity tests met USP requirements, while the mean hardness of the tablets was calculated in a value between 40 and 50 kg. According to DSC and XRD results, the crystallinity state of the Ticagrelor was converted to an amorphous one in the tablet matrix. Smooth surfaces with multiple deposited layers were observed using SEM. In comparison, the maximum Ticagrelor release of 100% after 120 min from Brilinta® tablets was decreased to 97% in 400 min from the 3D tablet at infill of 90%. Korsmeyer-Peppas kinetic model showed the drug release mechanism is affected by diffusion and swelling. In general, fabrication of the extended-release 3D printed tablet of Ticagrelor using HME-based-additive manufacturing has the potential to provide specific doses with tailored kinetic release for personalized medicine, improving adherence at point-of-care.

Utilization of PVP-PLA Combination in Fabricating Theophylline-loaded Filament for 3D Printing with Immediate Release Behavior

Fused deposition modeling (FDM), known as a highly effective 3D printing technique, holds promise as an alternative approach to tablet manufacturing. While commonly employing thermoplastic polymers as starting materials, the integration of established pharmaceutical excipients remains unexplored. Polyvinyl pyrrolidone (PVP) is a frequently used excipient known for its potential to confer immediate-release properties to drugs. However, its suitability for extrusion is hindered by its thermal and melt-rheological properties. In contrast, polylactic acid (PLA), which has robust mechanical strength and thermal plasticity, was expected to overcome PVP’s limitations. This study aims to obtain drug-loaded filaments using the combination of PVP and PLA through a hot-melt extrusion process, aiming for favorable mechanical properties and immediate-release behavior. Utilizing a twin-screw extruder, and theophylline was used as the model drug, three formulations were optimized –FP1, FP2, and FP3– containing 0%, 10%, and 20% theophylline, respectively. Subsequent evaluation including filament morphology, mechanical properties, drug content, and drug release profile, were performed to each filament. FP2 emerged as the most promising formulation, with 10.35% (w/w) drug load and over 95% drug released in an hour. All formulations exhibited slightly rough filament surfaces with diameters averaging 1.4-1.6 mm. Notably, an increase in the theophylline content correlates with the diminished filament strength, evident in reduced hardness and a rise in brittleness. This study emphasized the potential of PVP-PLA-based filaments for future pharmaceutical 3D printing formulations, providing immediate drug release characteristics.

Dissolution-permeation of hot-melt extruded amorphous solid dispersion comprising an experimental grade of HPMCAS.

Physicochemical properties of an amorphous solid dispersion (ASD) comprising an experimental grade of hydroxypropyl methylcellulose acetate succinate (HPMCAS-MX) with lower glass transition temperature have been previously investigated. This study aimed to evaluate applicability of HPMCAS-MX to hot-melt extrusion (HME) and dissolution-permeation performance of prepared ASDs using MicroFLUX. A physical mixture of indomethacin (IMC) and HPMCAS-MX or -MG (a commercial grade with higher transition temperature) at 20:80 weight ratio was hot-melt extruded to prepare an ASD (IMC-MX and IMC-MG, respectively). The dissolution-permeation performance and the stability of the ASDs were measured. A torque reduction at 120 °C implied that IMC-MX transformed into an amorphous state at this temperature, but IMC-MG required around 170 °C. This result was supported by Raman mapping of the the HME samples. IMC-MG and IMC-MX remained in an amorphous state at 40 °C for three months. The initial dissolution rate and solubility of the ASDs were higher than that of crystalline IMC. The apparent permeability of IMC from IMC-MX and IMC-MG was comparable but was approximately two-fold higher than that from crystalline IMC. HPMCAS-MX enabled HME process at a lower temperature and improved the dissolution-permeation performance of indomethacin.

Development of Lipid Polymer Hybrid Drug Delivery Systems Prepared by Hot-Melt Extrusion.

This study sought to develop polymer-lipid hybrid solid dispersions containing the poorly soluble drug lopinavir (LPV) by hot-melt extrusion (HME). Hence, the lipid and polymeric adjuvants were selected based on miscibility and compatibility studies. Film casting was used to assess the miscibility, whereas thermal, spectroscopic, and chromatographic analyses were employed to evaluate drug-excipient compatibility. Extrudates were obtained and characterized by physicochemical tests, including in vitro LPV dissolution. Preformulation studies led to select the most appropriate materials, i.e., the polymers PVPVA and Soluplus®, the plasticizers polyethylene glycol 400 and Kolliphor® HS15, phosphatidylcholine, and sodium taurodeoxycholate. HME processing did not result in LPV degradation and significantly increased entrapment efficiency (93.8% ± 2.8 for Soluplus® extrudate against 19.8% ± 0.5 of the respective physical mixture). LPV dissolution was also increased from the extrudates compared to the corresponding physical mixtures (p < 0.05). The dissolution improvement was considerably greater for the Soluplus®-based formulation (24.3 and 2.8-fold higher than pure LPV and PVPVA-based extrudate after 120 min, respectively), which can be attributed to the more pronounced effects of HME processing on the average size and LPV solid-state properties in the Soluplus® extrudates. Transmission electron microscopy and chemical microanalysis suggested that the polymer-lipid interactions in Soluplus®-based formulation depended on thermal processing.

An Detailed Overview on Mouth Dissolving Film

The present review aims to enlighten about a potential dosage form that is mouth dissolving films. Mouth dissolving film is a rapidly dissolving dosage form that dissolves in the mouth within a few seconds without the intake of water and is mainly used for pediatric and geriatric patients due to its flexibility and patient compliance. It is a potential dosage form for drugs having high metabolism and low bioavailability. Solvent casting, hot melt extrusion, solid dispersion, semisolid casting, rolling, and other processes can all be used to create mouth dissolving film, but solvent casting is the most popular due to its consistency and superior physical properties. Mouth dissolving film is evaluated for the following parameters like physical parameters and chemical parameters. The review sums up information on drug delivery by mouth dissolving films as a promising dosage form for delivering drugs to children and elderly patients, as well as information on its formulation considerations, preparation process, and evaluation criteria.&#x0D; Keywords: Mouth dissolving film, Buccal film, Improved patient compliance, Standard composition, Method of preparation, Evaluation

Manganese Sulfate Nanocomposites Fabricated by Hot-Melt Extrusion for Chemodynamic Therapy of Colorectal Cancer.

The development of metal salts-based nanocomposites is highly desired for the Fenton or Fenton-like reaction-based chemodynamic therapy of cancer. Manganese sulfate (MnSO4)-dispersed nanoparticles (NPs) were fabricated with a hot-melt extrusion (HME) system for the chemodynamic therapy of colorectal cancer in this study. MnSO4 was homogeneously distributed in polyethylene glycol (PEG) 6000 (as a hydrophilic polymer) with the aid of surfactants (Span 80 and Tween 80) by HME processing. Nano-size distribution was achieved after dispersing the pulverized extrudate of MnSO4-based composite in the aqueous media. The distribution of MnSO4 in HME extrudate and the interactions between MnSO4 and pharmaceutical additives were elucidated by Fourier-transform infrared, X-ray diffractometry, X-ray photoelectron spectroscopy, and scanning electron microscopy analyses. Hydroxyl radical generation efficiency by the Fenton-like chemistry capability of Mn2+ ion was also confirmed by catalytic assays. By using the intrinsic H2O2 in cancer cells, MnSO4 NPs provided an elevated cellular reactive oxygen species level, apoptosis induction capability, and antiproliferation efficiency. The designed HME-processed MnSO4 formulation can be efficiently used for the chemodynamic therapy of colorectal cancer.

Doped halloysite nanotubes as a nanocontainer for the fabrication of ciprofloxacin hydrochloride loaded 3D printed scaffolds

Burn injuries are considered to be the most catastrophic form of skin injury, with a slight risk of mortality. This type of injury has a significant negative impact on both individuals and health care system. The hollow nano-tubular structures of doped halloysite nanotubes (DHNTs) facilitate in loading a wide variety of active molecules and make a potential nanocarrier for the delivery of drugs. Coincidentally, the high mechanical strength, good biocompatibility, and hemostasis properties of DHNTs offer a new platform for the fabrication of scaffolds to promote faster wound healing activity. Ciprofloxacin hydrochloride (Cip HCl) was chosen as the model drug to control the bacterial proliferation at the site of injury. Therefore, the present study was aimed to design a customized drug loaded nano-polymeric scaffolds by three dimensional (3D) printing techniques for tissue engineered applications in pharmaceutical sciences. Cip HCl loaded DHNTs coated poly vinyl alcohol pellets were extruded for the preparation of filaments by the hot melt extrusion process, and the prepared filaments were further processed for the fabrication of 3D printed scaffolds by fused deposit modelling (FDM) technique. The pellets were free-flowing with a coating efficiency of 60.23 – 82.65%. Scaffold 1 (S1) presented an excellent porous structure, while scaffold 2 (S2) revealed a slight porous structure with the porosity of 60%. The average pore diameter for both scaffolds ranged from 50.82 ± 23 to 93.06 ± 52 μm. S1 expressed a conventional release pattern of 73.35% ± 0.02 within 2 h of the time profile, S2 evidenced an inaugural burst release of 42.84% ± 0.05 at 2 h, followed by a sustained release of 85.54% ± 0.17 up to 12 h. Thus the FDM technique proves to be an ideal approach for the design of drug nanofiller coated polymeric 3D scaffolds for personalized drug delivery systems in the arena of tissue engineering and pharmaceutical sciences.

Formulation and processing of solid self-emulsifying drug delivery systems (HME S-SEDDS): A single-step manufacturing process via hot-melt extrusion technology through response surface methodology

The objective of the current study is the formulation development and manufacturing of solid self-emulsifying drug delivery systems (HME S-SEDDS) via a single-step continuous hot-melt extrusion (HME) process. For this study, poorly soluble fenofibrate was selected as a model drug. From the results of pre-formulation studies, Compritol® HD5 ATO, Gelucire® 48/16, and Capmul® GMO-50 were selected as oil, surfactant and co-surfactant respectively for manufacturing of HME S-SEDDS. Neusilin® US2 was selected as a solid carrier. The design of experiments (response surface methodology) was employed to prepare formulations via a continuous HME process. The formulations were evaluated for emulsifying properties, crystallinity, stability, flow properties and drug release characteristics. The prepared HME S-SEDDS showed excellent flow properties, and the resultant emulsions were stable. The globule size of the optimized formulation was 269.6 nm. The DSC and XRD studies revealed the amorphous nature of the formulation and FTIR studies showed no significant interaction between fenofibrate and excipients. The drug release studies showed significant (p < 0.05) improvement in solubility compared to the pure drug (DE15 = 45.04 for the optimized formulation), as >90% of drug release was observed within 15 min. The stability studies for the optimized formulation were conducted for 3 months at 40 °C/75% RH.

Predicting Residence Time and Melt Temperature in Pharmaceutical Hot Melt Extrusion.

Hot-melt extrusion is increasingly applied in the pharmaceutical area as a continuous processing technology, used to design custom products by co-processing drugs together with functional excipients. In this context, the residence time and processing temperature during extrusion are critical process parameters for ensuring the highest product qualities, particularly of thermosensitive materials. Within this study, a novel strategy is proposed to predict the residence time distribution and melt temperature during pharmaceutical hot-melt extrusion processes based on experimental data. To do this, an autogenic extrusion mode without external heating and cooling was applied to process three polymers (Plasdone S-630, Soluplus and Eudragit EPO) at different specific feed loads, which were set by the screw speed and the throughput. The residence time distributions were modeled based on a two-compartment approach that couples the behavior of a pipe and a stirred tank. The throughput showed a substantial effect on the residence time, whereas the influence of the screw speed was minor. On the other hand, the melt temperatures during extrusion were mainly affected by the screw speed compared to the influence of the throughput. Finally, the compilation of model parameters for the residence time and the melt temperature within design spaces serve as the basis for an optimized prediction of pharmaceutical hot-melt extrusion processes.

Corroborating various material-sparing techniques with hot melt extrusion for the preparation of triclabendazole amorphous solid dispersions

Amorphous solid dispersions (ASD) are one of the most adopted technologies for improving the solubility of novel molecules. Formulation of ASDs using solvent free methods such as hot melt extrusion (HME) has been in the spotlight off-lately. However, early-stage formulation development is tricky and a difficult bridge to pass due to limited drug availability. Material-sparing techniques (theoretical & practical) have been used for selecting suitable polymeric carriers for formulating ASDs. However, these techniques have limitations in predicting the effect of process parameters. The objective of this study is to use both theoretical and practical material-sparing techniques to optimize a polymer for the developing Triclabendazole (TBZ) ASDs. Initial screening by theoretical approaches suggested that TBZ is highly miscible with Kollidon®VA64 (VA64) and poorly miscible with Parteck®MXP (PVA). However, results from ASDs prepared using SCFe were opposite to these predictions. ASDs prepared using either technique and both VA64 and PVA showed >200x increase in solubility. Each formulation released >85% of drug in less than 15 mins. Although the thermodynamic phase diagram suggested that VA64 was the ideal polymer for TBZ-ASDs, it has certain limitations in factoring the different elements during melt-processing and hence, practical approaches like SCFe could help in predicting the drug-polymer miscibility for HME processing.

Veering to a Continuous Platform of Fused Deposition Modeling Based 3D Printing for Pharmaceutical Dosage Forms: Understanding the Effect of Layer Orientation on Formulation Performance.

Three-dimensional (3D) printing of pharmaceuticals has been centered around the idea of personalized patient-based 'on-demand' medication. Fused deposition modeling (FDM)-based 3D printing processes provide the capability to create complex geometrical dosage forms. However, the current FDM-based processes are associated with printing lag time and manual interventions. The current study tried to resolve this issue by utilizing the dynamic z-axis to continuously print drug-loaded printlets. Fenofibrate (FNB) was formulated with hydroxypropyl methylcellulose (HPMC AS LG) into an amorphous solid dispersion using the hot-melt extrusion (HME) process. Thermal and solid-state analyses were used to confirm the amorphous state of the drug in both polymeric filaments and printlets. Printlets with a 25, 50, and 75% infill density were printed using the two printing systems, i.e., continuous, and conventional batch FDM printing methods. Differences between the two methods were observed in the breaking force required to break the printlets, and these differences reduced as the infill density went up. The effect on in vitro release was significant at lower infill densities but reduced at higher infill densities. The results obtained from this study can be used to understand the formulation and process control strategies when switching from conventional FDM to the continuous printing of 3D-printed dosage forms.

Preparation of a ternary amorphous solid dispersion using hot-melt extrusion for obtaining a stable colloidal dispersion of amorphous probucol nanoparticles

In our previous reports, ternary amorphous solid dispersions (ASDs) of probucol (PBC)/polymer/surfactant were prepared by spray-drying and cryo-grinding, and colloidal dispersions of amorphous PBC nanoparticles were obtained by dispersing the ternary ASD into water. In this study, hot-melt extrusion, which is a practical method for preparing ASD formulations, was utilized to obtain ternary ASDs and colloidal dispersions of amorphous PBC nanoparticles. Polyvinylpyrrolidone K12 (PVP) with a relatively low Tg (below 100 °C) was used as a polymer, while poloxamer P407 (P407), which is chemically stable during the hot-melt extrusion process, was utilized as a surfactant. Ternary ASDs were successfully produced with high weight ratios of PVP and P407. A hydrogen bond between the PBC hydroxyl proton and PVP carbonyl oxygen in the ternary ASD was detected using solid-state NMR spectroscopy, suggesting that amorphous PBC was stabilized mainly by PVP. Stable colloidal dispersions of amorphous PBC nanoparticles were obtained from the PBC/PVP/P407 ASD at a weight ratio of 1:4:2. The mean particle size was below 200 nm and the amorphous state of PBC remained stable upon storage at 25 °C for 14 d. Solution-state 1H NMR and zeta-potential measurements suggested that P407 mainly stabilized the colloidal dispersion of amorphous PBC nanoparticles by steric hindrance at the solid/liquid interface. The findings of this study demonstrate that hot-melt extrusion can form practical ternary ASDs that provide colloidal dispersion of amorphous drug nanoparticles. Thus, this study advocates for the use of hot-melt extrusion in the design of an amorphous formulation for a variety of poorly water-soluble drugs.

POLYMORPHIC STABILITY EVALUATION OF DARUNAVIR AND RITONAVIR IN FIXED DOSE DRUG COMBINATION PRODUCT BY X-RAY DIFFRACTION AND DIFFERENTIAL SCANNING CALORIMETRY TECHNIQUES

Evaluation of polymorphism for active ingredients and its stability during manufacturing and storage is a critical task for pharmaceutical firms. For solubility enhancement of ritonavir, hot melt extrusion process was selected through conversion of commercially available crystalline form to amorphous. XRD method (with normal and slow scan) and DSC method was considered for polymorphic evaluation in tablet formulation comprising darunavir 800 mg and ritonavir 100 mg. Specificity and precision of XRD method was justified by no interference of placebo and 5.6% RSD, respectively. The observed correlation coefficient of 0.9991 and average recovery of 98.7% (range 91.5 to 105.1) depicts linearity and recovery power of developed method. Studied DSC method shows exotherm for ritonavir crystalline form II at 127.4 °C and darunavir ethanolate at 105.7 °C, which were specific and sensitive to assess polymorphic form of available drug substances in ritonavir blend as well as in tablet formulation during release and stability period.

Enhancement of itraconazole solubility and release by hot-melt extrusion with Soluplus®

Formulation of poorly water-soluble drugs is a significant challenge in the development of oral solid dosage forms. The objective was to investigate the effect of hot-melt extrusion process and formulation variables on the solid state, solubility and release of an ionizable poorly soluble drug, itraconazole (ITZ). Amorphous solid dispersions (ASD) were prepared by hot-melt extrusion and characterized by differential scanning calorimetry, x-ray diffractometry, FTIR spectroscopy and drug release. ITZ with the amphiphilic polymer carrier, Soluplus® resulted in molecular dispersions and improved drug solubility. The release of ITZ increased with increasing Soluplus® amount. Supersaturation was maintained for >24 h due to molecular dispersion of the drug in the carrier and the subsequent solubilization effect of the carrier. A lower supersaturation was obtained at processing temperatures (130 °C) below the drug melting point. The drug release was relatively slow, but complete within 6-8 h from large 5 mm extrudates and increased significantly by milling the extrudates and was nearly independent of particle size below 425 μm. In conclusion, the ASD led to solubility and release enhancement of the poorly water-soluble drug ITZ.

Micro-Scale Vacuum Compression Molding as a Predictive Screening Tool of Protein Integrity for Potential Hot-Melt Extrusion Processes.

Hot-melt extrusion (HME) is used for the production of solid protein formulations mainly for two reasons: increased protein stability in solid state and/or long-term release systems (e.g., protein-loaded implants). However, HME requires considerable amounts of material even at small-scale (>2 g batch size). In this study, we introduced vacuum compression molding (VCM) as a predictive screening tool of protein stability for potential HME processing. The focus was to identify appropriate polymeric matrices prior to extrusion and evaluation of protein stability after thermal stress using only a few milligrams of protein. The protein stability of lysozyme, BSA, and human insulin embedded in PEG 20,000, PLGA, or EVA by VCM was investigated by DSC, FT-IR, and SEC. The results from the protein-loaded discs provided important insights into the solid-state stabilizing mechanisms of protein candidates. We demonstrated the successful application of VCM for a set of proteins and polymers, showing, in particular, a high potential for EVA as a polymeric matrix for solid-state stabilization of proteins and the production of extended-release dosage forms. Stable protein-polymer mixtures with sufficient protein stability after VCM could be then introduced to a combination of thermal and shear stress by HME and further investigated with regard to their process-related protein stability.

Disulfiram 3D printed film produced via hot-melt extrusion techniques as a potential anticervical cancer candidate

Cervical cancer is known globally as one of the most common health problems in women. Indeed, one of the most convenient approaches for its treatment is an appropriate bioadhesive vaginal film. This approach provides a local treatment modality, which inevitably decreases dosing frequency and improves patient compliance. Recently, disulfiram (DSF) has been investigated and demonstrated to possess anticervical cancer activity; therefore, it is employed in this work. The current study aimed to produce a novel, personalized three-dimensional (3D) printed DSF extended-release film using the hot-melt extrusion (HME) and 3D printing technologies. The optimization of the formulation composition and the HME and 3D printing processing temperatures was an important factor for overcoming the DSF heat-sensitivity issue. In addition, the 3D printing speed was specifically the most crucial parameter for alleviating heat-sensitivity concerns, which led to the production of films (F1 and F2) with an acceptable DSF content and good mechanical properties. The bioadhesion film study using sheep cervical tissue indicated a reasonable adhesive peak force (N) of 0.24 ± 0.08 for F1 and 0.40 ± 0.09 for F2, while the work of adhesion (N.mm) for F1 and F2 was 0.28 ± 0.14 and 0.54 ± 0.14, respectively. Moreover, the cumulative in vitro release data indicated that the printed films released DSF for up to 24 h. HME-coupled 3D printing successfully produced a patient-centric and personalized DSF extended-release vaginal film with a reduced dose and longer dosing interval.

The Effect of Sub- and Near-Critical Carbon Dioxide Assisted Manufacturing on Medical Thermoplastic Polyurethane.

Incorporating thermally labile active pharmaceutical ingredients for manufacturing multifunctional polymeric medical devices is restricted due to their tendency to degrade in the hot melt extrusion process. In this study, the potential of sub- and near-critical carbon dioxide (CO2) as a reversible plasticiser was explored by injecting it into a twin-screw hot melt extrusion process of Pellethane thermoplastic polyurethane to decrease its melt process temperature. Its morphological, throughput, thermal, rheological, and mechanical performances were also evaluated. The resultant extrudates were characterised using scanning electron microscopy, parallel plate rotational rheometer, differential scanning calorimetry, thermogravimetric analysis, and tensile testing. The process temperature decreased from 185 to 160 °C. The rheology indicated that the reduction in melt viscosity was from 690 Pa.s to 439 Pa.s (36%) and 414 Pa.s (40%) at 4.14 and 6.89 MPa, respectively. The tensile modulus in the elastomeric region is enhanced from 5.93 MPa, without CO2 to 7.71 MPa with CO2 at both 4.14 and 6.89 MPa. The results indicate that the employment of both sub- and near-critical CO2 as a processing aid is a viable addition to conventional hot melt extrusion and that they offer more opportunities for thermosensitive drugs to be more stable in the molten stream of Pellethane thermoplastic polyurethane.

The applications of machine learning to predict the forming of chemically stable amorphous solid dispersions prepared by hot-melt extrusion

Amorphous solid dispersion (ASD) is one of the most important strategies to improve the solubility and dissolution rate of poorly water-soluble drugs. As a widely used technique to prepare ASDs, hot-melt extrusion (HME) provides various benefits, including a solvent-free process, continuous manufacturing, and efficient mixing compared to solvent-based methods, such as spray drying. Energy input, consisting of thermal and specific mechanical energy, should be carefully controlled during the HME process to prevent chemical degradation and residual crystallinity. However, a conventional ASD development process uses a trial-and-error approach, which is laborious and time-consuming. In this study, we have successfully built multiple machine learning (ML) models to predict the amorphization of crystalline drug formulations and the chemical stability of subsequent ASDs prepared by the HME process. We utilized 760 formulations containing 49 active pharmaceutical ingredients (APIs) and multiple types of excipients. By evaluating the built ML models, we found that ECFP-LightGBM was the best model to predict amorphization with an accuracy of 92.8%. Furthermore, ECFP-XGBoost was the best in estimating chemical stability with an accuracy of 96.0%. In addition, the feature importance analyses based on SHapley Additive exPlanations (SHAP) and information gain (IG) revealed that several processing parameters and material attributes (i.e., drug loading, polymer ratio, drug's Extended-connectivity fingerprints (ECFP) fingerprints, and polymer's properties) are critical for achieving accurate predictions for the selected models. Moreover, important API's substructures related to amorphization and chemical stability were determined, and the results are largely consistent with the literature. In conclusion, we established the ML models to predict formation of chemically stable ASDs and identify the critical attributes during HME processing. Importantly, the developed ML methodology has the potential to facilitate the product development of ASDs manufactured by HME with a much reduced human workload.