Stability Of Amorphous Solid Dispersions Research Articles

Understanding the effect of plasticizers in film coat materials on the physical stability of amorphous solid dispersions

Amorphous solid dispersions (ASDs) have been extensively utilized to improve the bioavailability of drugs that have low aqueous solubility. The influence of different excipients on the conversion of amorphous drugs into their crystalline forms in ASDs has been extensively researched. However, there is limited knowledge examining the impact of film coating materials on the physical stability of oral tablet formulations containing ASDs. In this study, we demonstrate that plasticizers present in film coats can have a detrimental impact on the physical stability of ASDs. We systematically compared two frequently used plasticizers in film coats: triacetin and polyethylene glycol 3350 (PEG 3350). To gain mechanistic insights into the detrimental effects of plasticizers on the physical stability of ASDs, plasticizer leaching studies and physical stability studies of solvent-evaporated and spray-dried intermediates (SDI) using two BCS class II drugs were conducted. Triacetin was found to leach into the tablet core within one week when stressed at 40°C/75% RH, whereas no leaching was observed for PEG 3350, as discerned from spectroscopic studies. We also found that triacetin-containing ASDs exhibited greater amorphous to crystalline form conversion of the drug compared to PEG 3350-containing ASDs after stability testing. Moreover, the incorporation of triacetin into polymers was found to cause a significant depression of glass transition temperature and upon equilibration with moisture, a drop below room temperature. Overall, these observations underscore the importance of carefully selecting plasticizers to be present in film coatings when developing ASD pharmaceutical products.

A review on amorphous solid dispersions for improving physical stability and dissolution: Role of polymers

Amorphous solid dispersion (ASD) has been a successful strategy to improve solubility and dissolution rate of poorly soluble drugs. ASD improve the solubility and dissolution of drugs by existing as separate molecules in a polymer matrix. The stability of amorphous solid dispersions is dependent on thermodynamic, kinetic and environment factors. Thermodynamic factors include drug-polymer miscibility and solubility. Kinetic factors include glass transition temperatures, molecular mobility, drug-polymer interactions. Environment factors indirectly affect the stability of ASD by influencing the thermodynamic and kinetic factors. The focus of this review is to discuss the role of polymer in influencing the thermodynamic and kinetic stability of ASD.

Long-Term Physical Stability of Amorphous Solid Dispersions: Comparison of Detection Powers of Common Evaluation Methods for Spray-Dried and Hot-Melt Extruded Formulations

Although physical stability can be a critical issue during the development of amorphous solid dispersions (ASDs), there are no established protocols to predict/detect their physical stability. In this study, we have prepared fenofibrate ASDs using two representative manufacturing methods, hot-melt extrusion and spray-drying, to investigate their physical stability for one year. Intentionally unstable ASDs were designed to compare the detection power of each evaluation method, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and dissolution study. Each method did not provide the same judgment results on physical stability in some cases because of their different evaluation principles and sensitivity, which has been well-comprehended only for one-component glass. This study revealed that the detection powers of each evaluation method significantly depended on the manufacturing methods. DSC was an effective method to detect a small amount of crystals for both types of ASDs in a quantitative manner. Although the sensitivity of XRPD was always lower compared to that of DSC, interpretation of the data was the easiest. SEM was very effective for observing the crystallization of the small amount of drug for hot-melt extruded products, as the drug crystal vividly appeared on the large grains. The dissolution performance of spray-dried products could change even without any indication of physical change including crystallization. The advantage/disadvantage and complemental roles of each evaluation method are discussed for deeper understanding on the physical stability data of ASDs.

Simultaneous Water Sorption and Crystallization in ASDs 2: Modeling Long-Term Stabilities.

The physical stability of amorphous solid dispersions (ASDs) is a major topic in the formulation research of oral dosage forms. To minimize the effort of investigating the long-term stability using cost- and time-consuming experiments, we developed a thermodynamic and kinetic modeling framework to predict and understand the crystallization kinetics of ASDs during long-term storage below the glass transition. Since crystallization of the active phrarmaceutical ingredients (APIs) in ASDs largely depends on the amount of water absorbed by the ASDs, water-sorption kinetics and API-crystallization kinetics were considered simultaneously. The developed modeling approach allows prediction of the time evolution of viscosity, supersaturation, and crystallinity as a function of drug load, relative humidity, and temperature. It was applied and evaluated against two-year-lasting crystallization experiments of ASDs containing nifedipine and copovidone or HPMCAS measured in part I of this work. We could show that the proposed modeling approach is able to describe the interplay between water sorption and API crystallization and to predict long-term stabilities of ASDs just based on short-term measurements. Most importantly, it enables explaining and understanding the reasons for different and sometimes even unexpected crystallization behaviors of ASDs.

From waste to a resource? Hemicelluloses enhance the dissolution and stability of the amorphous state of carbamazepine

Both synthetic and natural polymers are used as excipients in various pharmaceutical preparations. Natural polymers offer advantages, such as abundant availability, cost-effectiveness, non-toxicity, biocompatibility, and biodegradability. Hemicelluloses are highly promising natural polymers for pharmaceutical applications due to their advantageous colloidal properties, but their ability to solubilize poorly water-soluble drugs and stabilize their amorphous form is currently virtually unexplored. In this study, we showed the applicability of birch, spruce and wheat straw hemicelluloses as tablet excipients and their ability to enhance dissolution and stability of a model drug, carbamazepine (CBZ), in amorphous solid dispersions. The hemicelluloses formed sufficiently strong tablets by direct-compression, although addition of CBZ weakened the tablets. The hemicelluloses did not modify drug release from the tablets when compared to plain CBZ powder. Solid dispersions with CBZ were identified as amorphous one-phase mixtures, with hydrogen bonding between the hemicelluloses and CBZ. The mixtures remained stable for at least nine months under 40 °C/23 % RH. Dissolution of the amorphous solid dispersions decreased with increasing hemicellulose molar mass. Up to 7.6-fold CBZ supersaturation was achieved, although it did not improve CBZ permeation through a PAMPA (parallel artificial membrane permeability assay) barrier when compared to the corresponding physical mixtures. In summary, birch, spruce, and wheat straw hemicelluloses formed direct-compressed tablets and stable amorphous solid dispersions that may improve dissolution properties of drugs. Differences exist between hemicelluloses from different plant sources and thus more research with structurally different drug substances is needed in the future.

The step-wise dissolution method: An efficient DSC-based protocol for verification of predicted API–polymer compatibility

The development of an amorphous solid dispersion (ASD) is a promising strategy for improving the low bioavailability of many poorly water-soluble active pharmaceutical ingredients (APIs). The construction of a temperature–composition (T–C) phase diagram for an API–polymer combination is imperative as it can provide critical information that is essential for formulating stable ASDs. However, the currently followed differential scanning calorimetry (DSC)-based strategies for API solubility determination in a polymer at elevated temperatures are inefficient and, on occasions, unreliable, which may lead to an inaccurate prediction at lower temperatures of interest (i.e., T = 25 °C). Recently, we proposed a novel DSC-based protocol called the “step-wise dissolution” (S-WD) method, which is both cost- and time-effective. The objective of this study was to test the applicability of the S-WD method regarding expeditious verification of the purely-predicted API–polymer compatibility via the perturbed chain-statistical associating fluid theory (PC-SAFT) equation of state (EOS). Fifteen API–polymer T–C phase diagrams were reliably constructed, with three distinct API–polymer case types being identified regarding the approach used for the S-WD method. Overall, the PC-SAFT EOS provided satisfactory qualitative descriptions of the API–polymer compatibility, but not necessarily accurate quantitative predictions of the API solubility in the polymer at T = 25 °C. The S-WD method was subsequently modified and an optimal protocol was proposed, which can significantly reduce the required experimental effort.

A multifaceted approach for grading of polymers for the development of stable amorphous solid dispersion of Riluzole

The current work involves grading three widely used polymers for preparing a kinetically and thermodynamically stable amorphous solid dispersion (ASD) of a neuroprotective drug Riluzole (RLZ) by evaluating the drug-polymer interactions. Polymers were screened based on their chemical interaction with RLZ and their ability to inhibit the crystallization of the drug. Detailed computational studies were performed to quantify the non-covalent interactions between RLZ and the modelled structures of polymers; polyacrylic acid (PAA), polyvinylpyrrolidone vinyl acetate (PVP VA), and hydroxypropyl methyl cellulose acetate succinate (HPMC AS) for calculating the interaction energies of drug-polymer complexes. Experimental characterization of drug-polymer complexes through analytical techniques further validated the formation of the drug-polymer complexes. The results indicated that RLZ interacts with the polymers in the order PAA > PVP VA > HPMC AS, giving an insight into the stability of drug-polymer complexes. In vitro dissolution study also showed higher dissolution profile of RLZ with PAA. Further, the drug-polymer miscibility was determined by employing Flory-Huggins theory and stability in accordance with Gibbs free energy of mixing and phase diagram. This work presented a multi-technique approach for the grading of polymers in search of a stable ASD of the poorly water-soluble drug RLZ.

Development and Evaluation of Amorphous Solid Dispersion of Riluzole with PBPK Model to Simulate the Pharmacokinetic Profile.

In the current work, screening of polymers viz. polyacrylic acid (PAA), polyvinyl pyrrolidone vinyl acetate (PVP VA), and hydroxypropyl methyl cellulose acetate succinate (HPMC AS) based on drug-polymer interaction and wetting property was done for the production of a stable amorphous solid dispersion (ASD) of a poorly water-soluble drug Riluzole (RLZ). PAA showed maximum interaction and wetting property hence, was selected for further studies. Solid state characterization studies confirmed the formation of ASD with PAA. Saturation solubility, dissolution profile, and in vivo pharmacokinetic data of the ASD formulation were generated in rats against its marketed tablet Rilutor. The RLZ:PAA ASD showed exponential enhancement in the dissolution of RLZ. Predicted and observed pharmacokinetic data in rats showed enhanced area under curve (AUC) and Cmax in plasma and brain with respect to Rilutor. Furthermore, a physiologically based pharmacokinetic (PBPK) model of rats for Rilutor and RLZ ASD was developed and then extrapolated to humans where physiological parameters were changed along with a biochemical parameter. The partition coefficient was kept similar in both species. The model was used to predict different exposure scenarios, and the simulated data was compared with observed data points. The PBPK model simulated Cmax and AUC was within two times the experimental data for plasma and brain. The Cmax and AUC in the brain increased with ASD compared to Rilutor for humans showing its potential in improving its biopharmaceutical performance and hence enhanced therapeutic efficacy. The model can predict the RLZ concentration in multiple compartments including plasma and liver.

Evaluation of a Three-Fluid Nozzle Spraying Process for Facilitating Spray Drying of Hydrophilic Polymers for the Creation of Amorphous Solid Dispersions.

Amorphous solid dispersions (ASDs) enable formulations to improve the solubility of poorly soluble active pharmaceutical ingredients (APIs). The amorphous state is reached through the disruption of the crystalline lattice of an API resulting in an increased apparent solubility with faster disintegration. Nevertheless, this form is characterized by a high-energy state which is prone to re-crystallization. To ensure a stable ASD, excipients, e.g., polymers that form a matrix in which an API is dispersed, are used. The applicable polymer range is usually linked to their solubility in the respective solvent, therefore limiting the use of hydrophilic polymers. In this work, we show the applicability of the hydrophilic polymer, polyvinyl alcohol (PVA), in spray-dried solid dispersions. Using a three-fluid nozzle approach, this polymer can be used to generate ASDs with a targeted dissolution profile that is characterized by a prominent spring and desired parachute effect showing both supersaturation and crystallization inhibition. For this purpose, the polymer was tested in formulations containing the weakly basic drug, ketoconazole, and the acidic drug, indomethacin, both classified as Biopharmaceutics Classification System (BSC) class II drugs, as well as the weakly basic drug ritonavir classified as BCS IV. Furthermore, ritonavir was used to show the enhanced drug-loading capacity of PVA derived from the advantageous viscosity profile that makes the polymer an interesting candidate for spray drying applications.

Polymer-inducing chemical degradation of amorphous solid dispersions driven by drug-polymer interactions for physical stabilization

Intermolecular interactions between active pharmaceutical ingredients (APIs) and carrier polymers are important for the long-term physical stability of amorphous solid dispersions (ASDs). However, the negative impact of intermolecular interactions on chemical stability has rarely been reported. In this study, the relationship between intermolecular interactions and physical and chemical stability was investigated using two ASDs composed of API and hydroxypropyl methylcellulose acetate succinate (HPMCAS) with different stabilities: ASD1 was physically stable but chemically unstable, whereas ASD2 was physically unstable but chemically stable. Ionic-bonding between the pyridine nitrogen in the API and succinyl group in HPMCAS was found in both ASDs. The additional interaction between the succinyl group in HPMCAS and the hydroxyl group in the API was suggested only in ASD1. It was concluded that the additional interaction contributed to the physical stability of ASD1; however, it accelerated the chemical reaction between the succinyl and hydroxyl groups to generate succinyl ester owing to its close proximity. This study shows that the intermolecular interaction between the API and carrier polymer is not always beneficial for chemical stability. Understanding the molecular states of APIs and polymers in ASDs is important for their successful development.

Dr DEVELOPMENT OF POSACONAZOLE DELAYED RELEASE FORMULATION FOR MUCORMYCOSIS BY HOT MELT EXTRUSION USING QBD APPROACH

Amorphous solid dispersion (ASD) by hot-melt extrusion (HME) is an industrially feasible approach to overcome the solubility and bioavailability limitations of poorly soluble active pharmaceutical actives. The creation of HME-based ASDs was significantly impacted by the implementation of Quality by Design (QbD). The objective of the study was to develop an ASD of posaconazole for the effective management of mucormycosis. The impact of change in levels of extra granular materials were identified as critical quality attributes (CQA's) for the development of delayed release tablet. A 23 full factorial design was employed to study the impact of independent variables HPMCAS (X1), HPC(X2) and CCS (X3) as CQA’s on the dependent variables such as hardness (Y1) and Disintegration Time (Y2) and % Drug release (Y3). The design was analyzed by using ANOVA by using MINITAB software. The influence of the extra granular components on the dissolution of tablet was closely evaluated while finalizing the optimized batch. The extrudes were also evaluated by FTIR, XRD and DSC analysis which confirmed the purity and in-situ conversion from crystalline to amorphous form ofthe drug. Systematic development of a bioavailable and stable ASD of posaconazole was achieved by studying the CQA’s at different levels by using the QbD and from the stability data, the optimized batch F4 was found to be stable up to 3 months at accelerated conditions40°C/75%Rh.

The influence of hydrogen bonding between different crystallization tendency drugs and PVPVA on the stability of amorphous solid dispersions

Amorphous solid dispersion (ASD) is one of the formulation strategies for drugs displaying low solubility and low oral bioavailability. In this study, high drug-loaded ASDs of drugs with different crystallization tendencies were prepared by spray drying. The aim was to investigate the influence of hydrogen bonding between the drug and the model polymer PVPVA on the physical stability of ASDs containing drugs with different crystallization tendencies. From the 60-day stability study results, the intermolecular hydrogen bonding has a considerable stabilizing effect on the ASDs of the drug with a moderate crystallization tendency. Nimesulide (hydrogen bond donor) can maintain the amorphous form for a longer time than Fenofibrate (no-hydrogen bond donor) during storage. In the ASDs with fast crystallization tendency drugs (naproxen and caffeine), intermolecular hydrogen bonds are not very effective in preventing drug crystallization, and the effect on the stability of ASD is relatively weak. However, for drugs with a slow tendency to crystallize (indomethacin and miconazole), the ASDs remained in an amorphous state during the monitored storage period, making it impossible to compare the effect of intermolecular hydrogen bonds on the stability of this type of ASDs. It also reveals that intermolecular hydrogen bonds can increase the drug loading capacity of ASDs. The relationship between drug loading and ASD stability was further analyzed by the state diagram. This study clearly pointed out that the physical stability of ASDs of drugs with different crystallization tendencies is affected to a different extent by intermolecular hydrogen bonds.

Emerging Applications of Hydroxypropyl Methylcellulose Acetate Succinate: Different Aspects in Drug Delivery and Its Commercial Potential.

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) has multi-disciplinary applications spanning across the development of drug delivery systems, in 3D printing, and in tissue engineering, etc. HPMCAS helps in maintaining the drug in a super-saturated condition by inhibiting its precipitation, thereby increasing the rate and extent of dissolution in the aqueous media. HPMCAS has several distinctive characteristics, such as being amphiphilic in nature, having an ionization pH, and a succinyl and acetyl substitution ratio, all of which are beneficial while developing formulations. This review provides insights regarding the various types of formulations being developed using HPMCAS, including amorphous solid dispersion (ASD), amorphous nanoparticles, dry coating, and 3D printing, along with their applicability in drug delivery and biomedical fields. Furthermore, HPMCAS, compared with other carbohydrate polymers, shows several benefits in drug delivery, including proficiency in imparting stable ASD with a high dissolution rate, being easily processable, and enhancing bioavailability. The various commercially available formulations, regulatory considerations, and key patents containing the HPMCAS have been discussed in this review.

Solvent electrospinning amorphous solid dispersions with high itraconazole, celecoxib, mebendazole and fenofibrate drug loading and release potential

In this work, the feasibility of ultra-high drug loaded amorphous solid dispersions (ASDs) for the poorly soluble itraconazole, mebendazole and celecoxib via solvent electrospinning in combination with poly(2-ethyl-2-oxazoline) and fenofibrate in combination with polyvinylpyrrolidone is demonstrated. By lowering the polymer concentration in the electrospinning solution below its individual spinnable limit, ASDs with a drug content of up to 80 wt% are obtained. This is attributed to drug-polymer interactions not being limited by default to hydrogen bonds, as also Van der Waals interactions can result in high drug loadings. The theoretically predicted miscibility by the Flory-Huggins theory is corroborated by the experimental findings based on (modulated) differential scanning calorimetry and x-ray diffraction. Globally, the maximally obtained amorphous drug loadings are higher compared to the loadings found in literature. Additionally, non-sink dissolution tests demonstrate an increase in solubility of up to 50 times compared to their crystalline counterparts. Moreover, due to the lack of precipitation biocompatible PEtOx succeeds in stabilizing the dissolved drug and inhibiting its instant precipitation. The current work thus demonstrates the broader applicability of the electrospinning technique for the production of physically stable ASDs with ultra-high drug loadings, a result which has been validated for several Biopharmaceutics Classification System class II drugs.

Orthogonal Gelations to Synthesize Core-Shell Hydrogels Loaded with Nanoemulsion-Templated Drug Nanoparticles for Versatile Oral Drug Delivery.

Hydrophobic active pharmaceutical ingredients (APIs) are ubiquitous in the drug development pipeline, but their poor bioavailability often prevents their translation into drug products. Industrial processes to formulate hydrophobic APIs are expensive, difficult to optimize, and not flexible enough to incorporate customizable drug release profiles into drug products. Here, a novel, dual-responsive gelation process that exploits orthogonal thermo-responsive and ion-responsive gelations is introduced. This one-step "dual gelation" synthesizes core-shell (methylcellulose-alginate) hydrogel particles and encapsulates drug-laden nanoemulsions in the hydrogel matrices. In situ crystallization templates drug nanocrystals inside the polymeric core, while a kinetically stable amorphous solid dispersion is templated in the shell. Drug release is explored as a function of particle geometry, and programmable release is demonstrated for various therapeutic applications including delayed pulsatile release and sequential release of a model fixed-dose combination drug product of ibuprofen and fenofibrate. Independent control over drug loading between the shell and the core is demonstrated. This formulation approach is shown to be a flexible process to develop drug products with biocompatible materials, facile synthesis, and precise drug release performance. This work suggests and applies a novel method to leverage orthogonal gel chemistries to generate functional core-shell hydrogel particles.

The Implications of Drug-Polymer Interactions on the Physical Stability of Amorphous Solid Dispersions.

Amorphous solid dispersions (ASDs) are a formulation and development strategy that can be used to increase the apparent aqueous solubility of poorly water-soluble drugs. Their implementation, however, can be hindered by destabilization of the amorphous form, as the drug recrystallizes from its metastable state. Factors such as the drug-polymer solubility, miscibility, mobility, and nucleation/crystal growth rates are all known to impact the physical stability of an ASD. Non-covalent interactions (NCI) between the drug and polymer have also been widely reported to influence product shelf-life. In this review, the relationship between thermodynamic/kinetic factors and adhesive NCI is assessed. Various types of NCIs reported to stabilize ASDs are described, and their role in affecting physical stability is examined. Finally, NCIs that have not yet been widely explored in ASD formulations, but may potentially impact their physical stability are also briefly described. This review aims to stimulate further theoretical and practical exploration of various NCIs and their applications in ASD formulations in the future.

Tailored ASD destabilization - Balancing shelf life stability and dissolution performance with hydroxypropyl cellulose

Amorphous solid dispersion (ASD) formulations are preferred enabling formulations for poorly water soluble active pharmaceutical ingredients (API) as they reliably enhance the dissolution behavior and solubility. Balancing a high stability against unwanted transformations such as crystallization and amorphous phase separation during storage on the one hand and optimizing the dissolution behavior of the formulation (high supersaturation and maintenance for long time) on the other hand are essential during formulation development. This study assessed the potential of ternary ASDs (one API and two polymers) containing the polymers hydroxypropyl cellulose together with poly(vinylpyrrolidone-co-vinyl acetate) (PVP VA64) or hydroxypropyl cellulose acetate succinate to stabilize the amorphously embedded APIs fenofibrate and simvastatin during storage and to enhance the dissolution performance. Thermodynamic predictions using the PC-SAFT model revealed for each combination of polymers the optimal polymer ratio, maximum API load that is thermodynamically stable as well as miscibility of the two polymers. The stability predictions were validated by three months enduring stability tests, followed by a characterization of the dissolution behavior. The thermodynamically most stable ASDs were found to be the ASDs with deteriorated dissolution performance. Within the investigated polymer combinations, physical stability and dissolution performance opposed each other.

Enhanced dissolution rate of nimodipine through β-lactoglobulin based formulation

Amorphous solid dispersions (ASD) have been considered as one of the most effective strategies to increase solubility and dissolution rate of poorly water-soluble drugs. Carriers, in which the poorly water-soluble drug is dispersed, contribute a large extent to the solid-state properties, stabilities and dissolution performance of ASDs. This study investigated the solid-state properties, physical stability, and in vitro dissolution behaviour of nimodipine ASDs formulated with a traditional polymeric carrier, i.e., polyvinylpyrrolidone (PVP) and a novel carrier, i.e., β-lactoglobulin (BLG). The ASDs with both carriers were prepared using ball milling as preparative technique at 10 %, 17.5 %, 25 %, 30 % and 40 % drug loadings (DLs). All the formulations were found to be amorphous upon milling for 60 min based on X-ray powder diffraction measurements, however, the ASDs were found to be homogeneous unequivocally only at DLs below 25 %. After open storage at accelerated conditions (40 °C/75 % relative humidity), only the ASDs formulated with BLG at 10 % and 17.5 % DLs maintained the amorphous form. The dissolution study revealed that all the freshly prepared ASDs formulated with PVP and the ASDs formulated with BLG at or above 25 % DLs, showed a low drug release (<30 µg/mL in simulated gastric fluid, < 70 µg/mL in simulated intestinal fluid). Whilst the ASD formulated with BLG at 10 % DL exhibited a high drug release with a maximum concentration (Cmax) of 251 µg/mL in simulated gastric fluid and 231 µg/mL in simulated intestinal fluid. Surprisingly, the ASD formulated with BLG at 17.5 % DL demonstrated an even higher drug release (Cmax, 643 µg/mL in simulated gastric fluid, 332 µg/mL in simulated intestinal fluid), compared to the ASD of 10 % DL. These findings underline the importance of rationally investigating both carrier types and DL in the design of ASDs, in order to obtain a stable ASD with the desired enhanced dissolution rate of poorly water-soluble drugs.

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.

Thermodynamic Mechanism of Physical Stability of Amorphous Pharmaceutical Formulations

Hygroscopicity is an important factor affecting the physical stability of amorphous solid dispersions (ASDs) during long-term storage. In this work, the effects of temperature, relative humidity (RH), and polymeric excipients on the phase behavior of amorphous irbesartan (IRB) and oxaprozin (OXA) were systematically investigated. The ASDs were prepared by the solvent evaporation method. The water sorption in formulations was measured under the conditions of 25 °C, 60% RH, 25 °C, 90% RH, and 40 °C, 75% RH. The results showed that the hygroscopicity of formulations containing polyvinylpyrrolidone (PVP) was stronger than that containing poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA 46) and the hygroscopicity increased with increasing temperature and RH. With increasing content of active pharmaceutical ingredients (APIs), the recrystallization phenomenon is significant at the same RH. PVP can better inhibit IRB recrystallization than PVPVA 46. In contrast, PVPVA 46 can better maintain the amorphous form of OXA than PVP. The thermodynamic phase diagrams of amorphous API/polymer formulations at 60% RH and anhydrous conditions were predicted using perturbed chain statistical associated fluid theory (PC-SAFT) and the Gordon–Taylor equation. Furthermore, the electrostatic potential (ESP) and binding energies between APIs and polymers were calculated with density functional theory (DFT), which explained the molecular interaction mechanism of ASDs. This work is expected to guide the screening of excipients and API loadings for designing ASDs and the selection of storage conditions.