Amorphous Solid Dispersion System Research Articles

Moisture-induced limited recrystallization may not reduce the dissolution of amorphous solid dispersions: A case of nitrendipine

As a promising strategy, amorphous solid dispersion (ASD) technology has been widely studied and employed. However, moisture affects the physical stability of ASD, leading to phase separation and recrystallization. This study aims to investigate the moisture-induced physical instability of the nitrendipine (NTD) ASD systems from apparent phenomenon to molecular mechanism. The critical relative humidity (CRH) of the ASD was identified as 50% RH through a dynamic vapor sorption study. After being stored above the CRH, ASDs exhibited obvious phase separation and recrystallization, owing to water competition hydrogen bond as evidenced by molecular docking. After 75% RH exposure, the ASD underwent obvious recrystallization thereafter the dissolution was reduced. However, the dissolution of ASD samples stored at 60% RH did not decrease obviously. This study helps to understand the environment humidities for ASD physical stability and gives hints at the relation between recrystallization and dissolution in the ASD system.

Navigating the Solution to Drug Formulation Problems at Research and Development Stages by Amorphous Solid Dispersion Technology

Abstract: Amorphous Solid Dispersions (ASDs) have indeed revolutionized the pharmaceutical industry, particularly in drug solubility enhancement. The amorphous state of a drug, which is a highenergy metastable state, can lead to an increase in the apparent solubility of the drug. This is due to the absence of a long-range molecular order, which results in higher molecular mobility and free volume, and consequently, higher solubility. The success of ASD preparation depends on the selection of appropriate excipients, particularly polymers that play a crucial role in drug solubility and physical stability. However, ASDs face challenges due to their thermodynamic instability or tendency to recrystallize. Measuring the crystallinity of the active pharmaceutical ingredient (API) and drug solubility is a complex process that requires a thorough understanding of drug-polymer miscibility and molecular interactions. Therefore, it is important to monitor drug solids closely during preparation, storage, and application. Techniques such as solid-state nuclear magnetic resonance (ssNMR), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), Raman spectroscopy, and dielectric spectroscopy have been successful in understanding the mechanism of drug crystallization. In addition, the continuous downstream processing of drug-loaded ASDs has introduced new automated methods for consistent ASD production. Advanced techniques such as hot melt extrusion, KinetiSol, electro spraying, and electrospinning have gained popularity. This review provides a comprehensive overview of Amorphous Solid Dispersions (ASDs) for oral drug delivery. It highlights the critical challenges faced during formulation, the impact of manufacturing variables, theoretical aspects of drug-polymer interaction, and factors related to drug-polymer miscibility. ASDs have been recognized as a promising strategy to improve the oral bioavailability of poorly water-soluble drugs. However, the successful development of an ASD-based drug product is not straightforward due to the complexity of the ASD systems. The formulation and process parameters can significantly influence the performance of the final product. Understanding the interactions between the drug and polymer in ASDs is crucial for predicting their stability and performance.

Amorphous Solid Dispersion as Drug Delivery Vehicles in Cancer.

Cancer treatment has improved over the past decades, but a major challenge lies in drug formulation, specifically for oral administration. Most anticancer drugs have poor water solubility which can affect their bioavailability. This causes suboptimal pharmacokinetic performance, resulting in limited efficacy and safety when administered orally. As a result, it is essential to develop a strategy to modify the solubility of anticancer drugs in oral formulations to improve their efficacy and safety. A promising approach that can be implemented is amorphous solid dispersion (ASD) which can enhance the aqueous solubility and bioavailability of poorly water-soluble drugs. The addition of a polymer can cause stability in the formulations and maintain a high supersaturation in bulk medium. Therefore, this study aimed to summarize and elucidate the mechanisms and impact of an amorphous solid dispersion system on cancer therapy. To gather relevant information, a comprehensive search was conducted using keywords such as "anticancer drug" and "amorphous solid dispersion" in the PubMed, Scopus, and Google Scholar databases. The review provides an overview and discussion of the issues related to the ASD system used to improve the bioavailability of anticancer drugs based on molecular pharmaceutics. A thorough understanding of anticancer drugs in this system at a molecular level is imperative for the rational design of the products.

Ternary Solid Dispersions: A Review of the Preparation, Characterization, Mechanism of Drug Release, and Physical Stability.

The prevalence of active pharmaceutical ingredients (APIs) with low water solubility has experienced a significant increase in recent years. These APIs present challenges in formulation, particularly for oral dosage forms, despite their considerable therapeutic potential. Therefore, the improvement of solubility has become a major concern for pharmaceutical enterprises to increase the bioavailability of APIs. A promising formulation approach that can effectively improve the dissolution profile and the bioavailability of poorly water-soluble drugs is the utilization of amorphous systems. Numerous formulation methods have been developed to enhance poorly water-soluble drugs through amorphization systems, including co-amorphous formulations, amorphous solid dispersions (ASDs), and the use of mesoporous silica as a carrier. Furthermore, the successful enhancement of certain drugs with poor aqueous solubility through amorphization has led to their incorporation into various commercially available preparations, such as ASDs, where the crystalline structure of APIs is transformed into an amorphous state within a hydrophilic matrix. A novel approach, known as ternary solid dispersions (TSDs), has emerged to address the solubility and bioavailability challenges associated with amorphous drugs. Meanwhile, the introduction of a third component in the ASD and co-amorphous systems has demonstrated the potential to improve performance in terms of solubility, physical stability, and processability. This comprehensive review discusses the preparation and characterization of poorly water-soluble drugs in ternary solid dispersions and their mechanisms of drug release and physical stability.

A prediction system: Regulating effect of small-molecule additives on properties of amorphous solid dispersions prepared by hot-melt extrusion technology

Amorphous solid dispersions (ASDs) with solubility advantage are suffering from the recrystallization risk and subsequent reduced dissolution triggered by high hygroscopicity of hydrophilic polymers and the supersaturation of ASD solutions. To address these issues, in this study, small-molecule additives (SMAs) in the Generally Recognized as Safe (GRAS) list were introduced into drug-polymer ASD. For the first time, we systematically revealed the intrinsic correlation between SMAs and properties of ASDs at the molecular level and constructed a prediction system for the regulation of properties of ASDs. The types and dosages of SMAs were screened by Hansen solubility and Flory-Huggins interaction parameters, as well as differential scanning calorimetry. X-ray photoelectron spectroscopy and adsorption energy (Eabs) calculation showed that the surface group distribution of ASDs and Eabs between ASD system and solvent were vital factors affecting the hygroscopicity and then stability. The radial distribution function revealed that interactions between components were proposed to be the critical factor for the dissolution performance. Based on this, a prediction system for regulating the properties of ASDs was successfully constructed mainly via molecular dynamics simulations and simple solid-state characterizations, and then validated by cases, which efficiently reduces the time and economic cost of pre-screening ASDs.

Assessing the performance of thermally crosslinked amorphous solid dispersions with high drug loadings

Continuing what previous studies had also intended, the present study aims to shed light on some unanswered questions concerning a recently introduced class of high drug loading (HD) amorphous solid dispersions (ASDs), based on the in-situ thermal crosslinking of poly (acrylic acid) (PAA) and poly (vinyl alcohols) (PVA). Initially, the effect of supersaturated dissolution conditions on the kinetic solubility profiles of the crosslinked HD ASDSs having indomethacin (IND) as a model drug, was determined. Subsequently, the safety profile of these new crosslinked formulations was determined for the first time by evaluating their cytotoxic effect on human intestinal epithelia cell line (Caco-2), while their ex-vivo intestinal permeability was also studied via the non–everted gut sac method. According to the obtained findings, the in-situ thermal crosslinked IND HD ASDs present similar kinetic solubility profiles when the dissolution studies are conducted with a steady sink index value, regardless of the different dissolution medium’s volume and the total dose of the API. Additionally, the results showed a concentration- and time- dependent cytotoxicity profile for all formulations, while the neat crosslinked PAA/PVA matrices did not elicit cytotoxicity during the first 24 h, even at the highest examined concentration. Finally, the newly proposed HD ASD system, resulted in a remarkably increased ex-vivo intestinal permeability of IND.

Amorphous solid dispersion preparation via coprecipitation improves the dissolution, oral bioavailability, and intestinal health enhancement properties of magnolol

Magnolol (MAG) is a multifunctional plant polyphenol with anti-inflammatory, antibacterial, antioxidant and antitumor properties. In poultry, it has been shown to improve growth performance, antioxidant, immune functions and intestinal health. However, its applications are limited by poor solubility and low oral bioavailability. This study aimed at improving the water solubility of MAG through solid dispersion and investigating its effects in Arbor Acre (AA) broilers. Hydroxypropyl methylcellulose succinic acid (HPMCAS) was used as a carrier to prepare magnolol solid dispersions (MAG-HPMCAS SD) via antisolvent coprecipitation, which were characterized thereafter. Optimal formulation proportions for SD were screened by in vitro dissolution assays, while its effects on improving absorption were investigated via in vivo pharmacokinetic assays. In addition, we evaluated the effects of MAG-HPMCAS SD on growth performance, antioxidant status, and gut microbiota in AA broilers. The powder samples prepared via antisolvent coprecipitation did not exhibit a crystal diffraction peak of MAG in powder X-ray diffractions or melting point peak in differential scanning calorimetry, proving the successful preparation of an amorphous solid dispersion system. The in vitro dissolution assay showed that the cumulative dissolution rate of MAG-HPMCAS(LF) SD (2:8, w/w) was 100%. Pharmacokinetic analyses revealed that the peak concentration (Cmax) of MAG-HPMCAS SD was 5.07 ± 0.73 μg/mL, which was 1.76 times greater than that of MAG. In addition, AUC0-48 and t1/2 of MAG-HPMCAS SD were 40.49 ± 6.29 g·h/mL and 9.15 ± 3.23 h, respectively, which were 2.17 and 2.56 times higher than those of MAG. Supplementation of MAG-HPMCAS SD in AA broilers significantly increased ADG (7-14 d and 15-21 d) and reduced feed conversion ratio (15-21 d) (P < 0.05). Bacterial diversity in the MAG-HPMCAS SD-supplemented group was greater than in the Control and MAG-supplemented group. Supplementation of MAG-HPMCAS SD stimulated the proliferation of beneficial bacteria, such as Lactobacillaceae and Bifidobacteriaceae. In conclusion, the MAG-HPMCAS SD prepared by coprecipitation improved the dissolution rate, the bioavailability of MAG, growth promotion, antioxidant effects and gut health in broilers.

Characterizing Phase Separation of Amorphous Solid Dispersions Containing Imidacloprid.

Amorphous-Amorphous phase separation (AAPS) is an important phenomenon that can impede the performance of amorphous solid dispersions (ASDs). The purpose of this study was to develop a sensitive approach relying on dielectric spectroscopy (DS) to characterize AAPS in ASDs. This includes detecting AAPS, determining the size of the active ingredient (AI) discrete domains in the phase-separated systems, and accessing the molecular mobility in each phase. Using a model system consisting of the insecticide imidacloprid (IMI) and the polymer polystyrene (PS), the dielectric results were further confirmed by confocal fluorescence microscopy (CFM). The detection of AAPS by DS was accomplished by identifying the decoupled structural (α-)dynamics of the AI and the polymer phase. The α-relaxation times corresponding to each phase correlated reasonably well with those of the pure components, implying nearly complete macroscopic phase separation. Congruent with the DS results, the occurrence of the AAPS was detected by means of CFM, making use of the autofluorescent property of IMI. Oscillatory shear rheology and differential scanning calorimetry (DSC) detected the glass transition of the polymer phase but not that of the AI phase. Furthermore, the otherwise undesired effects of interfacial and electrode polarization, which can appear in DS, were exploited to determine the effective domain size of the discrete AI phase in this work. Here, stereological analysis of CFM images probing the mean diameter of the phase-separated IMI domains directly stayed in reasonably good agreement with the DS-based estimates. The size of phase-separated microclusters showed little variation with AI loading, implying that the ASDs have presumably undergone AAPS upon manufacturing. DSC provided further support to the immiscibility of IMI and PS, as no discernible melting point depression of the corresponding physical mixtures was detected. Moreover, no signatures of strong attractive AI-polymer interactions could be detected by mid-infrared spectroscopy within this ASD system. Finally, dielectric cold crystallization experiments of the pure AI and the 60 wt % dispersion revealed comparable crystallization onset times, hinting at a poor inhibition of the AI crystallization within the ASD. These observations are in harmony with the occurrence of AAPS. In conclusion, our multifaceted experimental approach opens new venues for rationalizing the mechanisms and kinetics of phase separation in amorphous solid dispersions.

Effect of Span 20 Feeding Zone in the Twin Screw Extruder on the Properties of Amorphous Solid Dispersion of Ritonavir

A ternary amorphous solid dispersion (ASD) system consisting of drug/polymer/surfactant is receiving increased attention to improve the oral bioavailability of poorly water-soluble drugs. The effect of polymers has been extensively studied, while the impact of surfactants has not yet to be studied to the same extent. Challenging questions to be answered are whether the surfactants should be added with the drug or separately and the resulting differences between the two operating processes. By adjusting the liquid feeding zone for Span 20 in the hot-melt twin screw extruder equipment, we investigated the effect of Span 20 on the properties of the polyvinylpyrrolidone/vinyl acetate (PVPVA)-based ASD formulations of ritonavir. We found that with the delayed feeding positions of Span 20 in the twin screw extruder, the ability of the ternary ASDs to maintain the supersaturation of the milled extrudates was observed to be significantly enhanced. Furthermore, adding surfactant after a thorough mixing of polymer and drug could decrease the molecular mobility of ternary ASD formulations. In addition, the effects of Span 20 on the complex viscosity and structure of PVPVA were also investigated. The delayed addition of Span 20 could improve the complex viscosity of PVPVA, thus leading to the drug precipitation inhibition. In conclusion, the delayed addition of Span 20 in the twin screw extruder and prolonging the mixing time of the drug and polymer may be critical to the maintenance of supersaturation.

The role of surfactants in preserving the stability of amorphous solid dispersions: A review

In recent years among various formulation strategies, amorphous solid dispersions (ASDs) has gained tremendous recognition for improving the solubility of poorly soluble drug substances. Among various manufacturing strategies, hot melt extrusion (HME), spray drying, kinetisol, and electrospinning are the most widely employed for developing ASDs. Despite the improving solubility and bioavailability, the stability of ASDs is the major problem haunting the pharmaceutical industries. Various factors, such as miscibility, the solubility of the drug in polymer, drug-polymer interactions, glass transition temperature, hygroscopicity, and storage conditions, determine the stability of ASDs. The poor stability of amorphous drugs also limits the drug loading capacity, resulting in an increased volume of the dosage form affecting patient compliance. Apart from the physical stability of ASDs, solution-mediated recrystallization of the drug when present in a supersaturated state is another factor affecting the quality and performance of the formulations. In recent years incorporation of surfactants to hinder solution-mediated recrystallization of drugs, thereby improving the stability and performance of ASD formulations, is being most widely investigated. The incorporation of surfactant in the HME process will also act as a plasticizer, thereby allowing the process to be carried at lower temperatures. This review article mainly focuses on the role of surfactants in ASD systems and recent advancements. Still, research is warranted to understand the mechanism of surfactants and to establish screening criteria.

A Comparative Study between A Protein Based Amorphous Formulation and Other Dissolution Rate Enhancing Approaches: A Case Study with Rifaximin.

Amorphous solid dispersions (ASDs) based on proteins as co-formers have previously shown promising potential to improve the solubility and bioavailability of poorly water-soluble drugs. In particular, whey proteins have shown to be promising co-formers and amorphous stabilizers in ASD formulations, including at high drug loading. In this study, the feasibility of the whey protein β-lactoglobulin (BLG) as a co-former in ASDs was compared to the more traditional ASD co-formers based on synthetic polymers (hydroxypropyl methylcellulose acetate succinate and Eudragit® L) as well as to a nanocrystalline formulation. The poorly water-soluble drug rifaximin (RFX) was chosen as the model drug. All drug/co-former formulations were prepared as fully amorphous ASDs by spray drying at 50% (w/w) drug loading. The BLG-based ASD had the highest glass transition temperature and showed a faster dissolution rate and higher drug solubility in three release media with different pH values (1.2, 4.5, and 6.5) compared to the polymer-based ASDs and the nanocrystalline RFX. In conclusion, BLG is a promising co-former and amorphous stabilizer of RFX in ASD formulations, superior to the selected polymer-based ASD systems or the nanocrystalline formulation.

Hot melt extrusion: A single-step continuous manufacturing process for developing amorphous solid dispersions of poorly soluble drug substances

In today’s world with increasing patient population, the demand for pharmaceutical medications is increasing enormously. However, poor solubility of drug substances and underdeveloped manufacturing process are affecting the revenue of the pharmaceutical industries. Improving the solubility and establishing a robust manufacturing process is the primary prerequisite of the developmental scientists. Among various approaches amorphous solid dispersion has gained a tremendous response for improving the solubility of the drug substances. In addition, the process of hot melt extrusion has attracted the investigators from regulatory agencies and industries. The process of hot melt extrusion involves application of thermal and mechanical energy on to the processing material. The process requires no solvent and is referred as “green technique.” Various factors need to be taken into consideration for developing amorph amorphous solid dispersions. The miscibility of drug and polymer, solubility of drug in polymer, drug-polymer interactions, glass transition temperature, storage conditions majorly influence the stability of the amorphous solid dispersions systems. Though hot melt extrusion is most widely employed for developing amorphous solid dispersions still a lot of research is warranted for developing strategies to formulate high drug loading medications with improved stability. This review article mainly focuses on the instrumentation, and process for developing amorphous solid dispersions by hot melt extrusion with a small note on the various advantages and limitations.

Selecting the most appropriate formulation excipient for manufacture of amorphous solid dispersions: a case study of lumefantrine

This work demonstrated the importance of pre-formulation studies and proposed a generalised scheme for excipient screening in the early stage of amorphous solid dispersion(ASD) system development by profiling the excipients’ capability to solubilise, amorphisise, and stabilise the chosen active pharmaceutical ingredient (API) in an effort to rank their suitability. Lumefantrine, an antimalarial active compound with both poor solubility and permeability, was used as a model API and solvent evaporation film casting was used to prepare the candidate ASD matrices in this work.&amp;nbsp;

High spatial resolution ToF-SIMS imaging and image analysis strategies to monitor and quantify early phase separation in amorphous solid dispersions

Amorphous solid dispersions (ASDs) are formulations with enhanced drug solubility and dissolution rate compared to their crystalline counterparts, however, they can be inherently thermodynamically unstable. This can lead to amorphous phase separation and drug re-crystallisation, phenomena that are typically faster and more dominant at the product’s surfaces. This study investigates the use of high-resolution time of flight-secondary ion mass spectrometry (ToF-SIMS) imaging as a surface analysis technique combined with image-analysis for the early detection, monitoring and quantification of surface amorphous phase separation in ASDs. Its capabilities are demonstrated for two pharmaceutically relevant ASD systems with distinct re-crystallisation behaviours, prepared using hot melt extrusion (HME) followed by pelletisation or grinding: (1) paracetamol-hydroxypropyl methylcellulose (PCM-HPMC) pellets with drug loadings of 10%–50% w/w and (2) indomethacin-polyvinylpyrrolidone (IND-PVP) ground material with drug loadings of 20%–85% w/w. PCM-HPMC pellets showed intense phase separation, reaching 100% PCM surface coverage within 1–5 months. In direct comparison, IND-PVP HME ground material was more stable with only a moderate formation of isolated IND-rich clusters. Image analysis allowed the reliable detection and quantification of local drug-rich clusters. An Avrami model was applied to determine and compare phase separation kinetics. The combination of chemical sensitivity and high spatial resolution afforded by SIMS was crucial to enable the study of early phase separation and re-crystallisation at the surface. Compared with traditional methods used to detect crystalline material, such as XRPD, we show that ToF-SIMS enabled detection of surface physical instability already at early stages of drug cluster formation in the first days of storage.

Atomic Layer Coating to Inhibit Surface Crystallization of Amorphous Pharmaceutical Powders.

Preventing crystallization is a primary concern when developing amorphous drug formulations. Recently, atomic layer coatings (ALCs) of aluminum oxide demonstrated crystallization inhibition of high drug loading amorphous solid dispersions (ASDs) for over 2 years. The goal of the current study was to probe the breadth and mechanisms of this exciting finding through multiple drug/polymer model systems, as well as particle and coating attributes. The model ASD systems selected provide for a range of hygroscopicity and chemical functional groups, which may contribute to the crystallization inhibition effect of the ALC coatings. Atomic layer coating was performed to apply a 5-25 nm layer of aluminum oxide or zinc oxide onto ASD particles, which imparted enhanced micromeritic properties, namely, reduced agglomeration and improved powder flowability. ASD particles were stored at 40 °C and a selected relative humidity level between 31 and 75%. Crystallization was monitored by X-ray powder diffraction and scanning electron microscopy (SEM) up to 48 weeks. Crystallization was observable by SEM within 1-2 weeks for all uncoated samples. After ALC, crystallization was effectively delayed or completely inhibited in some systems up to 48 weeks. The delay achieved was demonstrated regardless of polymer hygroscopicity, presence or absence of hydroxyl functional groups in drugs and/or polymers, particle size, or coating properties. The crystallization inhibition effect is attributed primarily to decreased surface molecular mobility. ALC has the potential to be a scalable strategy to enhance the physical stability of ASD systems to enable high drug loading and enhanced robustness to temperature or relative humidity excursions.

Water-Resistant Drug-Polymer Interaction Contributes to the Formation of Nano-Species during the Dissolution of Felodipine Amorphous Solid Dispersions.

Drug-polymer interactions are of great importance in amorphous solid dispersion (ASD) formulation for both dissolution performance and physical stability considerations. In this work, three felodipine ASD systems with drug loading ranging from 5 to 20% were prepared using PVP, PVP-VA, or HPMC-AS as the polymer matrix. The amorphization and homogeneity were confirmed by differential scanning calorimetry and powder X-ray diffraction. The intrinsic dissolution behavior of these ASDs was studied in 0.05 M HCl and phosphate-buffered saline (PBS) (pH 6.5). In 0.05 M HCl, PVP-VA ASDs with low drug loading (<15%) showed rapid dissolution accompanied with nano-species generation, while in the PVP system, rapid dissolution and nano-species generation were observed only when drug loading was less than 10%, and HPMC-AS ASDs always released slowly with no nano-species formation. In PBS, PVP-VA ASDs with drug loading less than 10% showed rapid dissolution accompanied with nano-species generation, while for PVP ASDs, rapid dissolution and nano-species generation were observed only when drug loading was 5%. However, 20% drug loading HPMC-AS ASDs exhibited rapid dissolution of felodipine and nano-species generation. When the drug loading was above the transition point of PVP-VA ASDs and PVP ASDs, the release rate was significantly lowered, and no nano-species was generated. To understand this phenomenon, drug-polymer interactions were studied using the melting point depression method and the Flory-Huggins model fitting. The Flory-Huggins interaction parameters (χ) for felodipine/HPMC-AS, felodipine/PVP, and felodipine/PVP-VA were determined to be 0.62 ± 0.07, -0.55 ± 0.20, and -1.02 ± 0.21, respectively, indicating the existence of the strongest attractive molecular interaction between felodipine and PVP-VA, followed by felodipine/PVP, but not in felodipine/HPMC-AS. Furthermore, dynamic vapor sorption further revealed that the molecular interactions between felodipine and PVP or PVP-VA were resistant to water. We concluded that water-resistant drug-polymer interactions in felodipine/polymer systems were responsible for the formation of nano-species, which further facilitated the rapid initial drug dissolution.

Prediction and Construction of Drug-Polymer Binary System Thermodynamic Phase Diagram in Amorphous Solid Dispersions (ASDs).

Amorphous solid dispersion (ASD) has been well known as a potential strategy to improve the bioavailability and dissolution performance of poorly water-soluble drugs. The primary concern of this approach is the long-term stability of the amorphous drug in the solid dispersion. Accurate prediction and detection of the solubility and miscibility of drug in polymeric binary system will be a milestone to the development of ASDs. In this investigation, a method based on Flory-Huggins (F-H) theory was proposed to predict and calculate the solubility and miscibility of the drug in polymeric matrix and construct the phase diagram to identify the relevance between drug loading and temperature for ASDs development. Indomethacin (Indo) was chosen as the model drug, and polyvinyl pyrrolidone vinyl acetate (Kollidon® VA 64) was used as a polymeric carrier for the ASD systems. Physical mixtures were prepared with different drug loadings (10 to 90%) and analyzed by differential scanning calorimetry (DSC). The interaction parameter χ was calculated for physical mixtures by the melting point depression and solubility parameter contribution methods. The phase diagram was constructed to investigate the impact of other parameters like drug loading, processing temperature, and Gibbs free energy of mixing (ΔGmix). For further validation, formulations were developed using HME to verify the accuracy of the phase diagram and to guide in the hot-melt extrusion (HME) process design space and optimization.

Hot Melt Extrusion-Triggered Amorphization as a Continuous Process for Inducing Extended Supersaturable Drug Immediate-Release from saSMSDs Systems.

Hot melt extrusion (HME), a continuous manufacturing process for generating supersaturating amorphous self-micellizing solid dispersion systems (saSMSDs), holds promise for achieving amorphization of many pharmaceutical formulations. For saSMSDs generation, HME-triggered continuous processes offer advantages over traditional non-continuous processes such as fusion/quench cooling (FQC) and co-precipitation (CP). Here we employed HME, FQC, and CP to generate saSMSDs containing the water-insoluble BCS II drug nitrendipine (NIT) and self-micellizing polymer Soluplus®. Scanning electron microscopy, powder X-ray diffraction, and differential scanning calorimetry results revealed that saSMSDs formed when NIT–Soluplus® mixtures were subjected to the abovementioned amorphization methods. All saSMSDs outperformed crystalline NIT preparations and physical mixtures in achieving extended supersaturable immediate release states with superior solubility, “spring-parachute” process characteristics, and dissolution behaviors. Notably, Fourier transform-infrared spectroscopic results obtained for saSMSDs detected hydrogen bonding interactions between the drug and the carrier. Ultimately, our results revealed the advantages of HME-triggered amorphization as a continuous process for significantly improving drug dissolution, increasing solubility, and maintaining supersaturation as compared to traditional amorphization-based techniques.

Phase separation in surfactant-containing amorphous solid dispersions: Orthogonal analytical methods to probe the effects of surfactants on morphology and phase composition

Amorphous–amorphous phase separation (AAPS) is an important phase transition process for amorphous solid dispersion (ASD) performance both in terms of drug release as well as physical and chemical stability during storage. Addition of surfactants to ASD systems can impact both of these processes. One possible mechanism through which surfactants affect ASD performance is via their impact on AAPS. Unfortunately, despite their increasing usage in ASD formulations, the effect of surfactant on AAPS is still poorly understood, and there are limited analytical techniques that provide microstructural and composition information about phase separated ASDs. In this study, the impact of four surfactants (sodium dodecyl sulfate, Tween 80, Span 20 and Span 85) on water-induced phase separation in ASDs formulated with ritonavir and polyvinylpyrrolidone/vinyl acetate (PVPVA) was investigated using a variety of orthogonal analytical methods. Transparent films of ASDs with different compositions were prepared by spin coating. Fluorescence confocal microscopy in combination with an in situ humidity chamber was used to monitor the kinetics and morphology of phase separation following exposure to high relative humidity. Optical photothermal IR analysis of phase separated films enabled characterization of domain composition and surfactant distribution. Liquid-liquid phase separation concentration, zeta potential and solution nuclear magnetic resonance spectroscopy measurements enabled interpretation of interaction with and partition of surfactants into the drug-rich phase. It was found that phase separation kinetics and morphology were notably changed by the surfactants. Further, the surfactants showed different affinities for the drug-rich versus the aqueous/polymer-rich phases. The employed analytical techniques were found to be complementary in providing insight into surfactant location in phase separated systems. This study highlights the complexity of phase separation, especially in the presence of surfactants, and provides a foundation to understand the impact of AAPS on ASD performance.

The Physical Stability of Felodipine and Its Recrystallization from an Amorphous Solid Dispersion Studied by NMR Relaxometry.

The 1H nuclear magnetic resonance (NMR) relaxometry method was applied to investigate the physical stability of an active pharmaceutical ingredient (API) and, for the first time, its recrystallization process in an amorphous solid dispersion system (ASD). The ASD of felodipine and polyvinylpyrrolidone (PVP) was prepared using the solvent evaporation method in a mass ratio of 50:50. In the first stage of the study (250 days), the sample was stored at 0% relative humidity (RH). The recovery of magnetization was described by one-exponential function. In the second stage (300 days in 75% relative humidity), the recrystallization process of felodipine was studied, showing in the sample three components of equilibrium magnetization related to (i) crystalline felodipine, (ii) water, and (iii) felodipine and PVP remaining in the ASD. The study shows that the 1H NMR relaxometry method is a very useful tool for analysing the composition of a three-phase system mixed at the molecular level and for the investigation of recrystallization process of API in amorphous solid dispersion system.