Poly(vinylpyridine-co-vinylpyridine N-oxide) Excipients Mediate Rapid Dissolution and Sustained Supersaturation of Posaconazole Amorphous Solid Dispersions.

The chemical structure of excipients molecularly mixed in an amorphous solid dispersion (ASD) has a significant impact on properties of the ASD including dissolution behavior, physical stability, and bioavailability. Polymers used in ASDs require a balance between hydrophobic and hydrophilic functionalities to ensure rapid dissolution of the amorphous dispersion as well as sustained supersaturation of the drug in solution. This work demonstrates the use of postpolymerization functionalization of poly(vinylpyridine) excipients to elucidate the impact of polymer properties on the dissolution behavior of amorphous dispersions containing posaconazole. It was found that N-oxidation of pyridine functionalities increased the solubility of poly(vinylpyridine) derivatives in neutral aqueous conditions and allowed for nanoparticle formation which supplied posaconazole into solution at concentrations exceeding those achieved by more conventional excipients such as hydroxypropyl methylcellulose acetate succinate (HPMCAS) or Eudragit E PO. By leveraging these functional modifications of the parent poly(vinylpyridine) excipient to increase polymer hydrophilicity and minimize the effect of polymer on pH, a new polymeric excipient was optimized for rapid dissolution and supersaturation maintenance for a model compound.

Development of Ternary Amorphous Solid Dispersions Manufactured by Hot-Melt Extrusion and Spray-Drying─Comparison of In Vitro and In Vivo Performance.

Producing amorphous solid dispersions (ASDs) by hot-melt extrusion (HME) is favorable from an economic and ecological perspective but also limited to thermostable active pharmaceutical ingredients (APIs). A potential technology shift from spray-drying to hot-melt extrusion at later stages of drug product development is a desirable goal, however bearing the risk of insufficient comparability of the in vitro and in vivo performance of the final dosage form. Hot-melt extrusion was performed using API/polymer/surfactant mixtures with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as the polymer and evaluated regarding the extrudability of binary and ternary amorphous solid dispersions (ASDs). Additionally, spray-dried ASDs were produced, and solid-state properties were compared to the melt-extruded ASDs. Tablets were manufactured of a ternary ASD lead candidate comparing their in vitro dissolution and in vivo performance. The extrudability of HPMCAS was improved by adding a surfactant as plasticizer, thereby lowering the high melt-viscosity. d-α-Tocopheryl polyethylene glycol succinate (TPGS) as surfactant showed the most similar solid-state properties between spray-dried and extruded ASDs compared to those of poloxamer 188 and sodium dodecyl sulfate. The addition of TPGS, however, barely affected API/polymer interactions. The in vitro dissolution experiment and in vivo dog study revealed a higher drug release of tablets manufactured from the spray-dried ASD compared to the melt-extruded ASD; this was attributed to the different particle size. We could further demonstrate that the drug release can be controlled by adjusting the particle size of melt-extruded ASDs leading to a similar release profile compared to tablets containing the spray-dried dispersion, which confirmed the feasibility of a technology shift from spray-drying to HME upon drug product development.

Colyophilized Sugar-Polymer Dispersions for Enhanced Processing and Storage Stability.

Sucrose and trehalose pharmaceutical excipients are employed to stabilize protein therapeutics in a dried state. The mechanism of therapeutic protein stabilization is dependent on the sugars being present in an amorphous solid-state. Colyophilization of sugars with high glass transition polymers, polyvinylpyrrolidone (PVP), and poly(vinylpyrrolidone vinyl acetate) (PVPVA), enhances amorphous sugar stability. This study investigates the stability of colyophilized sugar-polymer systems in the frozen solution state, dried state postlyophilization, and upon exposure to elevated humidity. Binary systems of sucrose or trehalose with PVP or PVPVA were lyophilized with sugar/polymer ratios ranging from 2:8 to 8:2. Frozen sugar-PVPVA solutions exhibited a higher glass transition temperature of the maximally freeze-concentrated amorphous phase (Tg') compared to sugar-PVP solutions, despite the glass transition temperature (Tg) of PVPVA being lower than PVP. Tg values of all colyophilized systems were in a similar temperature range irrespective of polymer type. Greater hydrogen bonding between sugars and PVP and the lower hygroscopicity of PVPVA influenced polymer antiplasticization effects and the plasticization effects of residual water. Plasticization due to water sorption was investigated in a dynamic vapor sorption humidity ramping experiment. Lyophilized sucrose systems exhibited increased amorphous stability compared to trehalose upon exposure to the humidity. Recrystallization of trehalose was observed and stabilized by polymer addition. Lower concentrations of PVP inhibited trehalose recrystallization compared to PVPVA. These stabilizing effects were attributed to the increased hydrogen bonding between trehalose and PVP compared to trehalose and PVPVA. Overall, the study demonstrated how differences in polymer hygroscopicity and hydrogen bonding with sugars influence the stability of colyophilized amorphous dispersions. These insights into excipient solid-state stability are relevant to the development of stabilized biopharmaceutical solid-state formulations.

Understanding the Influence of API Conformations on Amorphous Dispersion Formation Potential Predictions using the R3m Molecular Descriptor.

The R3m molecular descriptor (R-GETAWAY third-order autocorrelation index weighted by the atomic mass) has previously been shown to encode molecular attributes that appear to be physically and chemically relevant to grouping diverse active pharmaceutical ingredients (API) according to their potential to form persistent amorphous solid dispersions (ASDs) with polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA). The initial R3m dispersibility model was built by using a single three-dimensional (3D) conformation for each drug molecule. Since molecules in the amorphous state will adopt a distribution of conformations, molecular dynamics simulations were performed to sample conformations that are probable in the amorphous form, which resulted in a distribution of R3m values for each API. Although different conformations displayed R3m values that differed by as much as 0.4, the median of each R3m distribution and the value predicted from the single 3D conformation were very similar for most structures studied. The variability in R3m resulting from the distribution of conformations was incorporated into a logistic regression model for the prediction of ASD formation in PVPVA, which resulted in a refinement of the classification boundary relative to the model that only incorporated a single conformation of each API.

The Influence of PVP Polymer Topology on the Liquid Crystalline Order of Itraconazole in Binary Systems.

This study presents a novel approach by utilizing poly(vinylpyrrolidone)s (PVPs) with various topologies as potential matrices for the liquid crystalline (LC) active pharmaceutical ingredient itraconazole (ITZ). We examined amorphous solid dispersions (ASDs) composed of ITZ and (i) self-synthesized linear PVP, (ii) self-synthesized star-shaped PVP, and (iii) commercial linear PVP K30. Differential scanning calorimetry, X-ray diffraction, and broad-band dielectric spectroscopy were employed to get a comprehensive insight into the thermal and structural properties, as well as global and local molecular dynamics of ITZ-PVP systems. The primary objective was to assess the influence of PVPs' topology and the composition of ASD on the LC ordering, changes in the temperature of transitions between mesophases, the rate of their restoration, and finally the solubility of ITZ in the prepared ASDs. Our research clearly showed that regardless of the PVP type, both LC transitions, from smectic (Sm) to nematic (N) and from N to isotropic (I) phases, are effectively suppressed. Moreover, a significant difference in the miscibility of different PVPs with the investigated API was found. This phenomenon also affected the solubility of API, which was the greatest, up to 100 µg/mL in the case of starPVP 85:15 w/w mixture in comparison to neat crystalline API (5 µg/mL). Obtained data emphasize the crucial role of the polymer's topology in designing new pharmaceutical formulations.

COSMOPharm: Drug-Polymer Compatibility of Pharmaceutical Amorphous Solid Dispersions from COSMO-SAC.

The quantum mechanics-aided COSMO-SAC activity coefficient model is applied and systematically examined for predicting the thermodynamic compatibility of drugs and polymers. The drug-polymer compatibility is a key aspect in the rational selection of optimal polymeric carriers for pharmaceutical amorphous solid dispersions (ASD) that enhance drug bioavailability. The drug-polymer compatibility is evaluated in terms of both solubility and miscibility, calculated using standard thermodynamic equilibrium relations based on the activity coefficients predicted by COSMO-SAC. As inherent to COSMO-SAC, our approach relies only on quantum-mechanically derived σ-profiles of the considered molecular species and involves no parameter fitting to experimental data. All σ-profiles used were determined in this work, with those of the polymers being derived from their shorter oligomers by replicating the properties of their central monomer unit(s). Quantitatively, COSMO-SAC achieved an overall average absolute deviation of 13% in weight fraction drug solubility predictions compared to experimental data. Qualitatively, COSMO-SAC correctly categorized different polymer types in terms of their compatibility with drugs and provided meaningful estimations of the amorphous-amorphous phase separation. Furthermore, we analyzed the sensitivity of the COSMO-SAC results for ASD to different model configurations and σ-profiles of polymers. In general, while the free volume and dispersion terms exerted a limited effect on predictions, the structures of oligomers used to produce σ-profiles of polymers appeared to be more important, especially in the case of strongly interacting polymers. Explanations for these observations are provided. COSMO-SAC proved to be an efficient method for compatibility prediction and polymer screening in ASD, particularly in terms of its performance-cost ratio, as it relies only on first-principles calculations for the considered molecular species. The open-source nature of both COSMO-SAC and the Python-based tool COSMOPharm, developed in this work for predicting the API-polymer thermodynamic compatibility, invites interested readers to explore and utilize this method for further research or assistance in the design of pharmaceutical formulations.

Physicochemical interaction of rifampicin and ritonavir-lopinavir solid dispersion: an in-vitro and ex-vivo investigation.

OBJECTIVE: To investigate the in-situ physicochemical interaction of Rifampicin and Ritonavir - Lopinavir Solid dispersion administered for the treatment of comorbid conditions i.e. Tuberculosis and HIV/AIDS. METHODS: pH-shift dissolution of Rifampicin (RIF) in presence of Ritonavir-Lopinavir solid dispersion (RL-SD) was carried out in USP phosphate buffer 6.8 and FaSSIF. Equilibrium and amorphous solubility were determined for the drugs. Pure drugs, their physical mixtures, and pH-shifted co-precipitated samples were characterized using DSC, PXRD, and FTIR. Fluorescence spectroscopy was used to investigate drug-rich and drug-lean phases. In-vitro and ex-vivo flux studies were also carried out. RESULTS: The results showed significant differences in the solubility and dissolution profiles of RTV and LOP in the presence of RIF, while RIF profile remained unchanged. Amorphicity, intermolecular interaction and aggregate formation in pH-shifted samples were revealed in DSC, XRD and FTIR analysis. Fluorescence spectroscopy confirmed the formation of drug-rich phase upon pH-shift. In-vitro and ex-vivo flux studies revealed significant reduction in the flux of all the drugs when studied in presence of second drug. CONCLUSION: RIF, RTV and LOP in presence of each other on pH-shift, results in co-precipitation in the amorphous form (miscible) which leads to reduction in the highest attainable degree of supersaturation. This reduction corresponds to the mole fraction of the RIF, RTV and LOP within the studied system. These findings suggest that the concomitant administration of these drugs may lead to physicochemical interactions and possible ineffective therapy.

An empirical predictive model for determining the aqueous solubility of BCS class IV drugs in amorphous solid dispersions.

CONTEXT: Determining solubility of drugs is laborious and time-consuming process that may not yield meaningful results. Amorphous solid dispersion (ASD) is a widely used solubility enhancement technique. Predictive models could streamline this process and accelerate the development of oral drugs with improved aqueous solubilities. OBJECTIVE: This study aimed to develop a predictive model to estimate the solubility of a compound from the ASDs in polymer matrices. METHODS: ASDs of model drugs (acetazolamide, chlorothiazide, furosemide, hydrochlorothiazide, sulfamethoxazole) with model polymers (PVP, PVPVA, HPMC E5, Soluplus) and a surfactant (TPGS) were prepared using hotmelt process. The prepared ASDs were characterized using DSC, FTIR, and XRD. The aqueous solubility of the model drugs was determined using shake-flask method. Multiple linear regression was used to develop a predictive model to determine aqueous solubility using the molecular descriptors of the drug and polymer as predictor variables. The model was validated using Leave-One-Out Cross-Validation. RESULTS: The ASDs' drug components were identified as amorphous via DSC and XRD Studies. There were no significant chemical interactions between the model drugs and the polymers based on FTIR studies. The ASDs showed a significant (p < 0.05) improvement in solubility, ranging from a 3-fold to 118-fold, compared with the pure drug. The developed empirical model predicted the solubility of the model drugs from the ASDs containing model polymer matrices with an accuracy greater than 80%. CONCLUSION: The developed empirical model demonstrated robustness and predicted the aqueous solubility of model drugs from the ASDs of model polymer matrices with an accuracy greater than 80%.

An innovative carrier for the formulation of amorphous solid dispersion by hot-melt extrusion with no further downstream processes: a case study with indomethacin.

The aim of this work was to study the possibility to use SepitrapTM as a carrier for the formulation of amorphous solid dispersions by HME (hot melt extrusion) processing aiming solubility enhancement of poorly water-soluble drugs. SepitrapTM is a microencapsulated powder solubilizer designed to simplify the manufacture of drugs in oral solid forms, not yet tested for this purpose. The performance of SepitrapTM was evaluated in HME processing for amorphous solid dispersions of poorly-water soluble drugs with indomethacin as a model drug. The study was conducted using a twin-screw extruder, two compositions of SepitrapTM and different loads of indomethacin, demonstrating that SepitrapTM could represent a new range of carriers for amorphous solid dispersions for HME processing, reducing necessary downstream steps such as grinding.

Can Pure Predictions of Activity Coefficients from PC-SAFT Assist Drug-Polymer Compatibility Screening?

The bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) can be improved via the formulation of an amorphous solid dispersion (ASD), where the API is incorporated into a suitable polymeric carrier. Optimal carriers that exhibit good compatibility (i.e., solubility and miscibility) with given APIs are typically identified through experimental means, which are routinely labor- and cost-inefficient. Therefore, the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state, a popular thermodynamic model in pharmaceutical applications, is examined in terms of its performance regarding the computational pure prediction of API-polymer compatibility based on activity coefficients (API fusion properties were taken from experiments) without any binary interaction parameters fitted to API-polymer experimental data (that is, kij = 0 in all cases). This kind of prediction does not need any experimental binary information and has been underreported in the literature so far, as the routine modeling strategy used in the majority of the existing PC-SAFT applications to ASDs comprised the use of nonzero kij values. The predictive performance of PC-SAFT was systematically and thoroughly evaluated against reliable experimental data for almost 40 API-polymer combinations. We also examined the effect of different sets of PC-SAFT parameters for APIs on compatibility predictions. Quantitatively, the total average error calculated over all systems was approximately 50% in the weight fraction solubility of APIs in polymers, regardless of the specific API parametrization. The magnitude of the error for individual systems was found to vary significantly from one system to another. Interestingly, the poorest results were obtained for systems with self-associating polymers such as poly(vinyl alcohol). Such polymers can form intramolecular hydrogen bonds, which are not accounted for in the PC-SAFT variant routinely applied to ASDs (i.e., that used in this work). However, the qualitative ranking of polymers with respect to their compatibility with a given API was reasonably predicted in many cases. It was also predicted correctly that some polymers always have better compatibility with the APIs than others. Finally, possible future routes to improve the cost-performance ratio of PC-SAFT in terms of parametrization are discussed.

Design of Redispersible High-Drug-Load Amorphous Formulations: Impact of Ionic vs Nonionic Surfactants on Processing and Performance.

Amorphous solid dispersions (ASDs) are an enabling formulation approach used to enhance bioavailability of poorly water-soluble molecules in oral drug products. Drug-rich amorphous nanoparticles generated in situ during ASD dissolution maintain supersaturation that drives enhanced absorption. However, in situ formation of nanoparticles requires large quantities of polymers to release drugs rapidly, resulting in an ASD drug load <25%. Delivering directly engineered drug-rich amorphous nanoparticles can reduce the quantities of polymers significantly without sacrificing bioavailability. Preparation of 90% drug-load amorphous nanoparticles (ANPs) of <300 nm diameter using solvent/antisolvent nanoprecipitation, organic solvent removal, and spray drying was demonstrated previously on model compound ABT-530 with Copovidone and sodium dodecyl sulfate (anionic). In this work, nonionic surfactant d-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or TPGS) was used to prepare ANPs as a comparison. Characterization of ANPs by dynamic light scattering, filtrate potency assay, scanning electron microscopy, and differential scanning calorimetry revealed differences in surface properties of nanoparticles afforded by surfactants. This work demonstrates the importance of understanding the impact of the stabilizing agents on nanoparticle behavior when designing a high-drug-load amorphous formulation for poorly water-soluble compounds as well as the impact on redispersion.

Probing Molecular Packing of Amorphous Pharmaceutical Solids Using X-ray Atomic Pair Distribution Function and Solid-State NMR.

The structural investigation of amorphous pharmaceuticals is of paramount importance in comprehending their physicochemical stability. However, it has remained a relatively underexplored realm primarily due to the limited availability of high-resolution analytical tools. In this study, we utilized the combined power of X-ray pair distribution functions (PDFs) and solid-state nuclear magnetic resonance (ssNMR) techniques to probe the molecular packing of amorphous posaconazole and its amorphous solid dispersion at the molecular level. Leveraging synchrotron X-ray PDF data and employing the empirical potential structure refinement (EPSR) methodology, we unraveled the existence of a rigid conformation and discerned short-range intermolecular C-F contacts within amorphous posaconazole. Encouragingly, our ssNMR 19F-13C distance measurements offered corroborative evidence supporting these findings. Furthermore, employing principal component analysis on the X-ray PDF and ssNMR data sets enabled us to gain invaluable insights into the chemical nature of the intermolecular interactions governing the drug-polymer interplay. These outcomes not only furnish crucial structural insights facilitating the comprehension of the underlying mechanisms governing the physicochemical stability but also underscore the efficacy of synergistically harnessing X-ray PDF and ssNMR techniques, complemented by robust modeling strategies, to achieve a high-resolution exploration of amorphous structures.

Drug-Polymer Miscibility and the Overlap Concentration (C*) as Measured by Rheology: Variation of Polymer Structure.

OBJECTIVES: Amorphous solid dispersions (ASDs), wherein a drug is molecularly dispersed in a polymer, can improve physical stability and oral bioavailability of poorly soluble drugs. Risk of drug crystallization is usually averted using high polymer concentrations. However, we demonstrated recently that the overlap concentration, C*, of polymer in drug melt is the minimum polymer concentration required to maintain drug in the amorphous state following rapid quench. This conclusion was confirmed for several drugs mixed with poly(vinylpyrrolidone) (PVP). Here we assess the solid-state stability of ASDs formulated with a variety of polymers and drugs and at various polymer concentrations (C) and molecular weights (MWs). We further test the hypothesis that degree of drug crystallization decreases with increasing C/C* and vanishes when C>C*, where C* depends on polymer MW and strength of drug-polymer interaction. METHODS: We test our hypothesis with ASDs consisting of ketoconazole admixed with polyacrylic acid, polymethacrylic acid and poly (methacrylic acid-co-ethyl acrylate); and felodipine admixed with PVP and poly (vinylpyrrolidone-co-vinyl acetate). Values of C* for polymers in molten drug are rheologically determined. Crystallization behavior is assessed by measuring enthalpy of fusion, ΔHf  and by X-ray diffraction. RESULTS: We confirm that ΔHf/ΔHf, C = 0 = f(C/C∗), and essentially no crystallization occurs when C>C*. CONCLUSIONS: Our findings will aid researchers in designing or selecting appropriate polymers to inhibit crystallization of poorly soluble drugs. This research also suggests that C* as determined by rheology can be used to compare drug-polymer interactions for similar molecular weight polymers.

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.

Composites of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamide with Polymers: Effect of Crystallinity on Solubility and Stability.

This work aimed to develop and characterize a water-soluble, high-release active pharmaceutical ingredient (API) composite based on the practically water-insoluble API N-butyl-N-methyl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamide (GML-3), a substance with antidepressant and anxiolytic action. This allows to ensure the bioavailability of the medicinal product of combined action. Composites obtained by the method of creating amorphous solid dispersions, where polyvinylpyrrolidone (PVP) or Soluplus® was used as a polymer, were studied for crystallinity, stability and the release of API from the composite into purified water. The resulting differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and dissolution test data indicate that the resulting composites are amorphous at 1:15 API: polymer ratios for PVP and 1:5 for Soluplus®, which ensures the solubility of GML-3 in purified water and maintaining the supercritical state in solution.

Preparation of Free-Flowing Spray-Dried Amorphous Composites Using Neusilin®.

A highly porous additive, Neusilin®, with high adsorption capability is investigated to improve bulk properties, hence processability of spray-dried amorphous solid dispersions (ASDs). Griseofulvin (GF) is applied as a model BCS class 2 drug in ASDs. Two grades of Neusilin®, US2 (coarser) and UFL2 (finer), were used as additives to produce spray-dried amorphous composite (AC) powders, and their performance was compared with the resulting ASDs without added Neusilin®. The resulting AC powders that included Neusilin® had greatly enhanced flowability (flow function coefficient (FFC) > 10) comparable to larger particles (100 µm) yet had finer particle size (< 50 µm), hence retaining the advantage of fast dissolution rate of finer sizes. Dissolution results demonstrated that achieved GF supersaturation for AC powders with Neusilin® was as high as 3 times that of crystalline GF concentration and was achieved within 30 min. In addition, 80% of drug was released within 4 min. The flowability improvement for AC powders with Neusilin® was more significant as compared to spray-dried ASDs without Neusilin®. Thus, the role of Neusilin® in flowability improvement was evident, considering that spray-dried AC with Neusilin® UFL2 has higher FFC than ASDs having a similar size. Lastly, the AC powders retained a fully amorphous state of GF after 3-month ambient storage. The overall results conveyed that the improved flowability and dissolution rate could outweigh the loss of drug loading resulted by addition of Neusilin®.

Influence of Poloxamer on the Dissolution and Stability of Hot-Melt Extrusion-Based Amorphous Solid Dispersions Using Design of Experiments.

The current study aimed to see the effects of poloxamer P407 on the dissolution performance of hydroxypropyl methylcellulose acetate succinate (AquaSolve™ HPMC-AS HG)-based amorphous solid dispersions (ASD). A weakly acidic, poorly water-soluble active pharmaceutical ingredient (API), mefenamic acid (MA), was selected as a model drug. Thermal investigations, including thermogravimetry (TG) and differential scanning calorimetry (DSC), were conducted for raw materials and physical mixtures as a part of the pre-formulation studies and later to characterize the extruded filaments. The API was blended with the polymers using a twin shell V-blender for 10 min and then extruded using an 11-mm twin-screw co-rotating extruder. Scanning electron microscopy (SEM) was used to study the morphology of the extruded filaments. Furthermore, Fourier-transform infrared spectroscopy (FT-IR) was performed to check the intermolecular interactions of the components. Finally, to assess the in vitro drug release of the ASDs, dissolution testing was conducted in phosphate buffer (0.1 M, pH 7.4) and hydrochloric acid-potassium chloride (HCl-KCl) buffer (0.1 M, pH 1.2). The DSC studies confirmed the formation of the ASDs, and the drug content of the extruded filaments was observed to be within an acceptable range. Furthermore, the study concluded that the formulations containing poloxamer P407 exhibited a significant increase in dissolution performance compared to the filaments with only HPMC-AS HG (at pH 7.4). In addition, the optimized formulation, F3, was stable for over 3 months when exposed to accelerated stability studies.

Impact of Polymer Type on Thermal Degradation of Amorphous Solid Dispersions Containing Ritonavir.

High-temperature exposure during hot melt extrusion processing of amorphous solid dispersions may result in thermal degradation of the drug. Polymer type may influence the extent of degradation, although the underlying mechanisms are poorly understood. In this study, the model compound, ritonavir (Tm = 126 °C), undergoes thermal degradation upon high-temperature exposure. The extent of degradation of ritonavir in amorphous solid dispersions (ASDs) formulated with poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone) vinyl acetate copolymer (PVP/VA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and hydroxypropyl methylcellulose (HPMC) following isothermal heating and hot melt extrusion was evaluated, and mechanisms related to molecular mobility and intermolecular interactions were assessed. Liquid chromatography-mass spectrometry (LC-MS/MS) studies were used to determine the degradation products and pathways and ultimately the drug-polymer compatibility. The dominant degradation product of ritonavir was the result of a dehydration reaction, which then catalyzed a series of hydrolysis reactions to generate additional degradation products, some newly reported. This reaction series led to accelerated degradation rates with protic polymers, HPMCAS and HPMC, while ASDs with aprotic polymers, PVP and PVP/VA, had reduced degradation rates. This work has implications for understanding mechanisms of thermal degradation and drug-polymer compatibility with respect to the thermal stability of amorphous solid dispersions.

Gaining Insight into the Role of the Solvent during Spray Drying of Amorphous Solid Dispersions by Studying Evaporation Kinetics.

Spray drying is one of the most commonly used manufacturing techniques for amorphous solid dispersions (ASDs). During spray drying, very fast solvent evaporation is enabled by the generation of small droplets and exposure of these droplets to a heated drying gas. This fast solvent evaporation leads to an increased viscosity that enables kinetic trapping of an active pharmaceutical ingredient (API) in a polymer matrix, which is favorable for the formulation of supersaturated, kinetically stabilized ASDs. In this work, the relation between the solvent evaporation rate and the kinetic stabilization of highly drug-loaded ASDs was investigated. Accordingly, thermal gravimetric analysis (TGA) was employed to study the evaporation kinetics of seven organic solvents and the influence of solutes, i.e., poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), fenofibrate (FNB), and naproxen (NAP), on the evaporation behavior. At 10 °C below the boiling point of the respective solvent, methanol (MeOH) had the lowest evaporation rate and dichloromethane (DCM) had the highest. PVPVA decreased the evaporation rate for all solvents, yet this effect was more pronounced for the relatively faster evaporating solvents. The APIs had opposite effects on the evaporation process: FNB increased the evaporation rate, while NAP decreased it. The latter might indicate the presence of interactions between NAP and the solvent or NAP and PVPVA, which was further investigated using Fourier transform-InfraRed (FT-IR) spectroscopy. Based on these findings, spray drying process parameters were adapted to alter the evaporation rate. Increasing the evaporation rate of MeOH and DCM enabled the kinetic stabilization of higher drug loadings of FNB, while the opposite trend was observed for ASDs of NAP. Even when higher drug loadings could be kinetically stabilized by adapting the process parameters, the improvement was limited, demonstrating that the phase behavior of these ASDs of FNB and NAP immediately after preparation was predominantly determined by the API-polymer-solvent combination rather than the process parameters applied.

Balancing Solid-State Stability and Dissolution Performance of Lumefantrine Amorphous Solid Dispersions: The Role of Polymer Choice and Drug-Polymer Interactions.

Amorphous solid dispersions (ASDs) are of great interest due to their ability to enhance the delivery of poorly soluble drugs. Recent studies have shown that, in addition to acting as a crystallization inhibitor, the polymer in an ASD plays a role in controlling the rate of drug release, notably in congruently releasing formulations, where both the drug and polymer have similar normalized release rates. The aim of this study was to compare the solid-state stability and release performance of ASDs when formulated with neutral and enteric polymers. One neutral (polyvinylpyrrolidone-vinyl acetate copolymer, PVPVA) and four enteric polymers (hypromellose acetate succinate; hypromellose phthalate; cellulose acetate phthalate, CAP; methacrylic acid-methyl methacrylate copolymer, Eudragit L 100) were used to formulate binary ASDs with lumefantrine, a hydrophobic and weakly basic antimalarial drug. The normalized drug and polymer release rates of lumefantrine-PVPVA ASDs up to 35% drug loading (DL) were similar and rapid. No drug release from PVPVA systems was detected when the DL was increased to 40%. In contrast, ASDs formulated with enteric polymers showed a DL-dependent decrease in the release rates of both the drug and polymer, whereby release was slower than for PVPVA ASDs for DLs < 40% DL. Drug release from CAP and Eudragit L 100 systems was the slowest and drug amorphous solubility was not achieved even at 5% DL. Although lumefantrine-PVPVA ASDs showed fast release, they also showed rapid drug crystallization under accelerated stability conditions, while the ASDs with enteric polymers showed much greater resistance to crystallization. This study highlights the importance of polymer selection in the formulation of ASDs, where a balance between physical stability and dissolution release must be achieved.