Amorphous Solid Dispersions Research Articles

Benefits of combining supersaturating and solubilizing formulations – Is two better than one?

A variety of enabling formulations has been developed to address poor oral drug absorption caused by insufficient dissolution in the gastrointestinal tract. As the in vivo performance of these formulations is a result of a complex interplay between dissolution, digestion and permeation, development of suitable in vitro assays that captures these phenomena are called for. The enabling-absorption (ENA) device, consisting of a donor and receiver chamber separated by a semipermeable membrane, has successfully been used to study the performance of lipid-based formulations. In this work, the ENA device was prepared with two different setups (a Caco-2 cell monolayer and an artificial lipid membrane) to study the performance of a lipid-based formulation (LBF), an amorphous solid dispersion (ASD) and the potential benefit of combining the two formulation strategies. An in vivo pharmacokinetic study in rats was performed to evaluate the in vitro-in vivo correlation. In the ENA, high drug concentrations in the donor chamber did not translate to a high mass transfer, which was particularly evident for the ASD as compared to the LBF. The solubility of the polymer used in the ASD was strongly affected by pH-shifts in vitro, and the ph_dependence resulted in poor in vivo performance of the formulation. The dissolution was however increased in vitro when the ASD was combined with a blank lipid-based formulation. This beneficial effect was also observed in vivo, where the drug exposure of the ASD increased significantly when the ASD was co-administered with the blank LBF. To conclude, the in vitro model managed to capture solubility limitations and strategies to overcome these for one of the formulations studied. The correlation between the in vivo exposure of the drug exposure and AUC in the ENA was good for the non pH-sensitive formulations. The deconvoluted pharmacokinetic data indicated that the receiver chamber was a better predictor for the in vivo performance of the drug, however both chambers provided valuable insights to the observed outcome in vivo. This shows that the advanced in vitro setting used herein successfully could explain absorption differences of highly complex formulations.

Microbeads produced by prilling/vibration technique: A new way to use polyvinyl alcohol in pediatric and veterinary formulations

Poly(vinyl alcohol) (PVA) is a widely used synthetic polymer and due to its hydrophilicity, biocompatibility, and biodegradability, it is considered a suitable polymer for the formulation of drug delivery systems. In this study, PVA was used in a prilling/vibration technology as a pharmaceutical grade excipient to produce microbeads for oral administration that improve class II drugs' solubility and dissolution rate according to the Biopharmaceutical Classification System (BCS). Specifically, Ibuprofen (IBU) is a weakly acidic drug with low solubility at pH 1.2 and Ketoconazole (KETO), a weakly basic drug characterized by low solubility at pH 6.8. These drugs were selected because of their requirements for specific dosing conditions in children or animals, which often differ from commercially available conventional drugs. The microbeads produced were fully characterized in terms of drug loading, encapsulation efficiency, size, morphology, and drug release experiments were also conducted in a gastric fluid for IBU-loaded microbeads and simulated intestinal fluid for KETO-loaded microbeads. Finally, PVA microbeads were compared with an amorphous solid dispersion (ASDs) of the respective APIs, showing the same increase in solubility and dissolution rate. Therefore, the use of the prilling/vibration technology to produce PVA-based microbeads containing BCS class II drugs improves solubility and dissolution profile, which represent fundamental requirements for good bioavailability. Furthermore, the manufactured microbeads provide a high degree of dosing flexibility, making them suitable for administration in pediatric or veterinary patients with swallowing difficulties and requiring customized dosing.

Use of Poly(vinyl alcohol) in Spray-Dried Dispersions: Enhancing Solubility and Stability of Proteolysis Targeting Chimeras.

PROTACs, proteolysis targeting chimeras, are bifunctional molecules inducing protein degradation through a unique proximity-based mode of action. While offering several advantages unachievable by classical drugs, PROTACs have unfavorable physicochemical properties that pose challenges in application and formulation. In this study, we show the solubility enhancement of two PROTACs, ARV-110 and SelDeg51, using Poly(vinyl alcohol). Hereby, we apply a three-fluid nozzle spray drying set-up to generate an amorphous solid dispersion with a 30% w/w drug loading with the respective PROTACs and the hydrophilic polymer. Dissolution enhancement was achieved and demonstrated for t = 0 and t = 4 weeks at 5 °C using a phosphate buffer with a pH of 6.8. A pH shift study on ARV-110-PVA is shown, covering transfer from simulated gastric fluid (SGF) at pH 2.0 to fasted-state simulated intestinal fluid (FaSSIF) at pH 6.5. Additionally, activity studies and binding assays of the pure SelDeg51 versus the spray-dried SelDeg51-PVA indicate no difference between both samples. Our results show how modern enabling formulation technologies can partially alleviate challenging physicochemical properties, such as the poor solubility of increasingly large 'small' molecules.

Characterization and Dissolution Mechanism of Low-Molecular-Weight Organic Acids or Inorganic Mesoporous Particle-Based Piperine Amorphous Solid Dispersions.

The objective of the current study is to prepare amorphous solid dispersions (ASDs) containing piperine (PIP) by utilizing organic acid glycyrrhizic acid (GA) and inorganic disordered mesoporous silica 244FP (MSN/244FP) as carriers and to investigate their dissolution mechanism. The physicochemical properties of ASDs were characterized with scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). Fourier transform infrared spectroscopy (FTIR) and one-dimensional proton nuclear magnetic resonance (1H NMR) studies collectively proved that strong hydrogen-bonding interactions formed between PIP and the carriers in ASDs. Additionally, molecular dynamic (MD) simulation was conducted to simulate and predict the physical stability and dissolution mechanisms of the ASDs. Interestingly, it revealed a significant increase in the dissolution of amorphous PIP in ASDs in in vitro dissolution studies. Rapid dissolution of GA in pH 6.8 medium resulted in the immediate release of PIP drugs into a supersaturated state, acting as a dissolution-control mechanism. This exhibited a high degree of fitting with the pseudo-second-order dynamic model, with an R2 value of 0.9996. Conversely, the silanol groups on the outer surface of the MSN and its porous nanostructures enabled PIP to display a unique two-step drug release curve, indicating a diffusion-controlled mechanism. This curve conformed to the Ritger-Peppas model, with an R2 > 0.9. The results obtained provide a clear evidence of the proposed transition of dissolution mechanism within the same ASD system, induced by changes in the properties of carriers in a solution medium of varying pH levels.

Cyclodextrin inclusion complex and amorphous solid dispersions as formulation approaches for enhancement of curcumin’s solubility and nasal epithelial membrane permeation

BackgroundCurcumin is a compound that occurs in the rhizomes of the turmeric plant (Curcuma longa) and has shown potential for the treatment of illnesses including certain neurodegenerative diseases. The bioavailability of curcumin is hindered by its extremely poor aqueous solubility.ResultsThis study aimed to apply formulation strategies such as inclusion complex formation with hydroxypropyl-β-cyclodextrin (HPβCD), as well as amorphous solid dispersion (ASD) formation with poly(vinylpyrrolidone-co-vinyl acetate) (PVP VA64) and hydroxypropyl methylcellulose (HPMC) to increase curcumin’s solubility and thereby its nasal epithelial membrane permeation. The curcumin formulations were evaluated by means of DSC, TGA, FT-IR, XRPD, microscopic imaging, aqueous solubility and membrane permeation across nasal respiratory and olfactory epithelial membranes. The solubility of curcumin was substantially increased by the formulations from 8.4 µg/ml for the curcumin raw material to 79.0 µg/ml for the HPβCD inclusion complex, 256.4 µg/ml for the HPMC ASD and 314.9 µg/ml for the PVP VA64 ASD. The HPMC ASD only slightly changed the membrane permeation of curcumin, while the PVP VA64 ASD decreased the membrane permeation of curcumin. The HPβCD inclusion complex enhanced the nasal epithelial membrane permeation of curcumin statistically significantly across the olfactory epithelial tissue and extensively across the respiratory epithelial tissue.ConclusionComplexation of curcumin with HPβCD enhanced the solubility of curcumin and thereby also increased its permeation across excised nasal respiratory and olfactory epithelial tissue. This indicated high potential of the curcumin-HPβCD complex for nose-to-brain delivery of curcumin for treatment of neurodegenerative diseases by means of intranasal administration.Graphical abstract

Exploring the influence of hydrogen bond donor groups on the microstructure and intermolecular interactions of amorphous solid dispersions containing diflunisal structural analogues

Drug-polymer intermolecular interactions, and H-bonds specifically, play an important role in the stabilization process of a compound in an amorphous solid dispersion (ASD). However, it is still difficult to predict whether or not interactions will form and what the strength of those interactions would be, based on the structure of drug and polymer. Therefore, in this study, structural analogues of diflunisal (DIF) were synthesized and incorporated in ASDs with poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) as a stabilizing polymer. The respective DIF derivatives contained different types and numbers of H-bond donor groups, which allowed to assess the influence of these structural differences on the phase behavior and the actual interactions formed in the ASDs. The highest possible drug loading of these derivatives in PVPVA were evaluated through film casting. Subsequently, a lower drug loading of each compound was spray dried. These spray dried ASDs were subjected to an in-depth solid-state nuclear magnetic resonance (ssNMR) study, including 1D spectroscopy and relaxometry, as well as 2D dipolar HETCOR experiments. The drug loading study revealed the highest possible loading of 50 wt% for the native DIF in PVPVA. The methoxy DIF derivative reached the second highest drug loading of 35 wt%, while methylation of the carboxyl group of DIF led to a sharp decrease in the maximum loading, to around 10 wt% only. Unexpectedly, the maximum loading increased again when both the COOH and OH groups of diflunisal were methylated in the dimethyl DIF derivative, to around 30 wt%. The ssNMR study on the spray dried ASD samples confirmed intermolecular H-bonding with PVPVA for native DIF and methoxy DIF. Studies of the proton relaxation decay times and 2D 1H–13C dipolar HETCOR experiments indicated that the ASDs with native DIF and methoxy DIF were homogenously mixed, while the ASDs containing DIF methyl ester and dimethyl DIF were phase separated at the nm level. It was established that, for these systems, the availability of the carboxyl group was imperative in the formation of intermolecular H-bonds with PVPVA and in the generation of homogenously mixed ASDs.

β-Lactoglobulin-based amorphous solid dispersions: A graphical review on the state-of-the-art

Proteins have recently caught attention as potential excipients for amorphous solid dispersions (ASDs) to improve oral bioavailability of poorly water-soluble drugs. Notably, the studies have highlighted whey protein isolates, particularly β-lactoglobulin (BLG), as promising candidates in amorphous stabilization, dissolution and solubility enhancement, achieving drug loadings of 50 wt% and higher. Consequently, investigations into the mechanisms underlying the solid-state stabilization of amorphous drugs and the enhancement of drug solubility in solution have been conducted. This graphical review provides a comprehensive overview of recent findings concerning BLG-based ASDs. Firstly, the dissolution performance of BLG-based ASDs is compared to more traditional polymer-based ASDs. Secondly, the drug loading onto BLG and the resulting amorphous stabilization mechanisms is summarized. Thirdly, interactions between BLG and drug molecules in solution are described as the mechanisms governing the improvement of drug solubility. Lastly, we outline the impact of the spray drying process on the secondary structure of BLG, and the resulting differences in amorphous stabilization and drug dissolution performance between α-helix-rich and β-sheet-rich BLG-based ASDs.

System-agnostic prediction of pharmaceutical excipient miscibility via computing-as-a-service and experimental validation

We applied computing-as-a-service to the unattended system-agnostic miscibility prediction of the pharmaceutical surfactants, Vitamin E TPGS and Tween 80, with Copovidone VA64 polymer at temperature relevant for the pharmaceutical hot melt extrusion process. The computations were performed in lieu of running exhaustive hot melt extrusion experiments to identify surfactant-polymer miscibility limits. The computing scheme involved a massively parallelized architecture for molecular dynamics and free energy perturbation from which binodal, spinodal, and mechanical mixture critical points were detected on molar Gibbs free energy profiles at 180 °C. We established tight agreement between the computed stability (miscibility) limits of 9.0 and 10.0 wt% vs. the experimental 7 and 9 wt% for the Vitamin E TPGS and Tween 80 systems, respectively, and identified different destabilizing mechanisms applicable to each system. This paradigm supports that computational stability prediction may serve as a physically meaningful, resource-efficient, and operationally sensible digital twin to experimental screening tests of pharmaceutical systems. This approach is also relevant to amorphous solid dispersion drug delivery systems, as it can identify critical stability points of active pharmaceutical ingredient/excipient mixtures.

Quantification of Soluplus for Dissolution Tests: SEC Method Development and Validation

The quantification of both polymer and drug during the dissolution of an amorphous solid dispersion (ASD) in aqueous media arouses great interest and may aid in the formulation. However, the available quantification methods for polymer excipients are limited, expensive, and challenging compared to drugs. In this work, a size exclusion chromatography method (HPLC-SEC) was developed and validated to determine the concentration of a frequently used polymer excipient, Soluplus® (Sol). In order to develop a method for the quantification of dissolved Soluplus®, two methods (SEC-UV and SEC-RID) with two injection volumes were tested with standard solutions of three different batches of Soluplus. The developed HPLC-SEC-UV method showed acceptable linearity (R2 > 0.9990) for all batches of Soluplus, good accuracies above a concentration of 0.1 mg/mL (coefficient of variation < 2 %), relatively good precision at a concentration of 0.1 mg/mL (coefficient of variation < 2.5 %), and high recoveries at a concentration of 0.75 mg/mL (coefficient of variation < 0.5 %). The presence of Felodipine (Fel) and Lumefantrine (Lum) in the liquid media did not interfere with Soluplus quantification. The use of various surfactants, such as Tween® 80, Tween® 20, Span® 80, Span® 20, Kolliphor® TPGS, and sodium lauryl sulphate at a low concentration (0.005 mg/mL) did not show any effect on Soluplus® and did not interfere with Soluplus® quantification with any of the Soluplus batches. The addition of lithium bromide (LiBr) to the mobile phase within a concentration range of 0.05–1.0 M did not improve Soluplus® quantification.

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.

Drug Solubility Enhancement Strategies Using Amorphous Solid Dispersion: Examination on Type and The Amount of the Polymer

Drug Solubility Enhancement Strategies Using Amorphous Solid Dispersion: Examination on Type and The Amount of the Polymer

Integrative approach for improved dofetilide solubility using β-cyclodextrin and two its substituted derivatives: Solutions and solid dispersions

The complexation an anti-arrhythmia drug dofetilide (DFT) with β-cyclodextrin (β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD) were studied using two main approaches: phase solubility diagrams and solid dispersions technique. The phase solubility diagrams were constructed in buffer solutions with physiological values рН 2.0 и 7.4. In accordance with the protolytic properties of the drug, the solubilizing effect of cyclodextrins turned out to be more effective in a neutral environment (buffer pH 7.4): the solubility improvement of DFT in the presence of β-CD, HP-β-CD and SBE-β-CD was 3.6, 11.8 and 18.1 times, respectively. In buffer pH 2.0, the tendency for an increase in the solubilizing effect, depending on the chemical nature of the CDs used, is maintained, but the solubility of the drug almost does not grow. The binding constants for the DFT/HP-β-CD and DFT/SBE-β-CD complexes equal to 344 L·mol−1 and 429 L·mol−1 in buffer pH 7.4 indicate the formation of stable inclusion complexes and belong to the optimal range for refinement bioavailability and stability of hydrophobic drugs. Amorphous solid dispersions DFT/β-CD, DFT/HP-β-CD and DFT/SBE-β-CD with stoichiometry 1:1 were obtained by grinding method. The combination FTIR, PXRD, DSC, TGA and SEM methods confirmed the inclusion complexes formation of the drug with cyclodextrins used. Dissolution profiles of solid dispersions DFT/β-CD, DFT/HP-β-CD and DFT/SBE-β-CD were graphing in buffer solutions рН 2.0 and 7.4. Enlargement factor of DFT solubility in the composition of solid dispersions DFT/β-CD, DFT/HP-β-CD and DFT/SBE-β-CD in the neutral medium are 3.4, 4.1 and 5.2, respectively. Whereas the formation of solid inclusion complexes DFT/CDs in an acidic buffer has virtually no effect on the increase in the equilibrium concentration of the active substance in the solution. Findings have demonstrated that the use of SBE-β-CD shows the best solubilization potential for DFT both in solution and as a solid dispersion.

Thermal investigation of relaxations of interacting and non-interacting amorphous solid dispersions

In the present research, thermal investigation of amorphous solid dispersions (ASDs) was performed in order to compare their relaxation transitions. Two different active pharmaceutical ingredients (APIs), namely naproxen (NAP) and spironolactone (SPIR), were used as model drugs and combined with polyvinylpyrrolidone vinyl acetate (PVPVA64) copolymer to form stable ASDs. The reason for the API selection was their different interacting potentials based on the presence (in the case of NAP) and the lack of H-bond donor group (in the case of SPIR). Determination of both Tg and sub-Tg transitions suggested that ASDs containing NAP and PVPVA64 are ‘interacting’ systems with respect to the H-bonding. Besides, temperature-dependent Raman spectroscopic experiments confirmed that the naphthalene ring of the NAP has a significant role in the sub-Tg relaxations. In contrast, SPIR-PVPVA64 systems proved to be ‘non-interacting’ ASDs according to the MDSC, TSDC, and Raman measurements. This study highlights that the combination of the results of different thermoanalytical investigations with spectroscopic methods helps to understand the molecular background of the relaxations in ASDs and thus contributes to the conscious design of stable amorphous pharmaceuticals in the early stage of development.

Effect of Polymer Architecture and Acidic Group Density on the Degree of Salt Formation in Amorphous Solid Dispersions.

Recent work has shown that an amorphous drug-polymer salt can be highly stable against crystallization under hot and humid storage conditions (e.g., 40 °C/75% RH) and provide fast release and that these advantages depend on the degree of salt formation. Here, we investigate the salt formation between the basic drug lumefantrine (LMF) and several acidic polymers: poly(acrylic acid) (PAA), hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), Eudragit L100, and Eudragit L100-55. Salt formation was performed by "slurry synthesis" where dry components were mixed at room temperature in the presence of a small quantity of an organic solvent, which was subsequently removed. This method achieved more complete salt formation than the conventional methods of hot-melt extrusion and rotary evaporation. The acidic group density of a polymer was determined by nonaqueous titration in the same solvent used for slurry synthesis; the degree of LMF protonation was determined by X-ray photoelectron spectroscopy. The polymers studied show very different abilities to protonate LMF when compared at a common drug loading, following the order PAA > (HPMCP ∼ CAP ∼ L100 ∼ L100-55) > HPMCAS, but the difference largely disappears when the degree of protonation is plotted against the concentration of the available acidic groups for reaction. This indicates that the extent of salt formation is mainly controlled by the acidic group density and is less sensitive to the polymer architecture. Our results are relevant for selecting the optimal polymer to control the degree of ionization in amorphous solid dispersions.

Microfluidics-on-a-chip for designing celecoxib-based amorphous solid dispersions: when the process shapes the product

AbstractThe fundamental idea underlying the use of amorphous solid dispersions (ASDs) is to make the most of the solubility advantage of the amorphous form of a drug. However, the drug stability becomes compromised due to the higher free energy and disorder of molecular packing in the amorphous phase, leading to crystallization. Polymers are used as a matrix to form a stable homogeneous amorphous system to overcome the stability concern. The present work aims to design ASD-based formulations under the umbrella of quality by design principles for improving oral drug bioavailability, using celecoxib (CXB) as a model drug. ASDs were prepared from selected polymers and tested both individually and in combinations, using various manufacturing techniques: high-shear homogenization, high-pressure homogenization, microfluidics-on-a-chip, and spray drying. The resulting dispersions were further optimized, resorting to a 32 full-factorial design, considering the drug:polymers ratio and the total solid content as variables. The formulated products were evaluated regarding analytical centrifugation and the influence of the different polymers on the intrinsic dissolution rate of the CXB-ASDs. Microfluidics-on-a-chip led to the amorphous status of the formulation. The in vitro evaluation demonstrated a remarkable 26-fold enhancement in the intrinsic dissolution rate, and the translation of this formulation into tablets as the final dosage form is consistent with the observed performance enhancement. These findings are supported by ex vivo assays, which exhibited a two-fold increase in permeability compared to pure CXB. This study tackles the bioavailability hurdles encountered with diverse active compounds, offering insights into the development of more effective drug delivery platforms. Graphical Abstract

Data-Driven Modeling of the Spray Drying Process. Process Monitoring and Prediction of the Particle Size in Pharmaceutical Production.

Spray drying is used in the pharmaceutical industry for particle engineering of amorphous solid dispersions (ASDs). The particle size of the spray-dried (SD) powders is one of their key attributes due to its impact on the downstream processes and the drug product's functional properties. Offline and inline laser diffraction methods can be used to estimate the product's particle size; however, the final release of these ASDs is based on offline instruments. This paper presents a novel data-driven modeling approach for predicting the particle size of SD products. The model-based characterization of the process and the product's particle size, as a critical quality attribute, follows the quality by design principles. The resulting model can be used for online process monitoring, reducing the risks of out-of-specifications products and supporting their real-time release. A Tucker3 model is trained to capture and factorize the deterministic variability of the process. Subsequently, a partial least-squares regression model is calibrated to model the impact that variability in the input material properties, the process parameters, and the spray nozzle have on the products' particle size. This strategy has been calibrated and validated using large scale production data for two intermediate drug products under high sparsity of particle size data. Despite the challenges, high accuracy was obtained in predicting the median particle size (dv50) for release. The 99% confidence interval results in an error of maximum 2.5 μm, which is less than 10% of the allowed range of variation.

Multivariate Analysis of Solubility Parameters for Drug-Polymer Miscibility Assessment in Preparing Raloxifene Hydrochloride Amorphous Solid Dispersions.

The success of obtaining solid dispersions for solubility improvement invariably depends on the miscibility of the drug and polymeric carriers. This study aimed to categorize and select polymeric carriers via the classical group contribution method using the multivariate analysis of the calculated solubility parameter of RX-HCl. The total, partial, and derivate parameters for RX-HCl were calculated. The data were compared with the results of excipients (N = 36), and a hierarchical clustering analysis was further performed. Solid dispersions of selected polymers in different drug loads were produced using solvent casting and characterized via X-ray diffraction, infrared spectroscopy and scanning electron microscopy. RX-HCl presented a Hansen solubility parameter (HSP) of 23.52 MPa1/2. The exploratory analysis of HSP and relative energy difference (RED) elicited a classification for miscible (n = 11), partially miscible (n = 15), and immiscible (n = 10) combinations. The experimental validation followed by a principal component regression exhibited a significant correlation between the crystallinity reduction and calculated parameters, whereas the spectroscopic evaluation highlighted the hydrogen-bonding contribution towards amorphization. The systematic approach presented a high discrimination ability, contributing to optimal excipient selection for the obtention of solid solutions of RX-HCl.

Generality of Enhancing the Dissolution Rates of Free Acid Amorphous Solid Dispersions by the Incorporation of Sodium Hydroxide.

The incorporation of a counterion into an amorphous solid dispersion (ASD) has been proven to be an attractive strategy to improve the drug dissolution rate. In this work, the generality of enhancing the dissolution rates of free acid ASDs by incorporating sodium hydroxide (NaOH) was studied by surface-area-normalized dissolution. A set of diverse drug molecules, two common polymer carriers (copovidone or PVPVA and hydroxypropyl methylcellulose acetate succinate or HPMCAS), and two sample preparation methods (rotary evaporation and spray drying) were investigated. When PVPVA was used as the polymer carrier for the drugs in this study, enhancements of dissolution rates from 7 to 78 times were observed by the incorporation of NaOH into the ASDs at a 1:1 molar ratio with respect to the drug. The drugs having lower amorphous solubilities showed greater enhancement ratios, providing a promising path to improve the drug release performance from their ASDs. Samples generated by rotary evaporation and spray drying demonstrated comparable dissolution rates and enhancements when NaOH was added, establishing a theoretical foundation to bridge the ASD dissolution performance for samples prepared by different solvent-removal processes. In the comparison of polymer carriers, when HPMCAS was applied in the selected system (indomethacin ASD), a dissolution rate enhancement of 2.7 times by the incorporated NaOH was observed, significantly lower than the enhancement of 53 times from the PVPVA-based ASD. This was attributed to the combination of a lower dissolution rate of HPMCAS and the competition for NaOH between IMC and HPMCAS. By studying the generality of enhancing ASD dissolution rates by the incorporation of counterions, this study provides valuable insights into further improving drug release from ASD formulations of poorly water-soluble drugs.

Synergistic effect of polymers in stabilizing amorphous pretomanid through high drug loaded amorphous solid dispersion.

Pretomanid (PTM), an oral antibiotic used in the treatment of adults with pulmonary extensively drug-resistant, nonresponsive multidrug-resistant tuberculosis (MDR-TB). It is a poor glass former, that shows high recrystallization tendency from the amorphous and supersaturated state, resulting in low aqueous solubility and suboptimal absorption through the gastrointestinal tract. The present investigation aimed to develop high drug loaded ternary amorphous solid dispersions (ASDs) of PTM with improved stability and enhanced biopharmaceutical performance by utilizing a combination of polymers. The polymers were comprehensively screened based on drug-polymer miscibility and saturation solubility analysis. A combination of Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS-HF) and Polyvinylpyrrolidone K-30 (PVP K-30) showed synergism in drug-polymer miscibility as evidenced through pronounced depression in the melting endotherm of PTM. The Powder X-ray Diffraction (P-XRD) diffractograms of 30% w/w PTM loaded ternary ASDs displayed the halo pattern, contrary to the binary ASDs. Drug-polymer interactions (hydrophobic forces) involved between PTM and polymers were detected through Fourier Transform Infrared Spectroscopy (FT-IR) and Nuclear Magnetic Resonance Spectroscopy (13C-NMR) which contributed to the synergistic enhancement in solubility and dissolution of ternary ASDs with sustained release over 12h. Ternary ASDs demonstrated better in-vivo performance compared to the binary ASDs, showing a 4.63-fold increase in maximum plasma concentration. All ASDs remained stable and resisted phase separation during short-term stability studies for 3 months at ambient conditions. It was concluded that the hydrophobic and hydrophilic polymeric combination (HPMCAS-HF and PVP K-30, respectively) effectively prevented the crystallization and ensured sustained drug release with improved in-vivo absorption of PTM.

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

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.