Amorphous Solid Dispersion Tablets Research Articles

The impact of diluents on the compaction, dissolution, and physical stability of amorphous solid dispersion tablets

Amorphous solid dispersion (ASD) is an effective approach for enhancing the solubility, dissolution, and bioavailability of poorly water-soluble drugs. However, these metastable forms can transform into more thermodynamically stable but less soluble crystalline forms. Despite this challenge, research on processing ASDs into solid dosage forms, such as tablets, is lacking. This work aims to fill this gap by investigating the impact of common diluents on the tableting behavior, dissolution, and physical stability of ASDs composed of itraconazole and hypromellose acetate succinate. Four widely used diluents found in commercially available ASD tablets were selected for the study: microcrystalline cellulose (MCC), anhydrous lactose, starch, and mannitol. The performance of ASD tablets varied significantly depending on the diluent used. Tablets prepared with MCC exhibited higher mechanical strength than those formulated using other diluents. ASD tablets containing mannitol and lactose revealed a faster release rate than those composed of MCC or starch. Notably, the study highlighted that the physical stability of ASDs within a tablet is not solely dependent on the amount of sorbed water; crystalline diluents like lactose and mannitol were found to facilitate ASD recrystallization within a tablet. In summary, the study underscores the importance of excipient selection, considering factors such as mechanical strength, dissolution rate, and physical stability of ASD tablets. These findings offer valuable insights into the selection of excipients for downstream ASD tablet development, leading to improved manufacturability, physical stability, and the overall quality of ASD drug products.

Comprehensive evaluation of polymer types and ratios in Spray-Dried Dispersions: Compaction, Dissolution, and physical stability

Amorphous solid dispersion (ASD) is a well-established strategy for enhancing the solubility and bioavailability of poorly soluble drugs. A significant portion of ASD products are in tablet form. However, the influence of common polymers and drug loading on the manufacturability of ASD tablets remains underexplored. This study focuses on investigating spray-dried ASDs from a tableting perspective by evaluating their physiochemical and mechanical properties. Itraconazole (ITZ) and indomethacin (IND), at the drug loadings ranging from 10% to 50%, were prepared with two polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidone (PVP), serving as representative systems. Our findings revealed that increasing the drug loading resulted in a decreased surface area in ITZ-HPMCAS, IND-HPMCAS, and IND-PVP ASDs. However, this trend was not observed in ITZ-PVP dispersions, possibly due to the morphological disparities. Compaction results demonstrated that tabletability improved with decreasing drug loadings, except for ITZ-PVP dispersions. A partial least square analysis underscored particle surface area as the key factor influencing the tensile strength of ASD tablets. Additionally, our study disclosed that ITZ-PVP ASDs exhibited the worst release profiles and stability performance. The comprehensive journey from characterizing ASD particles to analyzing their compaction behavior and investigating drug release and physical stability offered profound insights into the attributes crucial for the downstream processing of amorphous pharmaceuticals.

Effects of Additives on the Physical Stability and Dissolution of Polymeric Amorphous Solid Dispersions: a Review.

Polymeric amorphous solid dispersion (ASD) is a popular approach for enhancing the solubility of poorly water-soluble drugs. However, achieving both physical stability and dissolution performance in an ASD prepared with a single polymer can be challenging. Therefore, a secondary excipient can be added. In this paper, we review three classes of additives that can be added internally to ASDs: (i) a second polymer, to form a ternary drug-polymer-polymer ASD, (ii) counterions, to facilitate in situ salt formation, and (iii) surfactants. In an ASD prepared with a combination of polymers, each polymer exerts a unique function, such as a stabilizer in the solid state and a crystallization inhibitor during dissolution. In situ salt formation in ASD usually leads to substantial increases inthe glass transition temperature, contributing to improved physical stability. Surfactants can enhance the wettability of ASD particles, thereby promoting rapid drug release. However, their potential adverse effects on physical stability and dissolution, resulting from enhanced molecular mobility and competitive molecular interaction with the polymer, respectively, warrant careful consideration. Finally, we discuss the impact of magnesium stearate and inorganic salts, excipients added externally upon downstream processing, on the solid-state stability as well as the dissolution of ASD tablets.

Development of an Amorphous Solid Dispersion Formulation for Mitigating Mechanical Instability of Crystalline Form and Improving Bioavailability for Early Phase Clinical Studies.

In this work, an amorphous solid dispersion (ASD) formulation was systematically developed to simultaneously enhance bioavailability and mitigate the mechanical instability risk of the selected crystalline form of a development drug candidate, GDC-0334. The amorphous solubility advantage calculation was applied to understand the solubility enhancement potential by an amorphous formulation for GDC-0334, which showed 2.7 times theoretical amorphous solubility advantage. This agreed reasonably well with the experimental solubility ratio between amorphous GDC-0334 and its crystalline counterpart (∼2 times) in buffers of a wide pH range. Guided by the amorphous solubility advantage, ASD screening was then carried out, focusing on supersaturation maintenance and dissolution performance. It was found that although the type of polymer carrier did not impact ASD performance, the addition of 5% (w/w) sodium dodecyl sulfate (SDS) significantly improved the GDC-0334 ASD dissolution rate. After ASD composition screening, stability studies were conducted on selected ASD powders and their hypothetical tablet formulations. Excellent stability of the selected ASD prototypes with or without tablet excipients was observed. Subsequently, ASD tablets were prepared, followed by in vitro and in vivo evaluations. Similar to the effect of facilitating the dissolution of ASD powders, the added SDS improved the disintegration and dissolution of ASD tablets. Finally, a dog pharmacokinetic study confirmed 1.8 to 2.5-fold enhancement of exposure by the developed ASD tablet over the GDC-0334 crystalline form, consistent with the amorphous solubility advantage of GDC-0334. A workflow of developing an ASD formulation for actual pharmaceutical application was proposed according to the practice of this work, which could provide potential guidance for ASD formulation development in general for other new chemical entities.

Effect of different seed crystals on the supersaturation state of ritonavir tablets prepared by hot-melt extrusion

Hot-melt extrusion (HME) is a technology increasingly common for the commercial production of pharmaceutical amorphous solid dispersions (ASDs), especially for poorly water-soluble active pharmaceutical ingredients (APIs). However, recrystallization of the APIs during dissolution must be prevented to maintain the supersaturation state enabled by ASD. Unfortunately, the amorphous formulation may be contaminated by seed crystals during the HME manufacturing process, which could lead to undesirable crystal growth during the dissolution process. In this study, the dissolution behavior of ritonavir ASD tablets prepared using both Form I and Form II polymorphs was examined, and the effects of different seed crystals on crystal growth rates were investigated. The aim was to understand how the presence of seed crystals can impact the dissolution of ritonavir, and to determine the optimal polymorph and seeding conditions for the production of ASDs. The results showed that both Form I and Form II ritonavir tablets had similar dissolution profiles, which were also similar to the reference listed drug (RLD). However, it was observed that the presence of seed crystals, particularly the metastable Form I seed, led to more precipitation compared to the stable Form II seed in all formulations. The Form I crystals that precipitated from the supersaturated solution were easily dispersed in the solution and could serve as seeds to facilitate crystal growth. On the other hand, Form II crystals tended to grow more slowly and presented as aggregates. The addition of both Form I and Form II seeds could affect their precipitation behaviors, and the amount and form of the seeds had significant effects on the precipitation process of the RLD tablets, as are the tablets prepared with different polymorphs. In conclusion, the study highlights the importance of minimizing the contamination risk of seed crystals during the manufacturing process and selecting the appropriate polymorph for the production of ASDs.

Surface Characterization as a Tool for Identifying the Factors Affecting the Dissolution Rate of Amorphous Solid Dispersion Tablets.

An amorphous solid dispersion (ASD) is a commonly used approach to enhancing the dissolution of poorly aqueous soluble drugs. Selecting the desired polymer and drug loading can be time-consuming. Surface properties, such as surface composition and wetting behavior, are essential factors controlling the dissolution of ASD tablets. Thus, our study aims to use surface characterization to understand the factors that affect the dissolution rate of ASD tablets. In this work, we prepared ASDs with itraconazole and hypromellose acetate succinate (HPMCAS) using spray drying. ASDs were prepared using three grades of HPMCAS and different drug loading levels (10%, 30%, and 50%). We prepared ASD tablets with two porosities. For each tablet, contact angles were measured using the Drop Shape Analyzer; surface free energies, disperse, and polar fractions were calculated based on the contact angles. We conducted near-infrared (NIR) and dissolution measurements of ASD tablets. Principal component analysis (PCA) was carried out to investigate the NIR spectra further. The relative PCA scores were reported with other sample properties. A partial least square (PLS) model using NIR scores, tablets' wetting properties, and dissolution rates revealed that water and buffer contact angles, surface free energy, and polar fraction are the most significant factors attributing to the dissolution rate of ASD tablets. This work understood the interplay between the surface properties and the dissolution rate of ASD tablets. Moreover, surface characterization can be the tool to screen the formulation and compaction process of ASD tablets in early development.

Biopredictive capability assessment of two dissolution/permeation assays, µFLUX™ and PermeaLoop™, using supersaturating formulations of Posaconazole

The majority of new drug entities exhibits poor water solubility and therefore enabling formulations are often needed to ensure sufficient in vivo bioavailability upon oral administration. Several in vitro tools have been proposed for biopredictive screening of such drug formulations to facilitate formulation development. Among these, combined dissolution/permeation (D/P) assays have gained increasing interest in recent years, since they are presumed to better predict the absorption behavior as compared to single-compartment dissolution assays. Moreover, especially for supersaturating formulations, it has been demonstrated that the presence of an absorption sink better mimics the intraluminal supersaturation performance.The present study aimed to investigate the biopredictive abilities of two in vitro D/P setups to predict intestinal supersaturation and systemic absorption of supersaturable systems. Experiments were performed with a µFLUX™ and PermeaLoop™ apparatus, respectively, which differ primarily in their volume-to-area ratios between donor compartment and membrane as well as in the type of biomimetic barrier. A two-stage dissolution protocol was adopted to mimic the transit from acidic stomach to more neutral intestinal fluids using biomimetic media. Three formulations of the weakly basic compound Posaconazole (PCZ), namely an acidified and a neutral suspension and an amorphous solid dispersion (ASD) tablet, were tested.Under the present conditions, and for the specific set of formulations studied here, PermeaLoop™ showed a better biopredictive ability for intestinal supersaturation and systemic absorption for the three formulations than the µFLUX™ D/P setup. Interestingly, minor modifications of the two-stage D/P protocol in terms of medium transfer rates from simulated gastric fluid (SGF) to fasted state simulated intestinal fluid (FaSSIF) had a substantial impact particularly on the permeation of the crystalline PCZ suspension (“acidified suspension”). The ASD tablet was less sensitive to gradual medium changes than the crystalline PCZ suspensions. The current study confirms the usefulness of D/P assays for formulation ranking of weakly basic compounds and supersaturating formulations.

Preliminary investigation of peroxide levels of Plasdone™ copovidones on the purity of atorvastatin calcium amorphous solid dispersions: Impact of plasticizers on hot melt extrusion processability

Trace levels of peroxides in Plasdone™ S630 grades may cause both degradation and corresponding decreases in purity levels of drugs sensitive to oxidation. The present study focused on evaluating the effect of Plasdone™ 630 copovidone grades, namely Plasdone™ S630 (PS630) and Plasdone™ S630 Ultra (PS630U), on the degradation and purity levels of Atorvastatin calcium trihydrate (ACT) amorphous solid dispersions (ASDs) prepared via hot melt extrusion (HME). The influence of plasticizers (Tween 80 and polyethylene glycol 400) on HME processability was studied. Results concluded that extrusion of the binary physical mixture (PM) of drug-polymer (30:70 wt ratio) at 180 °C indicated a high torque value of above 70% of the instrument limit. The extrusion of binary PM in the presence of plasticizers resulted in a decreased torque value (<70%) and processing temperatures of 160 °C, 140 °C, for Tween 80 and PEG 400, respectively. Differential scanning calorimetry and Fourier transform infrared spectroscopy studies of ASDs revealed the formation of an amorphous system with intermolecular interactions between the drug and polymer. The in-vitro dissolution profile of binary and ternary ASDs exhibited a significant increase in dissolution rate (>90% drug release within 30 min) compared to the pure drug (approximately 36% within 30 min). The purity analysis of ACT ASD tablets also exhibited a 0.9%, 0.45%, and 0.2% decrease in purity of ACT for ACT/PS630, ACT/PS630/Tween 80, and ACT/PS630/PEG400 ASDs, respectively, compared to the binary and ternary ASDs containing PS630U polymer. These preliminary study results suggest the enhanced suitability of PS630U over PS630 in developing ASDs for drugs sensitive to oxidation.

Spray-Dried Paracetamol/Polyvinylpyrrolidone Amorphous Solid Dispersions: Part I-Stability of Powders and Tablets.

The formulation of active pharmaceutical ingredients (APIs) in amorphous solid dispersions (ASDs) is a promising approach to improve the bioavailability of poorly soluble compounds. However, problems often arise in the production of tablets from ASDs regarding the compressibility and recrystallization of the API. In the present study, the preparation of spray-dried ASDs of paracetamol (PCM) and four different types of polyvinylpyrrolidone (PVP) and their further processing into tablets were investigated. The influence of PVP type on the glass transition temperature (Tg) and the physical stability of ASD powders were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). ASD powders with 10 to 30% PCM were stable for at least 48 weeks. PCM contents of 40 to 50% led to recrystallization of the amorphous PCM within a few days or weeks. ASD with PVP/vinyl acetate (VA) copolymer (PVP/VA) was the most unstable and tended to recrystallize in PCM polymorphic form II. This formulation was therefore used for tablet studies. The influence of compression force on recrystallization, crushing strength, and drug release was investigated. Even high compression forces did not affect the stability of the ASD. However, the ASD tablets led to slow release of the API.

Efficient development of sorafenib tablets with improved oral bioavailability enabled by coprecipitated amorphous solid dispersion

An amorphous solid dispersion (ASD) of sorafenib (SOR) in hydroxypropyl methylcellulose acetate succinate (HPMC-AS), prepared by coprecipitation, was used to develop an immediate release tablet with improved oral bioavailability. An ASD of 40% drug loading with HPMC-AS (M grade), which exhibited superior physical stability and enhanced dissolution, was selected for tablet development. Systematic characterization of powder properties of the ASD led to the choice of the dry granulation process to overcome poor flowability of the ASD. The designed tablet formulation was evaluated using a material-sparing and expedited approach to optimize compaction conditions for manufacturing ASD tablets with low friability and rapid disintegration. The resulting SOR ASD tablets exhibited approximately 50% higher relative bioavailability in dogs than the marketed SOR tablet product, Nexavar®.

In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets.

Amorphous solid dispersion (ASD) dosage forms can improve the oral bioavailability of poorly water-soluble drugs, enabling the commercialization of new chemical entities and improving the efficacy and patient compliance of existing drugs. However, the development of robust, high-performing ASD dosage forms can be challenging, often requiring multiple formulation iterations, long timelines, and high cost. In a previous study, acalabrutinib/hydroxypropyl methylcellulose acetate succinate (HPMCAS)-H grade ASD tablets were shown to overcome the pH effect of commercially marketed Calquence in beagle dogs. This study describes the streamlined in vitro and in silico approach used to develop those ASD tablets. HPMCAS-H and -M grade polymers provided the longest acalabrutinib supersaturation sustainment in an initial screening study, and HPMCAS-H grade ASDs provided the highest in vitro area under the curve (AUC) in gastric to intestinal transfer dissolution tests at elevated gastric pH. In silico simulations of the HPMCAS-H ASD tablet and Calquence capsule provided good in vivo study prediction accuracy using a bottom–up approach (absolute average fold error of AUC0-inf < 2). This streamlined approach combined an understanding of key drug, polymer, and gastrointestinal properties with in vitro and in silico tools to overcome the acalabrutinib pH effect without the need for reformulation or multiple studies, showing promise for reducing time and costs to develop ASD drug products.

Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs.

Calquence® (crystalline acalabrutinib), a commercially marketed tyrosine kinase inhibitor (TKI), exhibits significantly reduced oral exposure when taken with acid-reducing agents (ARAs) due to the low solubility of the weakly basic drug at elevated gastric pH. These drug–drug interactions (DDIs) negatively impact patient treatment and quality of life due to the strict dosing regimens required. In this study, reduced plasma drug exposure at high gastric pH was overcome using a spray-dried amorphous solid dispersion (ASD) comprising 50% acalabrutinib and 50% hydroxypropyl methylcellulose acetate succinate (HPMCAS, H grade) formulated as an immediate-release (IR) tablet. ASD tablets achieved similar area under the plasma drug concentration–time curve (AUC) at low and high gastric pH and outperformed Calquence capsules 2.4-fold at high gastric pH in beagle dogs. In vitro multicompartment dissolution testing conducted a priori to the in vivo study successfully predicted the improved formulation performance. In addition, ASD tablets were 60% smaller than Calquence capsules and demonstrated good laboratory-scale manufacturability, physical stability, and chemical stability. ASD dosage forms are attractive for improving patient compliance and the efficacy of acalabrutinib and other weakly basic drugs that have pH-dependent absorption.

Assessment of the amorphous solid dispersion erosion behavior following a novel small-scale predictive approach

In general, the erosion rate of copovidone-based amorphous solid dispersions (ASDs) in contact with water diminishes with increasing drug load, causing poor drug release from the final drug product. A new easy-to-use tool with low material- and time-consumption, the microscopic erosion time test (METT), was established to allow prediction of the API-specific drug load threshold between an eroding and a non-eroding ASD. This API-specific drug load value is further described as the drug load dispersibility limit (DDL) and is the highest drug load at which an eroding ASD was still observed. A minor increase of 2.5% in drug load above the DDL already led to a non-eroding ASD and it was subsequently connected to the drug load-associated drop in API in vitro dissolution of ASD tablets and an impeded tablet disintegration. In total, 19 APIs in copovidone-based ASDs were characterized via the METT while a subset of these was investigated in more detail, namely indomethacin, celecoxib, dipyridamole, fenofibrate, naproxen and ritonavir. Furthermore, indomethacin- and celecoxib-containing ASDs with various drug loads were prepared and characterized to link the METT outcome with ASD tablet in vitro dissolution and disintegration performance.

Ternary Amorphous Solid Dispersions Containing a High-Viscosity Polymer and Mesoporous Silica Enhance Dissolution Performance†.

The aim of this study was to evaluate the benefits of a ternary amorphous solid dispersion (ASD) that was designed as an immediate-release tablet with a high drug load (e.g., 40% w/w) to produce heightened maintenance of drug supersaturation during dissolution testing, which will be henceforth referred to as the "maintenance ability". Ternary ASD granules were produced by hot melt extrusion (HME) and were comprised of itraconazole (ITZ) 50%, hypromellose (HPMC) 20%, and mesoporous silica (XDP) 30%, where amorphous ITZ incorporated into HPMC was efficiently absorbed in XDP pores. The ternary ASD granules containing a high-viscosity HPMC (AF4M) produced a significantly heightened maintenance ability of drug supersaturation in neutral pH dissolution media in which crystalline ITZ solubility is below 1 μg/mL. The final tablet formulation contained 80% w/w of the ASD granules (40% w/w ITZ), had an acceptable size, and exhibited both sufficient tablet hardness and disintegration. The dissolution behavior of the ternary ASD tablet exhibited a supersaturation maintenance ability similar to that of the ASD granules. Under neutral conditions, the ternary ASD tablet showed immediate and higher ITZ release compared with the binary ASD tablets, and this phenomenon could be explained by the difference in ITZ/AF4M particle size in the tablet. In high-resolution scanning electron microscopy (SEM), it was observed that ITZ and AF4M in the ternary formulation could easily form nano-sized particles (<1 μm) during the absorption process into/onto XDP pores prepared by HME, which contributed to the immediate ITZ release from the ternary ASD tablet under neutral pH conditions. Therefore, the ternary ASD containing high-viscosity HPMC and mesoporous silica prepared by HME made it possible to design a high ASD content, small-size tablet with an ideal dissolution profile in biorelevant media, and we expect that this technology can be applied for continuous HME ASD manufacturing.

Impact of polymer type, ASD loading and polymer-drug ratio on ASD tablet disintegration and drug release

Amorphous solid dispersion (ASD) has become an attractive strategy to enhance solubility and bioavailability of poorly water-soluble drugs. To facilitate oral administration, ASDs are commonly incorporated into tablets. Disintegration and drug release from ASD tablets are thus critical for achieving the inherent solubility advantage of amorphous drugs. In this work, the impact of polymer type, ASD loading in tablet and polymer-drug ratio in ASD on disintegration and drug release of ASD tablets was systematically studied. Two hydrophilic polymers PVPVA and HPMC and one relatively hydrophobic polymer HPMCAS were evaluated. Dissolution testing was performed, and disintegration time was recorded during dissolution testing. As ASD loading increased, tablet disintegration time increased for all three polymer-based ASD tablets, and this effect was more pronounced for hydrophilic polymer-based ASD tablets. As polymer-drug ratio increased, tablet disintegration time increased for hydrophilic polymer-based ASD tablets, however, it remained short and largely unchanged for HPMCAS-based ASD tablets. Consequently, at high ASD loadings or high polymer-drug ratios, HPMCAS-based ASD tablets showed faster drug release than PVPVA- or HPMC-based ASD tablets. These results were attributed to the differences between polymer hydrophilicities and viscosities of polymer aqueous solutions. This work is valuable for understanding the disintegration and drug release of ASD tablets and provides insight to ASD composition selection from downstream tablet formulation perspective.

Microwave induced dielectric heating for the on-demand development of indomethacin amorphous solid dispersion tablets

The poor aqueous solubility of drugs challenges their pharmaceutical development and oral bioavailability. At present, the development of dosage forms with poorly water-soluble active pharmaceutical ingredients (APIs) by means of amorphous solid dispersions (ASDs) approach has been an active area of research. Meanwhile, dielectric heating, a process in which a radio frequency (RF), radio wave or microwave electromagnetic radiation heats materials with dielectric properties, has been applied in the food industry and synthetic organic chemistry for many years. In this work, tablets of indomethacin (IND) ASDs with various polymer matrices were successfully obtained utilizing a novel dielectric heating method on-demand. A series of solid-state analyses, including differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), and polarized light microscopy (PLM) were used for examining drug/polymer miscibility, drug crystallinity and to determine the thermal stability of IND/polymer compositions. In addition, the comparative studies between the amorphous tablets and conventional directly compressed (DC) tablets exhibited higher hardness/compaction results for ASDs tablets (for Soluplus®, HPC HF), but smaller values for the other polymers (HPMC, HPMCAS, E PO, and P EO). The amorphous IND tablets showed improved drug release performance because the polymer matrix stabilized the solution that can maintain a thermodynamic environment for IND. An advanced release mechanism and kinetics study revealed that all ASD tablets exhibited mostly a Fickian diffusion. In contrast, non-cellulose polymer matrices showed swelling, erosion, or both swelling and erosion-controlled drug release. In summary, dielectric heating techniques offer a simple way to manufacture amorphous drug products and presents an alternative solution to the patient to optimize their treatment with conventional dosages.

Novel High-Drug-Loaded Amorphous Dispersion Tablets of Posaconazole; In Vivo and In Vitro Assessment.

Amorphous solid dispersions (ASDs) can increase the bioavailability of drugs with poor aqueous solubility. However, concentration-sustaining dispersion polymers (CSPs) incorporated in ASDs can result in low drug loading and, therefore, a large dosage-form size or multiple units to meet dose requirements, potentially decreasing patient compliance. To address this challenge, a high-loaded dosage-form (HLDF) architecture for ASDs was developed, in which a drug is first spray-dried with a high glass-transition temperature (Tg) dispersion polymer to facilitate high drug loading while maintaining physical stability. The ASD is then granulated with a CSP designed to extend supersaturation in solution. The HLDF differs from traditional ASD architectures in which the dispersion polymer inside the ASD acts as the CSP. By strategically combining two different polymers, one "inside" and one "outside" the ASD, solubilization performance, physical stability, and overall drug loading are maximized. This study demonstrates in vivo performance of the HLDF architecture using posaconazole as a model drug. Two sizes of HLDF tablets were tested in beagle dogs, along with traditional ASD architecture (benchmark) tablets, ASD tablets without a CSP, and a commercial crystalline oral suspension (Noxafil OS). HLDF tablets performed equivalently to the benchmark tablets, the smaller HLDF tablet being 40% smaller (by mass) than the benchmark tablet. The HLDF tablets doubled the blood plasma AUC relative to Noxafil OS. In line with the in vivo outcome, in vitro results in a multicompartment dissolution apparatus demonstrated similar area under the curve (AUC) values in the intestinal compartment for ASD tablets. However, the in vitro data underpredicted the relative in vivo AUC of Noxafil OS compared to the ASD tablets. This study demonstrated that the HLDF approach can increase drug loadings while achieving good performance for ASD drug products.

Physicochemical Properties of Poly-Vinyl Polymers and Their Influence on Ketoprofen Amorphous Solid Dispersion Performance: A Polymer Selection Case Study.

When developing an amorphous solid dispersion (ASD), a prudent choice of polymer is critical to several aspects of ASD performance including: processability, solid state stability and dissolution rate. However, there is little guidance available to formulators to aid judicious polymer selection and a “trial and error” approach is often taken. This study aims to facilitate rational polymer selection and formulation design by generating ASDs using a range of poly-vinyl polymers and ketoprofen as a model active pharmaceutical ingredient (API) and evaluating several aspects of their performance. The molecular weight of the polymer and the ratio of vinyl pyrrolidone to vinyl acetate in the polymer were found to influence the relative humidity at which the relative humidity induced glass transition occurred, as well as the extent of ketoprofen supersaturation achieved during dynamic solubility testing. Interestingly, ASD tablets containing polymers with the vinyl pyrrolidone functional group exhibited higher tensile strengths than those without. This points towards the binder functionality of vinyl pyrrolidone. In conclusion, the physicochemical properties of poly-vinyl polymers greatly influence ketoprofen ASD performance and due regard should be paid to these properties in order to develop an ASD with the desired attributes.

Congruent Release of Drug and Polymer from Amorphous Solid Dispersions: Insights into the Role of Drug-Polymer Hydrogen Bonding, Surface Crystallization, and Glass Transition.

Drug loading is an important parameter known to impact the release rate of a poorly soluble drug from an amorphous solid dispersion (ASD). Recent studies have shown that small increases in drug loading can dramatically reduce the drug release rate from ASDs prepared with poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). However, the link between drug physicochemical properties and the drug loading where the release is abruptly compromised is not well understood. This study probes the role of different factors on the relative dissolution rates of drug and polymer from PVPVA-based ASDs as a function of drug loading: (1) the impact of drug-polymer hydrogen bonding interactions on the initial dissolution rate of ASDs, investigated using two structural analogues, indomethacin (IND) and indomethacin methyl ester (INDester), (2) the influence of surface drug crystallization, observed for INDester ASDs, and (3) by changing temperature, the impact of the "wet" glass transition temperature (Tg). Scanning electron microscopy (SEM), with or without energy dispersive X-ray (EDX) analysis, Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffraction (PXRD) were utilized to study the solid-state phase behavior and/or drug enrichment on the partially dissolved ASD tablet surfaces. Nanoparticle tracking analysis (NTA) was utilized to study the solution-state phase behavior. It was found that, contrary to expectations, ASDs with drug-polymer hydrogen bonding exhibited poorer initial release at moderate drug loadings (15-25%) as compared to the non-hydrogen bonding analogue ASDs. Surface crystallization led to the deterioration of dissolution performance. Lastly, Tg relative to experimental temperatures also appeared to play a role in the observed dissolution behavior as a function of drug loading. These findings shed light on potential mechanisms governing ASD dissolution performance and will aid in the development of optimized ASD formulations with enhanced dissolution performance.

Congruent release of drug and polymer: A “sweet spot” in the dissolution of amorphous solid dispersions

Liquid-liquid phase separation (LLPS) occurs following amorphous solid dispersion (ASD) dissolution when the drug concentration exceeds the “amorphous solubility”, and is emerging as an important characteristic of formulations that may enhance the oral bioavailability of poorly soluble drugs. The purpose of this research was to identify criteria that impact the rate and extent of drug release and hence the occurrence or not of LLPS upon ASD dissolution. Specifically, the effect of drug log P, phase behavior of the hydrated but undissolved ASD matrix and the relative dissolution rates of drug and polymer were studied as a function of drug loading, using nilvadipine (Nil) (ClogP = 3.04) and cilnidipine (Cil) (ClogP = 5.54) as model drugs. The model polymer was poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA). Nil-PVPVA and Cil-PVPVA ASDs with different drug loadings were prepared. Surface area normalized dissolution rates of both the drug and the polymer from ASD tablets were studied. At a similar and relatively low drug loading (<20% w/w drug), dissolution of both Nil-PVPVA and Cil-PVPVA ASDs was found to switch from rapid, congruent (i.e., simultaneous) release of drug and polymer to incongruent release with slow release of drug. Only ASDs showing congruent release underwent LLPS, with the formation of amorphous drug-rich aggregates (~300nm). Scanning electron microscopy (SEM) and micro-computed tomography (micro-CT) showed the presence of characteristic “pits” on the surface of partially dissolved, incongruently releasing ASD tablets. These most likely arise due to faster polymer release in comparison to drug, whereby the drug-rich composition around these pits was confirmed by energy-dispersive X-ray (EDX) analysis and the surface drug enrichment on the compacts was confirmed by X-ray photoelectron spectroscopy (XPS). This study demonstrates two important findings, firstly, a link between congruent release of drug and polymer and the occurrence of LLPS and secondly, the switch between congruent and incongruent release of drug and polymer is a result of competitive kinetics between phase separation and the release rate of ASD components with minimal influence from drug hydrophobicity for two structural analogues.