Combining high-throughput ASD screening with the rDCS to streamline development of poorly soluble drugs.

Structural and Dynamic Properties of Amorphous Solid Dispersions: The Role of Solid-State Nuclear Magnetic Resonance Spectroscopy and Relaxometry

Lowering lattice forces of crystalline bases

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.

About 90% of active pharmaceutical ingredients (APIs) in the oral drug delivery system pipeline have poor aqueous solubility and low bioavailability. To address this problem, amorphous solid dispersions (ASDs) embed hydrophobic APIs within polymer excipients to prevent drug crystallization, improve solubility, and increase bioavailability. There are a limited number of commercial polymer excipients, and the structure-function relationships which lead to successful ASD formulations are not well-documented. There are, however, certain solid-state ASD characteristics that inform ASD performance. One characteristic shared by successful ASDs is a high glass transition temperature (Tg), which correlates with higher shelf stability and decreased drug crystallization. We aim to identify how polymer features such as side chain geometry, backbone methylation, and hydrophilic-lipophilic balance impact Tg to design copolymers capable of forming high-Tg ASDs. We tested a library of 50 ASD formulations (18 previously studied and 32 newly synthesized) of the model drug probucol with copolymers synthesized through automated photoinduced electron/energy transfer-reversible addition-fragmentation chain-transfer (PET-RAFT) polymerization. A machine learning (ML) algorithm was trained on the Tg data to identify the major factors influencing Tg, including backbone methylation and nonlinear side chain geometry. In both polymer alone and probucol-loaded ASDs, a Random Forest Regressor captured structure-function trends in the data set and accurately predicted Tg with an average R2 > 0.83 across a 10-fold cross validation. This ML model will be used to predict novel copolymers to design ASDs with high Tg, a crucial factor in predicting ASD success.

This article takes a step forward in understanding the mechanisms involved during the preparation and performance of cross-linked high-drug-loading (HDL) amorphous solid dispersions (ASDs). Specifically, ASDs, having 90 wt % poorly water-soluble drug indomethacin (IND), were prepared via in situ thermal cross-linking of poly(acrylic acid) (PAA) and poly(vinyl alcohol) (PVA) and thoroughly evaluated in terms of physical stability and in vitro supersaturation. Results showed that HDL ASDs having excellent active pharmaceutical ingredient (API) amorphous stability and prolonged in vitro supersaturation were prepared by fine tuning the cross-linking procedure. Unraveling of the processes involved during ASD's formation shed light on the significant role of the cross-linking conditions (i.e., temperature and time), the physicochemical properties of the API, and the hydrolysis level of the cross-linker as key factors in modulating ASD's stability. In-depth analysis of the prepared systems revealed the (1) reduction of API's molecular motions within the cross-linked polymeric networks (through API's strong spatial confinement), (2) the structural changes in the prepared cross-linked matrices (induced by the high API drug loading), and (3) the tuning of the cross-linking density via utilization of low-hydrolyzed PVA as the major mechanisms responsible for ASD's exceptional performance. Complementary analysis by means of molecular dynamics simulations also highlighted the vital role of strong drug-polymer intermolecular interactions evolving among the ASD components. Overall, the impression of the complexity of in situ cross-linked ASDs has been reinforced with the excessive variation of parameters investigated in the current study, offering thus insights up to the submolecular level to lay the groundwork and foundations for the comprehensive assessment of a new emerging class of HDL amorphous API formulations.

One way to increase the slow dissolution rate and the associated low bioavailability of newly developed active pharmaceutical ingredients (APIs) is to dissolve the API in a polymer, leading to a so-called amorphous solid dispersion (ASD). However, APIs are often supersaturated in ASDs and thus tend to crystallize during storage. The kinetics of the crystallization process is determined by the amount of water the ASD absorbs during storage at relative humidity (RH), storage temperature, polymer type, and the drug load of the ASD. Here, the crystallization kinetics and shelf life of spray-dried ASDs were investigated for ASDs consisting of nifedipine (NIF) or celecoxib (CCX) as the APIs and of poly(vinylpyrrolidone-co-vinyl acetate) or hydroxypropyl methylcellulose acetate succinate as polymers. Samples were stored over 2 years at different RHs covering conditions above and below the glass transition of the wet ASDs. Crystallization kinetics and onset time of the crystallization were qualitatively studied by using powder X-ray diffraction and microscopic inspection and were quantitatively determined by using differential scanning calorimetry. It was found that the NIF ASDs crystallize much faster than CCX ASDs at the same drug load and at the same storage conditions due to both higher supersaturation and higher molecular mobility in the NIF ASDs. Experimental data on crystallization kinetics were correlated using the Johnson-Mehl-Avrami-Kolmogorov equation. A detailed thermodynamic and kinetic modeling will be performed in Part 2 of this paper series.

Elucidating the effect of crystallization on drug release from amorphous solid dispersions in soluble and insoluble carriers.

Synergistic approach of salt formation and polymer-mediated stabilization to enhance the biopharmaceutical performance of Mebendazole.

Amorphous solid dispersions (ASDs) are state-of-the-art formulation strategies for improving the solubility and release of poorly water-soluble, small-molecule active pharmaceutical ingredients (APIs). However, high drug loads (DLs) in ASDs can lead to phase-separation phenomena, resulting in eventually incomplete/collapsed API release, classically referred to as loss of release. This study investigates the role of the surfactant d-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS) in mitigating this phenomenon in ASDs composed of ritonavir and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). As part of the investigations, we developed an improved sampling protocol to differentiate between ASD components molecularly dissolved and those released as nano droplets into the aqueous medium. The results showed that the addition of 3 wt % Vitamin E TPGS enhances release ability up to 30 wt % DL, compared to 25 wt % for the surfactant-free ASD. This enhancement is attributed to Vitamin E TPGS's ability to stabilize discrete RIT-rich domains in the ASD during phase separation. However, at 40 wt % DL, even high Vitamin E TPGS concentrations (up to 10 wt %) did not lead to full release of the API. This indicates that the aforementioned stabilization mechanism failed and could be traced back to a change in the phase separation behavior above an upper limit of Vitamin E TPGS concentrations. This study thus provides insights into the complex release mechanisms of high-DL ritonavir ASDs and the critical role of surfactants such as Vitamin E TPGS.

Thermal processing has gained much interest in the pharmaceutical industry, particularly for the enhancement of solubility, bioavailability, and dissolution of active pharmaceutical ingredients (APIs) with poor aqueous solubility. Formulation scientists have developed various techniques which may include physical and chemical modifications to achieve solubility enhancement. One of the most commonly used methods for solubility enhancement is through the use of amorphous solid dispersions (ASDs). Examples of commercialized ASDs include Kaletra®, Kalydeco®, and Onmel®. Various technologies produce ASDs; some of the approaches, such as spray-drying, solvent evaporation, and lyophilization, involve the use of solvents, whereas thermal approaches often do not require solvents. Processes that do not require solvents are usually preferred, as some solvents may induce toxicity due to residual solvents and are often considered to be damaging to the environment. The purpose of this review is to provide an update on recent innovations reported for using hot-melt extrusion and KinetiSol® Dispersing technologies to formulate poorly water-soluble APIs in amorphous solid dispersions. We will address development challenges for poorly water-soluble APIs and how these two processes meet these challenges.

Hydrate formation in polymer-based pharmaceutical formulations

Combining crystalline and polymeric excipients in API solid dispersions – Opportunity or risk?

A Mechanistic Model for Predicting the Physical Stability of Amorphous Solid Dispersions.

Electrospun amorphous solid dispersions of poorly water-soluble drugs: A review

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