Drug-Polymer Nanodroplet Formation and Morphology Drive Solubility Enhancement of GDC-0810.

Nanodroplet formation is important to achieve supersaturation of active pharmaceutical ingredients (APIs) in an amorphous solid dispersion. The aim of the current study was to explore how polymer composition, architecture, molar mass, and surfactant concentration affect polymer-drug nanodroplet morphology with the breast cancer API, GDC-0810. The impact of nanodroplet size and morphology on dissolution efficacy and drug loading capacity was explored using polarized light microscopy, dynamic light scattering, and cryogenic transmission electron microscopy. Poly(N-isopropylacrylamide-stat-N,N-dimethylacrylamide) (PND) was synthesized as two linear derivatives and two bottlebrush derivatives with carboxylated or PEGylated end-groups. Hydroxypropyl methylcellulose acetate succinate grade MF (HPMCAS-MF) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) were included as commercial polymer controls. We report the first copolymerization synthesis of a PVPVA bottlebrush copolymer, which was the highest performing excipient in this study, maintaining 688 µg/mL GDC-0810 concentration at 60 wt % drug loading. This is likely due to strong polymer-drug noncovalent interactions and the compaction of GDC-0810 along the PVPVA bottlebrush backbone. Overall, it was observed that the most effective formulations had a hydrodynamic radius less than 25 nm with tightly compacted nanodroplet morphologies.

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.

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.

Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS 1H Solid-State NMR Spectroscopy.

Active pharmaceutical ingredients (APIs) can be prepared in many different solid forms and phases that affect their physicochemical properties and suitability for oral dosage forms. The development and commercialization of dosage forms require analytical techniques that can determine and quantify the API phase in the final drug product. 13C solid-state NMR (SSNMR) spectroscopy is widely employed to characterize pure and formulated solid APIs; however, 13C SSNMR experiments on dosage forms with low API loading are often challenging due to low sensitivity and interference from excipients. Here, fast magic angle spinning 1H SSNMR experiments are shown to be applicable for the rapid characterization of low drug load formulations. Diagnostic 1H SSNMR spectra of APIs within tablets are obtained by using combinations of frequency-selective saturation and excitation pulses, two-dimensional experiments, and 1H spin diffusion periods. Selective saturation pulses efficiently suppress the broad 1H SSNMR signals from the most commonly encountered excipients such as lactose and cellulose, allowing observation of high-frequency API 1H NMR signals. 1H SSNMR provides a 1-3 orders of magnitude reduction in experiment time compared to standard 13C SSNMR experiments, enabling diagnostic SSNMR spectra of dilute APIs within tablets to be obtained within minutes. The 1H SSNMR spectra can be used for quantification, provided calibrations are performed on a standard sample with known API loading.

Investigation of Phase Mixing in Amorphous Solid Dispersions of AMG 517 in HPMC-AS Using DSC, Solid-State NMR, and Solution Calorimetry.

Intimate phase mixing between the drug and the polymer is considered a prerequisite to achieve good physical stability for amorphous solid dispersions. In this article, spray dried amorphous dispersions (ASDs) of AMG 517 and HPMC-as were studied by differential scanning calorimetry (DSC), solid-state NMR (SSNMR), and solution calorimetry. DSC analysis showed a weakly asymmetric (ΔTg ≈ 13.5) system with a single glass transition for blends of different compositions indicating phase mixing. The Tg-composition data was modeled using the BKCV equation to accommodate the observed negative deviation from ideality. Proton spin-lattice relaxation times in the laboratory and rotating frames ((1)H T1 and T1ρ), as measured by SSNMR, were consistent with the observation that the components of the dispersion were in intimate contact over a 10-20 nm length scale. Based on the heat of mixing calculated from solution calorimetry and the entropy of mixing calculated from the Flory-Huggins theory, the free energy of mixing was calculated. The free energy of mixing was found to be positive for all ASDs, indicating that the drug and polymer are thermodynamically predisposed to phase separation at 25 °C. This suggests that miscibility measured by DSC and SSNMR is achieved kinetically as the result of intimate mixing between drug and polymer during the spray drying process. This kinetic phase mixing is responsible for the physical stability of the ASD.

The effect of unloading and ejection conditions on the properties of pharmaceutical tablets.

This study investigates decompression and ejection conditions on tablet characteristics by comparing compact densities and tensile strengths made using regular rigid dies and custom-built die systems that enable triaxial decompression. Die-wall pressure evolution during decompression and ejection stresses did not meaningfully impact the density and tensile strength of the materials tested: microcrystalline cellulose, crystalline lactose monohydrate, and mannitol. Furthermore, the apparent differences in tensile strength between rectangular cuboids and cylindrical compacts are unrelated to decompression and ejection conditions, but rather a consequence of their shapes and of the test configurations. This suggests that elastic and plastic deformations that may occur during decompression and ejection are not significantly influenced by die-wall pressure evolution. We thus conclude that while triaxial decompression and constraint-free ejection may allow the production of defect-free compacts for materials that otherwise are defect prone using a rigid die, they seem to pose no benefits when the materials already produce defect-free compacts using a rigid die.

Physicochemical and structural insights into lyophilized mRNA-LNP from lyoprotectant and buffer screenings.

The surge in RNA therapeutics has revolutionized treatments for infectious diseases like COVID-19 and shows the potential to expand into other therapeutic areas. However, the typical requirement for ultra-cold storage of mRNA-LNP formulations poses significant logistical challenges for global distribution. Lyophilization serves as a potential strategy to extend mRNA-LNP stability while eliminating the need for ultra-cold supply chain logistics. Although recent advancements have demonstrated the promise of lyophilization, the choice of lyoprotectant is predominately focused on sucrose, and there remains a gap in comprehensive evaluation and comparison of lyoprotectants and buffers. Here, we aim to systematically investigate the impact of a diverse range of excipients including oligosaccharides, polymers, amino acids, and various buffers, on the quality and performance of lyophilized mRNA-LNPs. From the screening of 45 mRNA-LNP formulations under various lyoprotectant and buffer conditions for lyophilization, we identified previously unexplored formulation compositions, e.g., polyvinylpyrrolidone (PVP) in Tris or acetate buffers, as promising alternatives to the commonly used oligosaccharides to maintain the physicochemical stability of lyophilized mRNA-LNPs. Further, we delved into how physicochemical and structural properties influence the functionality of lyophilized mRNA-LNPs. Leveraging high-throughput small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM), we showed that there is complex interplay between mRNA-LNP structural features and cellular translation efficacy. We also assessed innate immune responses of the screened mRNA-LNPs in human peripheral blood mononuclear cells (PBMCs), and showed minimal alterations of cytokine secretion profiles induced by lyophilized formulations. Our results provide valuable insights into the structure-activity relationship of lyophilized formulations of mRNA-LNP therapeutics, paving the way for rational design of these formulations. This work creates a foundation for a comprehensive understanding of mRNA-LNP properties and in vitro performance change resulting from lyophilization.

Pilot-scale binder jet 3D printing of sustained release solid dosage forms.

The additive nature and versatility of 3D printing show great promise in the rapid prototyping of solid dosage forms for clinical trials and mass customization for personalized medicine applications. This paper reports the formulation and process development of sustained release solid dosage forms, termed "printlets", using a pilot-scale binder jetting (BJT) 3D printer and acetaminophen (APAP) as the model drug. With the inclusion of hydroxypropyl methylcellulose (HPMC) as a release retardant polymer in the print powder, the drug release time of APAP increased considerably from minutes to hours. However, given the swelling propensity of HPMC, a thicker layer of powder must be laid down during printing to avoid any shape distortion of the printlets. For a fixed print volume, the level of binder saturation (i.e., ratio between the liquid binder and powder in the as-printed sample) is inversely proportional to the thickness of the spread powder layer. An increase in the spread powder layer inadvertently resulted in a lower level of binder saturation and consequently weaker printlets. By increasing the level of binder saturation with jetting from more print heads, the mechanical strength of printlets containing 18% HPMC was successfully restored. The resultant printlets have a drug release time of 3.5 h and a breaking force of 12.5 kgf that is comparable to the fast-disintegrating printlets containing no HPMC and surpasses manually pressed tablets with the same HPMC content.

Release Mechanisms and Practical Percolation Threshold for Long-acting Biodegradable Implants: An Image to Simulation Study.

The development of long-acting drug formulations requires efficient characterization technique as the designed 6-12 months release duration renders real-time in vitro and in vivo experiments cost and time prohibitive. Using a novel image-based release modeling method, release profiles were predicted from X-Ray Microscopy (XRM) of T0 samples. A validation study with the in vitro release test shows good prediction accuracy of the initial burst release. Through fast T0 image-based release prediction, the impact of formulation and process parameters on burst release rate was investigated. Recognizing the limitations of XRM, correlative imaging with Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) was introduced. A water stress test was designed to directly elucidate the formation of pores through polymer-drug-water interplay. Through an iterative correction method that considers poly(lactic-co-glycolic acid) (PLGA) polymer degradation, good agreement was achieved between release predictions  using FIB-SEM images acquired from T0 samples and in vitro testing data. Furthermore, using image-based release simulations, a practical percolation threshold was identified that has profound influence on the implant performance.  It is proposed as an important critical quality attribute for biodegradable long-acting delivery system, that needs to be investigated and quantified.

Microstructure, Quality, and Release Performance Characterization of Long-Acting Polymer Implant Formulations with X-Ray Microscopy and Quantitative AI Analytics.

Long-acting implants are typically formulated using carrier(s) with specific physical and chemical properties, along with the active pharmaceutical ingredient (API), to achieve the desired daily exposure for the target duration of action. In characterizing such formulations, real-time in-vitro and in-vivo experiments that are typically used to characterize implants are lengthy, costly, and labor intensive as these implants are designed to be long acting. A novel characterization technique, combining high resolution three-dimensional X-Ray microscopy imaging, image-based quantification, and transport simulation, has been employed to provide a mechanistic understanding of formulation and process impact on the microstructures and performance of a polymer-based implant. Artificial intelligence-based image segmentation and image data analytics were used to convert morphological features visualized at high resolution into numerical microstructure models. These digital models were then used to calculate key physical parameters governing drug transport in a polymer matrix, including API uniformity, API domain size, and permeability. This powerful new tool has the potential to advance the mechanistic understanding of the interplay between drug-microstructure and performance and accelerate the therapeutic development long-acting implants.

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.

Impact of Surfactant and Surfactant-Polymer Interaction on Desupersaturation of Clotrimazole.

The impact of surfactants on supersaturation of clotrimazole solutions was systematically evaluated. Four clinically relevant surfactants, sodium dodecyl sulfate, vitamin E TPGS, Tween 80, and docusate sodium were studied. The induction time for nucleation and rate of desupersaturation were determined at a supersaturation ratio of 90% amorphous solubility. Measurement was also performed in the presence of predissolved hydroxypropyl methylcellulose acetate succinate to study the effect of surfactant-polymer interaction on desupersaturation. The 4 surfactants showed varied effects on desupersaturation. From supersaturation maintenance perspective, in the presence of hydroxypropyl methylcellulose acetate succinate, the rank order for the 4 surfactants was found to be: docusate sodium > vitamin E TPGS > sodium dodecyl sulfate > Tween 80. Given the importance of maintaining supersaturation and varied effect of surfactants on nucleation kinetics and desupersaturation rate, a careful examination of active pharmaceutical ingredient, polymer and surfactant interaction on an individual basis is recommended for selecting an appropriate surfactant for use in amorphous solid dispersion formulation.

Comparative Assessment of Miniaturized Screening Approaches for Selection of Polymers for Amorphous Drug Stabilization.

The present work highlights the use of miniaturized approaches to screen and prioritize development of solid dispersions that provide stabilization of the amorphous drug against crystallization and enhanced dissolution over the crystalline form. The approaches evaluated include solvent casting and solvent displacement-based techniques. Four compounds were evaluated with both these screening approaches. A dual-pH dilution method using fasted state simulated gastric fluid and fasted state simulated intestinal fluid as media was used to evaluate solubility enhancement ratio in each well of the screen. The concentration at 15 mins after dilution with fasted state simulated intestinal fluid and super-saturation ratio at the end of the dissolution study is used as 2 descriptors of solubility enhancement. The empirical screening approaches were supplemented with theoretical calculations of solubility enhancement to gauge the best-performing amorphous solid dispersion (ASD). Physical stability of the amorphous systems was also evaluated, where applicable. Lead ASD compositions from the screens were scaled up to verify the predictions. To our knowledge, this is the first report where the 2 most common screening approaches for the development of ASDs are compared head to head. These approaches are rapid, material sparing, and can be adapted to accommodate screening of multiple variables such as polymer type, drug load, and ternary systems simultaneously. The strengths, limitations, and most suitable applications for each of the 2 methods are also discussed.

A rational approach towards development of amorphous solid dispersions: Experimental and computational techniques.

The purpose of this study was to determine the drug-polymer miscibility of GENE-A, a Genentech molecule, and hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), a polymer, using computational and experimental approaches. The Flory-Huggins interaction parameter,χ, was obtained by calculating the solubility parameters for GENE-A and HPMC-AS over the temperature range of 25-100°C to obtain the free energy of mixing at different drug loadings (0-100%) using the Materials Studio modeling and simulation platform (thermodynamic approach). Solid-state nuclear magnetic spectroscopy (ssNMR) was used to measure the proton relaxation times for both drug and polymer at different drug loadings (up to 60%) at RT (kinetic approach). Thermodynamically, the drug and polymer were predicted to show favorable mixing as indicated by a negative Gibbs free energy of mixing from 25 to 100°C. ssNMR showed near identical relaxation times for both drug and polymer in the solid dispersion at RT and 40°C for a period up to 6 months showing phase mixing between the API and polymer on <10nm scale. Orthogonal computational and experimental approaches indicate phase mixing of the system components.

Humidity induced phase transformation of poloxamer 188 and its effect on physical stability of amorphous solid dispersion of AMG 579, a PDE10A inhibitor.

Poloxamer 188, a commonly used emulsifying and solubilizing agent, was found to be the cause of crystallization of an investigational drug, AMG 579, from its amorphous solid dispersion at accelerated storage conditions. Investigation of this physical stability issue included thorough characterization of poloxamer 188 at non-ambient conditions. At 40°C, poloxamer 188 becomes deliquescent above relative humidity of 75%. Upon returning to ambient conditions, the deliquescent poloxamer 188 loses water and re-solidifies. The reversible phase transformation of poloxamer 188 may cause physical and chemical stability issues and this risk should be assessed when selecting it as an excipient for formulation development.

Viscoelastic and mechanical behavior of recombinant protein elastomers.

Recombinant DNA synthesis was employed to produce elastin-mimetic protein triblock copolymers containing chemically distinct midblocks. These materials displayed a broad range of mechanical and viscoelastic responses ranging from plastic to elastic when examined as hydrated gels and films. These properties could be related in a predictable fashion to polymer block size and structure. While these materials could be easily processed into films and gels, electrospinning proved a feasible strategy for creating protein fibers. All told, the range of properties exhibited by this new class of protein triblock copolymer in combination with their easy processability suggests potential utility in a variety of soft prosthetic and tissue engineering applications.

Amorphous solid dispersions: a robust platform to address bioavailability challenges.

Amorphous solid dispersions (ASDs) are being used with increasing frequency for poorly soluble pharmaceutical compounds in development. These systems consist of an amorphous active pharmaceutical ingredient stabilized by a polymer to produce a system with improved physical and solution stability. ASDs are commonly considered as a means of improving the apparent solubility of an active pharmaceutical ingredient. This review will discuss methods of preparation and characterization of ASDs with an emphasis on understanding and predicting stability. Theoretical understanding of supersaturation and predicting in vivo performance will be stressed. Additionally, a summary of preclinical and clinical development efforts will be presented to give the reader an understanding of risks and key pitfalls when developing an ASD.

Alterations in physical cross-linking modulate mechanical properties of two-phase protein polymer networks.

Physically cross-linked protein-based materials possess a number of advantages over their chemically cross-linked counterparts, including ease of processing and the ability to avoid the addition or removal of chemical reagents or unreacted intermediates. The investigations reported herein sought to examine the nature of physical cross-links within two-phase elastin-mimetic protein triblock copolymer networks through an analysis of macroscopic viscoelastic properties. Given the capacity of solution processing conditions, including solvent type and temperature to modulate the microstructure of two-phase protein polymer networks, viscoelastic properties were examined under conditions in which interphase block mixing had been either accentuated or diminished during network formation. Protein networks exhibited strikingly different properties in terms of elastic modulus, hysteresis, residual deformability, and viscosity in response to interdomain mixing. Thus, two-phase protein polymer networks exhibit tunable responses that extend the range of application of these materials to a variety of tissue engineering applications.