Threading the needle: Achieving simplicity and performance in cellulose alkanoate ω-carboxyalkanoates for amorphous solid dispersion.

Most active pharmaceutical ingredients (APIs) suffer from poor water solubility, often keeping them from reaching patients. To overcome the issues of poor drug solubility and subsequent low bioavailability, amorphous solid dispersions (ASDs) have garnered much attention. Cellulose ester derivatives are of interest for ASD applications as they are benign, sustainable-based, and successful in commercial drug delivery systems, e.g. in osmotic pump systems and as commercial ASD polymers. Synthesis of carboxy-pendant cellulose esters is a challenge, due in part to competing reactions between carboxyls and hydroxyls, forming ester crosslinks. Herein we demonstrate proof-of-concept for a scalable synthetic route to simple, yet highly promising ASD polymers by esterifying cellulose polymers through ring-opening of cyclic succinic or glutaric anhydride. We describe the complexity of such ring-opening reactions, not previously well-described, and report ways to avoid gelation. We report synthesis, characterization, and preliminary in vitro ASD evaluations of fifteen such derivatives. Synthetic routes were designed to accommodate these criteria: no protecting groups, no metal catalysts, mild conditions with standard reagents, simple purification, and one-pot synthesis. Finally, these designed ASD polymers included members that maintained fast-crystallizing felodipine in solution and release it from an ASD at rather high 20 % drug loading (DL).

Dissolution Mechanisms of Amorphous Solid Dispersions: Application of Ternary Phase Diagrams To Explain Release Behavior.

The use of amorphous solid dispersions (ASDs) in commercial drug products has increased in recent years due to the large number of poorly soluble drugs in the pharmaceutical pipeline. However, the release behavior of ASDs is complex and remains not well understood. Often, the drug release from ASDs is rapid and complete at lower drug loadings (DLs) but becomes slow and incomplete at higher DLs. The DL where release becomes hindered is termed the limit of congruency (LoC). Currently, there are no approaches to predict the LoC. However, recent findings show that one potential cause leading to the LoC is a change in phase morphology after water-induced phase separation at the ASD/solution interface. In this study, the phase behavior of ASDs in contact with aqueous solutions was described thermodynamically by constructing experimental and computational ternary phase diagrams, and these were used to predict morphology changes and ultimately the LoC. Experimental ternary phase diagrams were obtained by equilibrating ASD/water mixtures over time. Computational ternary phase diagrams were obtained by Perturbed Chain Statistical Associating Fluid Theory (PC-SAFT). The morphology of the hydrophobic phase was studied with fluorescence confocal microscopy. It was demonstrated that critical point (plait point) composition approximately corresponded to the ASD DL, where the hydrophobic phase, formed during phase separation, became interconnected and hindered ASD release. This work provides mechanistic insights into the ASD release behavior and highlights the potential of in silico ASD design using phase diagrams.

Interplay of Drug-Polymer Interactions and Release Performance for HPMCAS-Based Amorphous Solid Dispersions.

The interplay between drug and polymer chemistry and its impact on drug release from an amorphous solid dispersion (ASD) is a relatively underexplored area. Herein, the release rates of several drugs of diverse chemistry from hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based ASDs were explored using surface area normalized dissolution. The tendency of the drug to form an insoluble complex with HPMCAS was determined through coprecipitation experiments. The role of pH and the extent of drug ionization were probed to evaluate the role of electrostatic interactions in complex formation. Relationships between the extent of complexation and the drug release rate from an ASD were observed, whereby the drugs could be divided into two groups. Drugs with a low extent of insoluble complex formation with HPMCAS tended to be neutral or anionic and showed reasonable release at pH 6.8 even at higher drug loadings. Cationic drugs formed insoluble complexes with HPMCAS and showed poor release when formulated as an ASD. Thus, and somewhat counterintuitively, a weakly basic drug showed a reduced release rate from an ASD at a bulk solution pH where it was ionized, relative to when unionized. The opposite trend was observed in the absence of polymer for the neat amorphous drug. In conclusion, electrostatic interactions between HPMCAS and lipophilic cationic drugs led to insoluble complex formation, which in turn resulted in ASDs with poor release performance.

Reductive amination of oxidized hydroxypropyl cellulose with ω-aminoalkanoic acids as an efficient route to zwitterionic derivatives.

Zwitterionic polymers, with their equal amounts of cationic and anionic functional groups, have found widespread utility including as non-fouling coatings, hydrogel materials, stabilizers, antifreeze materials, and drug carriers. Polysaccharide-derived zwitterionic polymers are attractive because of their sustainable origin, potential for lower toxicity, and possible biodegradability, but previous methods for synthesis of zwitterionic polysaccharide derivatives have been limited in terms of flexibility and attainable degree of substitution (DS) of charged entities. We report herein successful design and synthesis of zwitterionic polysaccharide derivatives, in this case based on cellulose, by reductive amination of oxidized 2-hydroxypropyl cellulose (Ox-HPC) with ω-aminoalkanoic acids. Reductive amination products could be readily obtained with DS(cation) (= DS(anion)) up to 1.6. Adduct hydrophilic/hydrophobic balance (amphiphilicity) can be influenced by selecting the appropriate chain length of the ω-aminoalkanoic acid. This strategy is shown to produce a range of amphiphilic, water-soluble, moderately high glass transition temperature (Tg) polysaccharide derivatives in just a couple of efficient steps from commercially available building blocks. The adducts were evaluated as crystallization inhibitors. They are strong inhibitors of crystallization even for the challenging, poorly soluble, fast-crystallizing prostate cancer drug enzalutamide, as supported by surface tension and Flory-Huggins interaction parameter results.

Drug Dissolution in Oral Drug Absorption: Workshop Report.

The in-person workshop "Drug Dissolution in Oral Drug Absorption" was held on May 23-24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk. Topics that repeatedly surfaced across breakout sessions were the following: (1) meaning and assessment of "dissolved drug," particularly of poorly water soluble drug in colloidal environments (e.g., fed conditions, ASDs); (2) potential limitations of a test that employs sink conditions for a poorly water soluble drug; (3) non-compendial methods (e.g., two-stage or multi-stage method, dissolution/permeation methods); (4) non-compendial conditions (e.g., apex vessels, non-sink conditions); and (5) potential benefit of having both a quality control method for batch release and a biopredictive/biorelevant method for biowaiver or bridging scenarios. An identified obstacle to non-compendial methods is the uncertainty of global regulatory acceptance of such methods.

Does Media Choice Matter When Evaluating the Performance of Hydroxypropyl Methylcellulose Acetate Succinate-Based Amorphous Solid Dispersions?

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is a weakly acidic polymer that is widely used in the formulation of amorphous solid dispersions (ASDs). While the pH-dependent solubility of HPMCAS is widely recognized, the role of other solution properties, including buffer capacity, is less well understood in the context of ASD dissolution. The goal of this study was to elucidate the rate-limiting steps for drug and HPMCAS release from ASDs formulated with two poorly water soluble model drugs, indomethacin and indomethacin methyl ester. The surface area normalized release rate of the drug and/or polymer in a variety of media was determined. The HPMCAS gel layer apparent pH was determined by incorporating pH sensitive dyes into the polymer matrix. Water uptake extent and rate into the ASDs were measured gravimetrically. For neat HPMCAS, the rate-limiting step for polymer dissolution was observed to be the polymer solubility at the polymer-solution interface. This, in turn, was impacted by the gel layer pH which was found to be substantially lower than the bulk solution pH, varying with medium buffer capacity. For the ASDs, the HPMCAS release rate was found to control the drug release rate. However, both drugs reduced the polymer release rate with indomethacin methyl ester having a larger impact. In low buffer capacity media, the presence of the drug had less impact on release rates when compared to observations in higher strength buffers, suggesting changes in the rate-limiting steps for HPMCAS dissolution. The observations made in this study can contribute to the fundamental understanding of acidic polymer dissolution in the presence and absence of a molecularly dispersed lipophilic drug and will help aid in the design of more in vivo relevant release testing experiments.

Crystallinity: A Complex Critical Quality Attribute of Amorphous Solid Dispersions.

Does the performance of an amorphous solid dispersion rely on having 100% amorphous content? What specifications are appropriate for crystalline content within an amorphous solid dispersion (ASD) drug product? In this Perspective, the origin and significance of crystallinity within amorphous solid dispersions will be considered. Crystallinity can be found within an ASD from one of two pathways: (1) incomplete amorphization, or (2) crystal creation (nucleation and crystal growth). While nucleation and crystal growth is the more commonly considered pathway, where crystals originate as a physical stability failure upon accelerated or prolonged storage, manufacturing-based origins of crystallinity are possible as well. Detecting trace levels of crystallinity is a significant analytical challenge, and orthogonal methods should be employed to develop a holistic assessment of sample properties. Probing the impact of crystallinity on release performance which may translate to meaningful clinical significance is inherently challenging, requiring optimization of dissolution test variables to address the complexity of ASD formulations, in terms of drug physicochemical properties (e.g., crystallization tendency), level of crystallinity, crystal reference material selection, and formulation characteristics. The complexity of risk presented by crystallinity to product performance will be illuminated through several case studies, highlighting that a one-size-fits-all approach cannot be used to set specification limits, as the risk of crystallinity can vary widely based on a multitude of factors. Risk assessment considerations surrounding drug physicochemical properties, formulation fundamentals, physical stability, dissolution, and crystal micromeritic properties will be discussed.

Kinetic Barriers to Disproportionation of Salts of Weakly Basic Drugs.

Disproportionation is a major issue in formulations containing salts of weakly basic drugs. Despite considerable interest in risk assessment approaches for disproportionation, the prediction of salt-to-base conversion remains challenging. Recent studies have highlighted several confounding factors other than pHmax that appear to play an important role in salt disproportionation and have suggested that kinetic barriers need to be considered in addition to the thermodynamic driving force when assessing the risk of a salt to undergo conversion to parent free base. Herein, we describe the concurrent application of in situ Raman spectroscopy and pH monitoring to investigate the disproportionation kinetics of three model salts, pioglitazone hydrochloride, sorafenib tosylate, and atazanavir sulfate, in aqueous slurries. We found that even for favorable thermodynamic conditions (i.e., pH ≫ pHmax), disproportionation kinetics of the salts were very different despite each system having a similar pHmax. The importance of free base nucleation kinetics was highlighted by the observation that the disproportionation conversion time in the slurries showed the same trend as the free base nucleation induction time. Pioglitazone hydrochloride, with a free base induction time of <1 min, rapidly converted to the free base in slurry experiments. In contrast, atazanavir sulfate, where the free base induction time was much longer, took several hours to undergo disproportionation in the slurry for pH ≫ pHmax. Additionally, we altered an established thermodynamically based modeling framework to account for kinetic effects (representing the nucleation kinetic barrier) to estimate the solid-state stability of salt formulations. In conclusion, a solution-based thermodynamic model is mechanistically appropriate to predict salt disproportionation in a solid-state formulation, when kinetic barriers are also taken into consideration.

Enteric coating of tablets containing an amorphous solid dispersion of an enteric polymer and a weakly basic drug: A strategy to enhance in vitro release.

Recent work has highlighted that amorphous solid dispersions (ASDs) containing delamanid (DLM) and an enteric polymer, hypromellose phthalate (HPMCP), appear to be susceptible to crystallization during immersion in simulated gastric fluids. The goal of this study was to minimize contact of the ASD particles with the acidic media via application of an enteric coating to tablets containing the ASD intermediate, and improve the subsequent drug release at higher pH conditions. DLM ASDs were prepared with HPMCP and formulated into a tablet that was then coated with a methacrylic acid copolymer. Drug release was studied in vitro using a two-stage dissolution test where the pH of the gastric compartment was altered to reflect physiological variations. The medium was subsequently switched to simulated intestinal fluid. The gastric resistance time of the enteric coating was probed over the pH range of 1.6-5.0. The enteric coating was found to be effective at protecting the drug against crystallization in pH conditions where HPMCP was insoluble. Consequently, the variability in drug release following gastric immersion under pH conditions reflecting different prandial states was notably reduced when compared to the reference product. These findings support closer examination of the potential for drug crystallization from ASDs in the gastric environment where acid-insoluble polymers may be less effective as crystallization inhibitors. Further, addition of a protective enteric coating appears to provide a promising remediation strategy to prevent crystallization at low pH environments, and may mitigate variability associated with prandial state that arises due to pH changes.

Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer.

Weakly acid polymers with pH-responsive solubility are being used with increasing frequency in amorphous solid dispersion (ASD) formulations of drugs with low aqueous solubility. However, drug release and crystallization in a pH environment where the polymer is insoluble are not well understood. The aim of the current study was to develop ASD formulations optimized for release and supersaturation longevity of a rapidly crystallizing drug, pretomanid (PTM), and to evaluate a subset of these formulations in vivo. Following screening of several polymers for their ability to inhibit crystallization, hypromellose acetate succinate HF grade (HPMCAS-HF; HF) was selected to prepare PTM ASDs. In vitro release studies were conducted in simulated fasted- and fed-state media. Drug crystallization in ASDs following exposure to dissolution media was evaluated by powder X-ray diffraction, scanning electron microscopy, and polarized light microscopy. In vivo oral pharmacokinetic evaluation was conducted in male cynomolgus monkeys (n = 4) given 30 mg PTM under both fasted and fed conditions in a crossover design. Three HPMCAS-based ASDs of PTM were selected for fasted-state animal studies based on their in vitro release performance. Enhanced bioavailability was observed for each of these formulations relative to the reference product that contained crystalline drug. The 20% drug loading PTM-HF ASD gave the best performance in the fasted state, with subsequent dosing in the fed state. Interestingly, while food improved drug absorption of the crystalline reference product, the exposure of the ASD formulation was negatively impacted. The failure of the HPMCAS-HF ASD to enhance absorption in the fed state was hypothesized to result from poor release in the reduced pH intestinal environment resulting from the fed state. In vitro experiments confirmed a reduced release rate under lower pH conditions, which was attributed to reduced polymer solubility and an enhanced crystallization tendency of the drug. These findings emphasize the limitations of in vitro assessment of ASD performance using standardized media conditions. Future studies are needed for improved understanding of food effects on ASD release and how this variability can be captured by in vitro testing methodologies for better prediction of in vivo outcomes, in particular for ASDs formulated with enteric polymers.

Drug Release from Surfactant-Containing Amorphous Solid Dispersions: Mechanism and Role of Surfactant in Release Enhancement.

PURPOSE: To understand how surfactants affect drug release from ternary amorphous solid dispersions (ASDs), and to investigate different mechanisms of release enhancement. METHODS: Ternary ASDs containing ritonavir (RTV), polyvinylpyrrolidone/vinyl acetate (PVPVA) and a surfactant (sodium dodecyl sulfate (SDS), Tween 80, Span 20 or Span 85) were prepared with rotary evaporation. Release profiles of ternary ASDs were measured with surface normalized dissolution. Phase separation morphologies of ASD compacts during hydration/dissolution were examined in real-time with a newly developed confocal fluorescence microscopy method. The water ingress rate of different formulations was measured with dynamic vapor sorption. Microscopy was employed to check for matrix crystallization during release studies. RESULTS: All surfactants improved drug release at 30% DL, while only SDS and Tween 80 improved drug release at higher DLs, although SDS promoted matrix crystallization. The dissolution rate of neat polymer increased when SDS and Tween 80 were present. The water ingress rate also increased in the presence of all surfactants. Surfactant-incorporation affected both the kinetic and thermodynamics factors governing phase separation of RTV-PVPVA-water system, modifying the phase morphology during ASD dissolution. Importantly, SDS increased the miscibility of RTV-PVPVA-water system, whereas other surfactants mainly affected the phase separation kinetics/drug-rich barrier persistence. CONCLUSION: Incorporation of surfactants enhanced drug release from RTV-PVPVA ASDs compared to the binary system. Increased drug-polymer-water miscibility and disruption of the drug-rich barrier at the gel-solvent interface via plasticization are highlighted as two key mechanisms underlying surfactant impacts based on direct visualization of the phase separation process upon hydration and release.

Release Enhancement by Plasticizer Inclusion for Amorphous Solid Dispersions Containing High Tg Drugs.

PURPOSE: Plasticizers are commonly used in the preparation of amorphous solid dispersions (ASDs) with the main goal of aiding processability; however, to the best of our knowledge, the impact of plasticizers on drug release has not been explored. The goal of this study was to evaluate diverse plasticizers, including glycerol and citrate derivatives, as additives to increase the drug loading where good drug release could be achieved from copovidone (PVPVA)-based dispersions, focusing on high glass transition (Tg) drugs, atazanavir (ATZ) and ledipasvir (LED). METHODS: ASDs were prepared using the high Tg compounds, atazanavir (ATZ) and ledipasvir (LED), as model drugs. Release was evaluated using surface normalized dissolution testing. Differential scanning calorimetry was used to measure glass transition temperature and water vapor sorption was performed on select samples. RESULTS: The presence of a plasticizer at 5% w/w for ATZ and 10% w/w for LED ASDs, led to improved drug release. For ATZ ASDs, in the absence of plasticizer, release was very poor at drug loadings of 10% w/w and above. Good release was obtained for plasticized ASDs up to a drug loading of 25%. The corresponding improvement for LED was from 5 to 20% DL. Interestingly, for a low Tg compound, ritonavir, relatively smaller improvements in release as a function of drug loading were achieved through plasticizer incorporation. CONCLUSIONS: The use of plasticizers represents a potential new strategy to increase drug loading in ASDs for high Tg compounds with a low tendency to crystallize and may help improve a major limitation of ASD formulations, namely the high excipient burden.

Dissolution Mechanisms of Amorphous Solid Dispersions: A Close Look at the Dissolution Interface.

Despite the recent success of amorphous solid dispersions (ASDs) at enabling the delivery of poorly soluble small molecule drugs, ASD-based dosage forms are limited by low drug loading. This is partially due to a sharp decline in drug release from the ASD at drug loadings surpassing the 'limit of congruency' (LoC). In some cases, the LoC is as low as 5% drug loading, significantly increasing the risk of pill burden. Despite efforts to understand the mechanism responsible for the LoC, a clear picture of the molecular processes occurring at the ASD/solution interface remains elusive. In this study, the ASD/solution interface was studied for two model compounds formulated as ASDs with copovidone. The evolution of a gel layer and its phase behavior was captured in situ with fluorescence confocal microscopy, where fluorescent probes were added to label the hydrophobic and hydrophilic phases. Phase separation was detected in the gel layer for most of the ASDs. The morphology of the hydrophobic phase was found to correlate with the release behavior, where a discrete phase resulted in good release and a continuous phase formed a barrier leading to poor release. The continuous phase formed at a lower drug loading for the system with stronger drug-polymer interactions. This was due to incorporation of the polymer into the hydrophobic phase. The study highlights the complex molecular and phase behavior at the ASD/solution interface of copovidone-based ASDs and provides a thermodynamic argument for qualitatively predicting the release behavior based on drug-polymer interactions.

Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers.

Enteric polymers are widely used in amorphous solid dispersion (ASD) formulations. The aim of the current study was to explore ASD failure mechanisms across a wide range of pH conditions that mimic in vivo gastric compartment variations where enteric polymers such as hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) are largely insoluble. Delamanid (DLM), a weakly basic drug used to treat tuberculosis, was selected as the model compound. Both DLM free base and the edisylate salt were formulated with HPMCP, while DLM edisylate ASDs were also prepared with different grades of HPMCAS. Two-stage release testing was conducted with the gastric stage pH varied between pH 1.6 and 5.0, prior to transfer to intestinal conditions of pH 6.5. ASD particles were collected following suspension in the gastric compartment and evaluated using X-ray powder diffraction and scanning electron microscopy. Additional samples were also evaluated with polarized light microscopy. In general, ASDs with HPMCP showed improved overall release for all testing conditions, relative to ASDs with HPMCAS. ASDs with the edisylate salt likewise outperformed those with DLM free base. Impaired release for certain formulations at intestinal pH conditions was attributed to surface drug crystallization that initiated during suspension in the gastric compartment where the polymer is insoluble; crystallization appeared more extensive for HPMCAS ASDs. These findings suggest that gastric pH variations should be evaluated for ASD formulations containing weakly basic drugs and enteric polymers.