Drug Crystals Research Articles

A Study on the Stability of High Drug Solubility Characteristics of Hydroxyphenyl Adhesives under the Interference of CPEs.

Novel hydroxyphenyl adhesives (HP-PSAs) could significantly increase drug solubility and control drug release through a doubly ionic hydrogen bond (DIH bond) in the patch. However, chemical penetration enhancers (CPEs) always destroy the performance of most adhesives. As a result, this work investigated the stability of both the HP-PSA features and the DIH bond under the interference of the CPEs. Donepezil (DON) was chosen as the model drug, and CPEs with hydroxyl, carboxyl, amido, and ester groups were selected as model CPEs. Unlike the commonly used neutral H-bond, the DIH bond between DON and the HP-PSA was still stable under the interference of the CPEs, resulting in the 2-3-fold drug solubility in the HP-PSA, which was higher than that in the nonfunctional PSA, which reduced the drug crystallization risk and the difficulty of formulation design. FT-IR, 1H NMR, XPS, dynamic simulation, and molecular docking revealed the mechanism of the stability feature of both the DIH bond and the high drug solubility of the HP-PSA, which was that the formed neutral H-bond interaction caused by CPEs is weaker than that of the DIH bond between DON and the HP-PSA. Furthermore, the drug release, skin permeation, and CPE release study showed that the newly formed weak H-bond and strong ionic H-bond interaction promoted or controlled both DON and CPE release, respectively, thereby influencing drug skin permeation, which provided a theoretical basis for drug release regulation. To summarize, besides the reversible, strong features of the DIH bond in our previous study, the stability of the interaction made the HP-PSA's high drug solubility potential to be applied in the TDDS.

Computational Support to Explore Ternary Solid Dispersions of Challenging Drugs Using Coformer and Hydroxypropyl Cellulose.

A majority of drugs marketed in amorphous formulations have a good glass-forming ability, while compounds less stable in the amorphous state still pose a formulation challenge. This work explores ternary solid dispersions of two model drugs with a polymer (i.e., hydroxypropyl cellulose) and a coformer as stabilizing excipients. The aim was to introduce a computational approach by preselecting additives using solubility parameter intervals (i.e., overlap range of solubility parameter, ORSP) followed by more advanced COSMO-RS theory modeling. Thus, a mapping of calculated mixing enthalpy and melting points is proposed for in silico evaluation prior to hot melt extrusion. Following experimental testing of process feasibility, the selected formulations were tested for their physical stability using conventional bulk analytics and by confocal laser scanning and atomic force microscopy imaging. In line with the in silico screening, dl-malic and l-tartaric acid (20%, w/w) in HPC formulations showed no signs of early drug crystallization after 3 months. However, l-tartaric acid formulations displayed few crystals on the surface, which was likely a humidity-induced surface phenomenon. Although more research is needed, the conclusion is that the proposed computational small-scale extrusion approach of ternary solid dispersion has great potential in the formulation development of challenging drugs.

Time and Temperature Dependence of Drug Crystallization─The Role of Molecular Mobility.

Using the time-temperature-transformation diagrams, we demonstrated a correlation between molecular mobility and crystallization in amorphous solid dispersions of nifedipine (NIF) with each polyvinylpyrrolidone vinyl acetate (PVPVA64) and polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus). The behavior was compared with the NIF dispersions prepared with each polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) [Lalge et al., Mol. Pharmaceutics 2023, 20(3), 1806-1817]. Each system was characterized by a unique temperature at which the crystallization onset time was the shortest. Below this temperature, a coupling was observed between the α-relaxation time determined by dielectric spectroscopy and crystallization onset time. Above this temperature, the activation barrier for crystallization had a more significant role than molecular mobility. In the solid state, PVP and PVPVA64 dispersion exhibited higher resistance to crystallization than HPMCAS and Soluplus. The role of polymers in inhibiting crystal growth in nucleated systems was discerned by monitoring crystallization following wetting of the amorphous dispersion with the dissolution medium. PVPVA64 and Soluplus dispersions exhibited higher resistance to crystal growth than PVP and HPMCAS.

Predicting the Release Mechanism of Amorphous Solid Dispersions: A Combination of Thermodynamic Modeling and In Silico Molecular Simulation

Background: During the dissolution of amorphous solid dispersion (ASD) formulations, the drug load (DL) often impacts the release mechanism and the occurrence of loss of release (LoR). The ASD/water interfacial gel layer and its specific phase behavior in connection with DL strongly dictate the release mechanism and LoR of ASDs, as reported in the literature. Thermodynamically driven liquid-liquid phase separation (LLPS) and/or drug crystallization at the interface are the key phase transformations that drive LoR. Methods: In this study, a combination of Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) thermodynamic modeling and in silico molecular simulation was applied to investigate the release mechanism and the occurrence LoR of an ASD formulation consisting of ritonavir as the active pharmaceutical ingredient (API) and the polymer, polyvinylpyrrolidone-co-vinyl acetate (PVPVA64). A thermodynamically modeled ternary phase diagram of ritonavir (PVPVA64) and water was applied to predict DL-dependent LLPS in the ASD/water interfacial gel layer. Microscopic Erosion Time Testing (METT) was used to experimentally validate the phase diagram predictions. Additionally, in silico molecular simulation was applied to provide further insights into the phase separation, the release mechanism, and aggregation behavior on a molecular level. Results: Thermodynamic modeling, molecular simulation, and experimental results were consistent and complementary, providing evidence that ASD/water interactions and phase separation are essential factors driving the dissolution behavior and LoR at 40 wt% DL of the investigated ritonavir/PVPVA64 ASD system, consistent with previous studies. Conclusions: This study provides insights into the potential of blending thermodynamic modeling, molecular simulation, and experimental research to comprehensively understand ASD formulations. Such a combined approach can be leveraged as a computational framework to gain insights into the ASD dissolution mechanism, thereby facilitating in silico screening, designing, and optimization of formulations with the benefit of significantly reducing the number of experimental tests.

Dissolution, phase behavior and mass transport of amorphous solid dispersions in aspirated human intestinal fluids

Amorphous solid dispersions (ASDs) typically show improved dissolution and generate supersaturated solutions, enhancing the oral bioavailability of poorly soluble drugs. To gain insights into intraluminal ASD behavior, we utilized two poorly soluble drugs with different crystallization tendencies, atazanavir and posaconazole, prepared as ASDs at a 10% drug loading with hydroxypropyl methylcellulose acetyl succinate (HPMCAS). We evaluated their release in aspirated fasted-state human intestinal fluid (FaHIF), and multi-component fasted-state simulated intestinal fluid (composite-FaSSIF), characterizing the supersaturation profiles and drug-rich nanodroplets that formed. Complete release was observed for atazanavir ASDs over a 90 min period. Flux for dissolved atazanavir ASDs remained high over the experimental time period of 3 h. In contrast, posaconazole solution concentrations were initially high and then decreased. Likewise, flux was initially high and then decreased where these changes are attributed to crystallization of the drug. Generation of spherical nano-sized amorphous droplets of ∼100-150 nm was found to occur in ex vivo FaHIF media for both ASDs, maximizing the diffusive flux during the supersaturation window. Moreover, buffer capacity differences were postulated to influence release rates of ASDs in simulated vs aspirated fluids. Importantly, the solution phase phenomena observed during ASD release in simulated fluids, namely amorphous nanodroplet formation and drug crystallization, were also found to occur in aspirated luminal fluids.

Dissolution of copovidone-based amorphous solid dispersions: Influence of atomic layer coating, hydration kinetics, and formulation

Atomic layer coating (ALC) is an emerging, solvent-free technique to coat amorphous solid dispersion (ASD) particles with a nanolayer ceramic coating that has been shown to improve powder characteristics and limit drug crystallization. Herein, we evaluate the impact of aluminum oxide coatings with varying thickness and conformality on the dissolution of ritonavir/copovidone ASDs. Release performance of powders, neat tablets, and formulated tablets was studied. Confocal fluorescence microscopy (CFM) was used to visualize particle hydration and phase separation during immersion of the ASD in aqueous media. CFM revealed particle hydration requires defects for solvent penetration, but coatings, regardless of thickness, had minor impacts on powder dissolution provided defects were present. In tablets where less surface area is exposed to the dissolution media due to gel formation, slowed hydration kinetics resulted in phase separation of the drug from the polymer in coated samples, limiting release. Formulation with two superdisintegrants, crospovidone and croscarmellose sodium, as well as lactose achieved ∼90% release in less than 10 minutes, matching the uncoated ASD particles of the same formulation. This study highlights the importance of hydration rate, as well as the utility of confocal fluorescence microscopy to provide insight into release and phase behavior of ASDs.

Study on the crystallinity of PEG on the crystalline size of flavonoids in a crystalline dispersion system

Poor water solubility and low bioavailability of flavonoids present significant barriers to their development and application. To address these challenges, this study explores the use of crystalline solid dispersions (CSDs) to reduce drug crystalline size and enhance in vivo bioavailability. The CSDs were prepared using a spray-drying technique with chrysin (CHY) and quercetin (QUR) as model drugs and various molecular weights of polyethylene glycol (PEG) as carriers. The authors systematically investigated the factors influencing the interaction between flavonoids and PEG in CSDs. These factors included the relationships between intermolecular interactions and PEG molecular weight, crystallinity, microstructures such as crystalline domain size and crystal morphology of the flavonoids and PEG in CSDs, crystalline size of the drug in CSDs, and in vitro dissolution rate and in vivo pharmacokinetics. Our results indicated that the interaction between flavonoids and PEG in CSDs was influenced more by PEG crystallinity than by its molecular weight. Lower crystallinity of PEG, achieved through recrystallization, led to stronger intermolecular interactions with the drugs. Specifically, PEG8000 exhibited the lowest crystallinity, indicating a higher content of PEG in the amorphous state, which interacted more effectively with the amorphous drug in CSDs. This interaction significantly inhibited drug crystallization growth, resulting in a marked decrease in drug crystalline domain size and crystalline size. Consequently, PEG8000 was identified as the optimal carrier for preparing CSDs, achieving the best cumulative dissolution percentage. The QUR/PEG8000-CSD formulation increased the cumulative dissolution percentage and oral bioavailability of QUR by 18.76 and 20.66 times, respectively, compared to QUR alone. This study demonstrates that PEG crystallinity, following recrystallization, directly affects its intermolecular interactions with the drug, thereby impacting drug crystalline size and dissolution rate.

ω-Carboxyl Terminated Cellulose Esters are Effective Crystallization Inhibitors for Challenging Drugs.

Polymeric additives are widely used to delay drug crystallization from supersaturated solutions, which is critical for enhancing oral bioavailability by amorphous solid dispersion (ASD). The efficacy of these polymers relies on their capacity to inhibit nucleation and subsequent crystal growth. Drug nucleation is pivotal to crystallization; therefore, effective polymers are essential for suppressing nucleation from supersaturated solutions. We studied the performance of cellulose ω-carboxyalkanoates designed as crystallization inhibitors by measuring their influence on nucleation induction times of poorly soluble drugs celecoxib, posaconazole, and enzalutamide, from supersaturated solutions. In the absence of polymers, crystallization occurred within 5 to 15 minutes for all three drugs. Polymer hydrophobicity strongly influenced effectiveness in crystallization inhibition. Hydrophobic polymers prolonged induction times for up to 8 hours, while hydrophilic polymers were less effective, except for cellulose acetate glutarate (CA1.18-GA1.21; degrees of substitution acetate 1.18, glutarate 1.21). The cellulose ω-carboxyalkanoates had glass transition temperatures well above 100 °C, outstanding for ASD stability requirements. We investigated the impact of these designed polymers on surface tension and found that it only weakly influenced crystallization inhibition. Among the nine crafted cellulose derivatives, water-soluble CA1.18-GA1.21 emerged as a highly promising ASD polymer, preventing crystallization for 2-8 hours for all fast-crystallizing model compounds.

Application of shadowgraph imaging (SGI) particle characterisation data to interpret the impact of varying test conditions on powder dissolution and to develop an automated agglomeration identification method (AIM) in the USP flow-through apparatus

The aims of this work were 1) to explore the application of shadowgraph imaging (SGI) as a real time monitoring tool to characterize ibuprofen particle behaviour during dissolution testing under various conditions in the USP 4 flow-through apparatus and 2) to investigate the potential to develop an SGI-based automated agglomeration identification method (AIM) for real time agglomerate detection during dissolution testing. The effect of surfactant addition, changes in the drug mass and flow rate, the use of sieved and un-sieved powder fractions, and the use of different drug crystal habits were investigated. Videos at every sampling time point during dissolution were taken and analysed by SGI. The AIM was developed to characterize agglomerates based on two criteria – size and solidity. All detections were confirmed by manual video observation and a reference agglomerate data set. The method was validated under new dissolution conditions with un-sieved particles. Characterisation of particle dispersion behaviour by SGI enabled interpretation of the impact of dissolution test conditions. Higher numbers of early detections reflected greater dissolution rates with increased surfactant concentration, using sieved fraction or plate-shaped crystals, but was impacted by drug mass tested. An AIM was successfully developed and applied to detect agglomerates during dissolution, suggesting potential, with appropriate method development, for application in quality control.

Avoidance of crystallization of hydrophobic drugs in an amorphous solid dispersion during spray-drying and storage

The study examined the efficacy of additives in preventing the crystallization of functional ingredients during the spray-drying process. Spray-drying of a hydrophobic drug from alcohol in the presence of a hydrophilic carrier-forming agent was utilized as a representative scenario, which frequently leads to the crystallization of the main drug component induced by the drying process. Ibuprofen (IBP) and its four congeners were employed as representatives of readily crystallizable hydrophobic pharmaceutical compounds. Disaccharides were intentionally employed as components of the drug carrier to create conditions conducive to crystallization. Ten materials, including the IBP congeners, were investigated for their anti-crystallization properties. The findings indicated that additives with a hydrophobic moiety similar to that of IBP and a carboxylic acid salt moiety effectively prevented IBP and its congeners from crystallizing when the additive content was ≥0.2 g/g-drug during spray-drying and storage at 30 °C over silica gel.

Manufacture, characterization, and elucidation of drug release mechanisms of etonogestrel implants based on ethylene vinyl acetate

In this work, etonogestrel implants were manufactured using coextrusion. The purpose of the study was to correlate changes in microstructure and transport properties that occurred in etonogestrel implants to drug release mechanisms. The implants consisted of an EVA 28 (28 % vinyl acetate) core containing dispersed and dissolved etonogestrel, and an EVA 15 (15 % vinyl acetate) skin. The drug release was determined to be via diffusion at a controlled rate and governed by implant dimensions. In-vitro release revealed evidence of supersaturation in the implant core and skin, likely from the intense mechanical energy input during the twin-screw manufacturing process. Subsequently during storage under ambient conditions, supersaturation resulted in recrystallization of drug crystals, preferentially in the implant core. Etonogestrel solubility and diffusivity in EVA were determined by permeation experiments and used for release modeling. Drug release from the EVA skin layer deviated from the predicted values due to 1) formation of a drug depletion zone in the core and 2) presence of a stagnant media layer adjacent to the skin. Drug release from implant ends was significantly faster than predicted. Air-filled pores were observed in the implant core using microCT which likely contributed to the faster release from implant ends.

First promising non-stimulant (guanfacine) transdermal patch for long-acting treatment of ADHD by solid dispersion technique

Guanfacine (GFC) extended-release tablet (Intuniv®) is an effective non-stimulant medication prescribed for attention deficit hyperactivity disorder (ADHD), presenting limitations regarding patient compliance and safety risks. The study aimed to design a novel long-acting transdermal delivery system of GFC to address these issues. Polyvinylpyrrolidone (PVP)-GFC solid dispersions were constructed by the co-evaporation method to improve drug-loading capacity to approximately 10 % (w/w). A PVP-GFC ratio of 3:1 was determined to prevent drug crystallization and promote rapid dissolution. The mechanisms underlying solid dispersion formation were revealed by XRD, DSC, molecular docking, FTIR, and Raman imaging. Hydrogen-bond interactions between PVP and GFC played a crucial role. The prescription and preparation process were optimized using single-factor and Box-Behnken design experiments. The optimized patch exhibited excellent crystallization resistance and adhesion for at least six months. Additionally, superior rheology, mechanical strength, in vitro drug release, and percutaneous permeation characteristics were observed. In human pharmacokinetic studies, the therapeutic efficacy, skin safety, and adhesion of transdermal patches were initially demonstrated for the three-day treatment of ADHD. Therefore, the innovative work expands the comprehension of solid dispersion techniques and facilitates the industrialization and commercialization of the first non-stimulant transdermal patches, providing a promising alternative for ADHD therapy.

Data-Driven Design of Novel Polymer Excipients for Pharmaceutical Amorphous Solid Dispersions.

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.

Design and Characterization of a Continuous Melt Milling Process Tailoring Submicron Drug Particles

Solid crystalline suspensions (SCSs) containing submicron particles were introduced as a competitive solution to increase dissolution rates and the bioavailability of poorly water-soluble drugs. In an SCS, poorly water-soluble drug crystals are finely dispersed in a hydrophilic matrix. Lately, melt milling as an adapted wet milling process at elevated temperatures has been introduced as a suitable batch manufacturing process for such a formulation. In this work, the transfer from batch operation to a two-step continuous process is demonstrated to highlight the potential of this technology as an alternative to other dissolution-enhancing methods. In the first step, a powder mixture of a model drug (griseofulvin) and a carrier (xylitol) is fed to an extruder, where a uniform suspension is obtained. In the second step, the suspension is transferred to a custom-built annular gap mill, where comminution down to the submicron region takes place. The prototype’s design was based on batch grinding results and a narrow residence time distribution, intended to deliver large quantities of submicron particles in the SCS. The throughput of the mill was found to be limited by grinding media compression. By inclining the mill at an angle, the grinding media position was manipulated, such that compression was avoided. Different states of the grinding media in the grinding chamber were identified under surrogate conditions. This strategy allows the maintenance of an energy-optimized comminution without adaption of the associated process parameters, even at high throughputs. Using this new process, the production of an SCS with 80–90 % submicron particles in a single passthrough was demonstrated.

Effect of in-line filtration in newborns: study protocol of the Intravenous Neonatal Central Access Safety (INCAS) randomized controlled trial

BackgroundParticulate contamination due to infusion therapy (administration of parenteral nutrition and medications) carries a potential health risk for infants in neonatal intensive care units (NICUs). This particulate consists of metals, drug crystals, glass fragments, or cotton fibers and can be generated by drug packaging, incomplete reconstitution, and chemical incompatibilities. In-line filters have been shown to remove micro-organisms, endotoxin, air, and particles in critically ill adults and older infants, but its benefits in newborn remain to be demonstrated. Moreover, 50% of inflammatory episodes in the setting of NICUs are blood culture-negative. These episodes could be partly related to the presence of particles in the infusion lines.MethodsA multicenter randomized single-blind controlled trial was designed. All infants admitted to NICUs for which prolonged infusion therapy is expected will be enrolled in the study and randomized to the Filter or Control arm. All patients will be monitored until discharge, and data will be analyzed according to a “full analysis set.” The primary outcome is the frequency of patients with at least one sepsis-like event, defined by any association of suspected sepsis symptoms with a level of c-reactive protein (CRP) > 5 mg/L in a negative-culture contest. The frequency of sepsis, phlebitis, luminal obstruction, and the duration of mechanical ventilation and of catheter days will be evaluated as secondary outcomes. The sample size was calculated at 368 patients per arm.DiscussionThis is the first multicenter randomized control trial that compares in-line filtration of parenteral nutrition and other intravenous drugs to infusion without filters. Sepsis-like events are commonly diagnosed in clinical practice and are more frequent than sepsis in a positive culture contest. The risk of these episodes in the target population is estimated at 30–35%, but this data is not confirmed in the literature. If the use of in-line filters results in a significant decrease in sepsis-like events and/or in any other complications, the use of in-line filters in all intravenous administration systems may be recommended in NICUs.Trial registrationClinicalTrials.gov, NCT05537389, registered on 12 September 2022 (https://classic.clinicaltrials.gov/ct2/show/results/NCT05537389?view=results).

Strategic design of a multifunctional urea-triphenylamine benzotriazole-based material

The search for multifunctional derivatives is of paramount importance in material science considering sustainability, practicality, and applicability. For this reason, this article presents a multifunctional benzotriazole derivative synthesized through rational design, showcasing its versatility across diverse applications. The tailored functionality of the compound enables it to serve in photonics as an optical waveguide, as smart material as stimuli responsiveness material, and as a gelator for drug crystallization in pharmaceuticals. This work underscores the power of rational design for organic synthesis in creating versatile materials with broad applicability.

Development of a solid dispersion system for polyvinyl alcohol nanofibers embedded with silicon dioxide particles via emulsion electrospinning for improved solubility of poorly water-soluble drugs

This study explored the development of solid dispersions of probucol (PBC), a poorly water-soluble drug, embedded within polyvinyl alcohol (PVA) nanofibers at a high concentration (30 %) via emulsion electrospinning. This study addressed the issues of low solubility and dissolution rates of such drugs by examining the incorporation of various types of silica particles—Aerosil 200 (A200), Sylisia 320 (SY320), Aerosil R972, and Sylophobic 100—as additives in oil-in-water emulsions. The results revealed that regardless of their hydrophilic or hydrophobic properties, silica particles preserved the amorphous state of PBC within the nanofibers without altering its crystallinity. Notably, all nanofibers embedded with silica particles demonstrated improved drug solubility compared to those without silica. This suggests that silica plays a role in mitigating the reduced solubility of drugs associated with their higher concentrations. Stability assessments of nanofibers embedded with A200 and SY320 under accelerated conditions revealed that A200 nanofibers preserved drug crystallinity and solubility, thus exhibiting superior storage stability. In contrast, SY320 nanofibers underwent drug crystallization, leading to a decrease in solubility upon storage. In conclusion, this study highlights the potential of silica particles in enhancing the solubility and stability of PBC in PVA nanofibers, suggesting that emulsion electrospinning with suitable silica additives is an effective strategy for developing advanced drug delivery systems for poorly water-soluble drugs.

Novel Proniosomes of Manidipine: Optimization and In-vivo Evaluation

The objective of the current study is to produce proniosomes of manidipine using the thin film hydration method for the management of hypertension. Statistical optimization was performed using the Box-Behnken design. The generated formulations were tested for particle size, entrapment effectiveness, and drug release at 12 hours. The improved proniosomes were further assessed for surface morphology, ATR, and differential scanning calorimetry (DSC). The improved proniosomes were also assessed for an in-vitro and in-vivo investigation on dexamethasone-induced hypertension. It was noted that there was no significant interaction with excipients. DSC indicated a considerable shift in the endothermal peak and showed interaction with the study’s excipients. Niosomes and drug crystals were seen to be dispersed in small areas during the scanning electron microscope (SEM) analysis. The study also showed that the optimized proniosomes have asymmetrical surfaces and appearances. The zeta value in the research was -6.7 mV, indicating stability. According to the optimized proniosomes formulation, F14 released 99.97% of the drug at its highest concentration in 12 hours. ANOVA results from an in-vivo investigation confirmed a satisfactory outcome in decreasing raised blood pressure, as shown by the F and p-values.

Surfactant-Polymer Complexation and Competition on Drug Nanocrystal Surfaces Control Crystallinity.

Nanosizing drug crystals has emerged as a successful approach to enabling oral bioavailability, as increasing drug crystal surface area improves dissolution kinetics and effective solubility. Recently, bottom-up methods have been developed to directly assemble nanosized crystals by leveraging polymer and surfactant excipients during crystallization to control crystal size, morphology, and structure. However, while significant research has investigated how polymers and other single additives inhibit or promote crystallization in pharmaceutical systems, there is little work studying the mechanistic interactions of multiple excipients on drug crystal structure and the extent of crystallinity, which can influence formulation performance. This study explores how the structure and crystallinity of a model hydrophobic drug crystal, fenofibrate, change as a result of competitive interfacial chemisorption between common nonionic surfactants (polysorbate 80 and sorbitan monooleate) and a surface-active polymer excipient (methylcellulose). Classical molecular dynamics simulations highlight how key intermolecular interactions, including surfactant-polymer complexation and surfactant screening of the crystal surface, modify the resulting crystal structure. In parallel, experiments generating drug nanocrystals in hydrogel thin films validate that drug crystallinity increases with an increasing weight fraction of surfactant. Simulation results reveal a connection between accelerated dynamics in the bulk crystal and the experimentally measured extent of crystallinity. To our knowledge, these are the first simulations that directly characterize structural changes in a drug crystal as a result of excipient surface composition and relate the experimental extent of crystallinity to structural changes in the molecular crystal. Our approach provides a mechanistic understanding of crystallinity in nanocrystallization, which can expand the range of orally deliverable small molecule therapies.

Long-Term Physical Stability of Amorphous Solid Dispersions: Comparison of Detection Powers of Common Evaluation Methods for Spray-Dried and Hot-Melt Extruded Formulations

Although physical stability can be a critical issue during the development of amorphous solid dispersions (ASDs), there are no established protocols to predict/detect their physical stability. In this study, we have prepared fenofibrate ASDs using two representative manufacturing methods, hot-melt extrusion and spray-drying, to investigate their physical stability for one year. Intentionally unstable ASDs were designed to compare the detection power of each evaluation method, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and dissolution study. Each method did not provide the same judgment results on physical stability in some cases because of their different evaluation principles and sensitivity, which has been well-comprehended only for one-component glass. This study revealed that the detection powers of each evaluation method significantly depended on the manufacturing methods. DSC was an effective method to detect a small amount of crystals for both types of ASDs in a quantitative manner. Although the sensitivity of XRPD was always lower compared to that of DSC, interpretation of the data was the easiest. SEM was very effective for observing the crystallization of the small amount of drug for hot-melt extruded products, as the drug crystal vividly appeared on the large grains. The dissolution performance of spray-dried products could change even without any indication of physical change including crystallization. The advantage/disadvantage and complemental roles of each evaluation method are discussed for deeper understanding on the physical stability data of ASDs.