Non-sink Conditions Research Articles

Dissolution mechanisms of amorphous solid dispersions: Role of polymer molecular weight and identification of a new failure mode

The mechanisms of drug release from amorphous solid dispersions (ASDs) are complex and not fully explored, making it difficult to optimize for in vivo performance. A recurring behavior has been the limit of congruency (LoC), a drug loading above which the ASD surface forms an amorphous drug-rich barrier in the presence of water, which hinders release, especially in non-sink conditions. Drug-polymer interactions and drug glass transition temperature were reported to affect the LoC. However, the effect of polymer molecular weight has not been explored. ASDs of clotrimazole and different molecular weight grades of poly (vinylpyrrolidone) (PVP) were studied for their release to obtain their LoC drug loadings. Failure modes underpinning the LoC were investigated using fluorescence confocal microscopy to analyze the ASD/solution interface and phase behavior of ASD films at high relative humidity. ASDs with good release formed stable drug-rich nanodroplets at the ASD/solution interface, while ASDs with poor release were limited by one of two failure modes, depending on PVP molecular weight. In Failure Mode I the nanodroplets quickly agglomerated, while in Failure Mode II the system underwent phase inversion. This work highlights the importance of identifying the mechanisms underlying the LoC to improve the release of higher drug loading ASDs.

Molecular-properties based formulation guidance tree for amorphous and supersaturable mesoporous silica preparations of poorly soluble compounds

A huge majority of new chemical entities (NCEs) advancing through the drug discovery pipeline often have poor aqueous solubility. This requires formulation scientists to search for solubility enhancement strategies, within the constraints of time and material. To address these challenges, a strategic platform formulation is often required for a rapid compound screening to enable early exploratory PK and toxicology studies. Through this work, we present an option of a material-sparing, high yielding and solubility-enabling amorphous API and HPMCAS-L co-loaded mesoporous silica-based formulation. The usability of this platform formation strategy was assessed for a physico-chemically diverse set of eleven compounds. The formulation approach was successful in stabilizing the model compounds mesoporous silica. Additionally, through the presence of HPMCAS-L, the precipitation risk in supersaturable aqueous environment was significantly reduced. Finally, this manuscript provides fundamental, computational and experimental molecular-properties based formulation guidance tree to a priori gauge the (1) possibility of generating solid-state stable amorphous formulations and (2) sustaining in vitro supersaturation in extreme non-sink dissolution conditions. This unique and conceptual formulation guidance tree is believed to be extremely beneficial to drug discovery formulators to triage NCEs and streamline solubility-enabling formulation efforts.

Impact of sink conditions on drug release behavior of controlled-release formulations

Developing a controlled release (CR) formulations is a complex and iterative process, often requiring preclinical or clinical studies to establish in vitro-in vivo correlations. This can be particularly challenging for poorly soluble drugs due to the non-sink conditions encountered in vitro. Although compendial dissolution methods (e.g., USP II, IV) have historically been used to understand the dissolution performance of CR formulations, there is increasing interest in more physiologically relevant experimental techniques to improve the predictive ability. In this study, traditional USP apparatus as well as the biorelevant absorptive dissolution apparatus were employed to understand the impact of apparatus type and sink condition on the release mechanisms of CR formulations and in turn evaluate the application of absorptive dissolution apparatus for dissolution testing of CR formulations. Release mechanisms were further analyzed using the Peppas equations, providing additional mechanistic insights. The release behavior showed a strong dependence on sink conditions for drugs with low intrinsic solubility, while highly soluble drugs were unaffected by dissolution conditions. Interestingly, the dissolution mechanism was found to be independent of the apparatus type. The study clearly underscores the importance of considering the sink conditions in developing more predictive and biorelevant dissolution testing methods for CR formulations. Furthermore, the study highlights the potential impact on the sink and resultant differences in the drug release mechanisms as a function of the dose.

Excipient effects on supersaturation, particle size dynamics, and thermodynamic activity of multidrug amorphous formulations

Multidrug formulations enhance patient compliance and extend the life cycle of pharmaceutical products. To overcome solubility challenges for multidrug combinations, amorphous formulations are commonly used. However, the excipients for creating amorphous formulations are often selected without an understanding of their effects on the bioavailability of the drugs. In this context, we investigated the impact of three types of excipients (polymers, surfactants and amino acids) on the supersaturation and thermodynamic activity of multidrug amorphous formulations. Additionally, we studied the particle size dynamics of the colloidal phase formed as a result of liquid–liquid phase separation. The amorphous solubility of two drugs, atazanavir and ritonavir, was determined in solutions containing predissolved excipients and the particle size dynamics of the colloidal particles was measured by dynamic light scattering. Dissolution experiments of atazanavir and ritonavir were conducted in predissolved sodium dodecyl sulfate (SDS), an anionic surfactant, and alanine solutions under non-sink conditions. Membrane transport of the drugs was evaluated using a MicroFLUX setup. The polymers had only minor effects on the amorphous solubility, but SDS significantly increased the solubilities of both drugs. In contrast, the other non-ionic surfactants and amino acids reduced the solubility of atazanavir but had no negative effect on ritonavir. Polymers were effective in maintaining supersaturation and preventing the coarsening of the colloidal particles. Conversely, alanine was neither able to inhibit the solution crystallization nor increase the flux of either drug. Despite the increase in the amorphous solubility of both drugs in SDS, flux was reduced. These results highlight the importance of properly selecting excipients for supersaturating amorphous formulations. The choice of excipient impacts the thermodynamic activity, the phase behaviour of the drugs and hence, the resulting absorption after oral intake.

Evaluation of Suitable Polymeric Matrix/Carriers during Loading of Poorly Water Soluble Drugs onto Mesoporous Silica: Physical Stability and In Vitro Supersaturation.

The application of mesoporous carriers in formulations of amorphous solid dispersions (ASDs) has been suggested to enhance the stability of amorphous drugs. However, mesoporous carriers do not demonstrate satisfactory inhibitory effects on the precipitation of active pharmaceutical ingredients (APIs), and the inclusion of an appropriate polymer within ASDs becomes imperative to maintaining drug supersaturation. The aim of this study was to evaluate ternary olanzapine (OLN) ASDs with Syloid 244FP and to find an appropriate polymeric carrier. The polymer's selection criteria were based on the physical stability of the ASDs and the release rate of the drug from the systems. The polymers investigated were hydroxypropylmethyl cellulose (HPMC) and copovidone (coPVP). The formation of ASDs was achievable in all investigated cases, as demonstrated by the complete lack of crystallinity confirmed through both powder X-ray diffraction (pXRD) analysis and differential scanning calorimetry (DSC) for all developed formulations. The solvent shift method was employed to evaluate the ability of the studied carriers to inhibit the precipitation of supersaturated OLN. coPVP emerged as a more suitable precipitation inhibitor compared with HPMC and Syloid 244 FP. Subsequently, in vitro dissolution studies under non-sink conditions revealed a higher degree of supersaturation in ternary systems where coPVP was used as a polymeric carrier, as these systems exhibited, under the examined conditions, up to a 2-fold increase in the released OLN compared with the pure crystalline drug. Moreover, stability studies conducted utilizing pXRD demonstrated that ternary formulations incorporating coPVP and Syloid 244 FP maintained stability for an extended period of 8 months. In contrast, binary systems exhibited a comparatively shorter stability duration, indicating the synergistic effect of coPVP and Syloid 244 FP on the physical stability of the amorphous API. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) studies showed that the development of stronger molecular interactions can be provided as an explanation for this synergistic effect, as the formation of robust H-bonds may be considered responsible for inhibiting the precipitation of the supersaturated API. Therefore, the incorporation of coPVP into OLN ASDs with Syloid 244 FP is considered a highly promising technique for increasing the degree of OLN supersaturation in in vitro dissolution studies and improving the stability of systems.

Optimizing Nonsink Dissolution Testing for Amorphous Solid Dispersions: Exploring Sample Handling Variables.

This study aims to investigate key variables affecting the dissolution of amorphous pharmaceuticals. We examined sample treatment methods (centrifugation vs syringe filtration), time delays between sample collection and processing (immediate, 2, or 24 h), and different sample preparations (bare powder, capsules, or tablets). These factors were evaluated through both sink and nonsink dissolution experiments, using controlled supersaturation conditions (sink index ≈ 0.1) with amorphous solid dispersions (ASDs) containing low-substituted hydroxypropyl cellulose (L-HPC) and either indomethacin or posaconazole as model drugs. Our results highlighted the significant impact of syringe filtration on nonsink dissolutions, particularly the notable reduction in dissolved drug concentration, possibly due to filtration-induced precipitation. Moreover, introducing a delay of 2 or 24 h between sample collection and quantitation under nonsink conditions led to substantial concentration changes. This effect was not as pronounced when samples underwent centrifugation, and only the analysis was delayed for 2 h. The findings also emphasize the importance of accounting for delays introduced by pharmaceutical formulations, particularly in assessing the kinetic-solubility profiles of ASDs. This research offers valuable insights into the field of ASDs, enhancing our understanding of how these variables can influence dissolution results.

Development and characterization of co-amorphous griseofulvin/L-leucin by modified solvent processing hot-melt extrusion

Co-amorphous systems (CAMS) were developed between griseofulvin (GRI) and L-leucine (LEU) at 2:1 wt ratio, by application of a novel solvent assisted hot-melt extrusion (HME) method that involved wet processing/drying of the feeds prior to extrusion. CAMS formation was confirmed by powder crystallography (pXRD) and thermal analysis (DSC). Intermolecular H-bonding between the carbonyl groups of GRI and the hydroxyl and amino groups of LEU were identified by vibrational spectroscopy (ATR-FTIR). The measured glass transition temperatures (Tg) of the extrudates from feeds processed with aqueous acetic acid (AcOH) were markedly lower than that of neat amorphous GRI and values predicted from Gordon-Taylor equation, indicating plasticizing action of AcOH. Drug concentrations during dissolution of CAMS under non-sink conditions (Sink Index 0.0115) were up to x82 higher at plateau compared to crystalline drug solubility. The degree of supersaturation lasted for at least 24 h. Plasticizer (Compritol®/Kolliphor® 75/25) added before extrusion did not impact significantly on CAMS formation but altered the dissolution profile from a spring-and-parachute profile to gradual rise to maximum. These findings reinforce the application of drug/amino acid-based CAMS in formulation, particularly for high-dose drugs, for which polymers are unsuited due to the required large proportions.

KOENZİM Q10 YÜKLÜ MİSEL İÇEREN KONTAKT LENSLERİN HAZIRLANMASI VE İN-VİTRO KARAKTERİZASYONU

Objective: Coenzyme Q10 (CoQ10) offers potential therapeutic benefits for ocular health, yet faces challenges of poor solubility and bioavailability when applied to the eye. This study aimed to enhance CoQ10 delivery using contact lenses by incorporating CoQ10-loaded polymeric micelles, using Pluronic F127 and solvent evaporation technique. Material and Method: Polymeric micelles encapsulating CoQ10 were produced via solvent evaporation with Pluronic F127. Commercial contact lenses were subsequently loaded with these micelles. Characterization of the loaded lenses included assessments of light transmittance, swelling behavior, and drug release profile under non-sink conditions, simulating the constraints of the ocular surface. Result and Discussion: The unloaded lenses exhibited a light transmittance of 91.78±3.29% and swelling percentage of 47.51±4.45% while micelle-loaded lenses demonstrated high light transmittance levels (95.31±0.80%), ensuring optical clarity. Swelling studies showed a slight increase in size to 48.1±4.4%. The lenses effectively encapsulated 403.6±21.8 µg of CoQ10. In vitro release profile exhibited controlled release over six hours, indicating potential for sustained drug delivery. These results highlight the feasibility of micelle-loaded contact lenses for efficient ocular drug delivery, warranting further exploration into their long-term effectiveness and safety.

Utilizing Drug Amorphous Solid Dispersions for the Preparation of Dronedarone per os Formulations

Dronedarone (DRN), an antiarrhythmic drug, exhibits potent pharmacological effects in the management of cardiac arrhythmias. Despite its therapeutic potential, DRN faces formulation challenges due to its low aqueous solubility. Hence, the present study is dedicated to the examination of amorphous solid dispersions (ASDs) as a strategic approach for enhancing the solubility of DRN. Initially, the glass forming ability (GFA) of API was assessed alongside its thermal degradation profile, and it was revealed that DRN is a stable glass former (GFA III compound) that remains thermally stable up to approximately 200 °C. Subsequently, five commonly used ASD matrix/carriers, i.e., hydroxypropyl methylcellulose (HPMC), povidone (PVP), copovidone (PVP/VA), Soluplus® (SOL), and Eudragit® E PO (EPO), were screened for the formation of a DRN-based ASD using film casting and solvent shift methods, along with miscibility evaluation measurements. SOL proved to be the most promising matrix/carrier among the others, and, hence, was used to prepare DRN ASDs via the melt-quench method. The physicochemical characterization of the prepared systems (via pXRD) revealed the complete amorphization of the API within the matrix/carrier, while the system was physically stable for at least three months after its preparation. In vitro release studies for the ASDs, conducted under non-sink conditions, revealed the sustained supersaturation of the drug for at least 8 h. Finally, the use of attenuated total reflectance (ATR) FTIR spectroscopy showed the formation of a strong molecular interaction between the drug molecules and SOL.

Bentonite as a water-insoluble amorphous solid dispersion matrix for enhancing oral bioavailability of poorly water-soluble drugs

Bentonite (BT), an orally administrable natural clay, is widely used for medical and pharmaceutical purposes due to its unique properties, including swelling, adsorption and ion-exchange. However, its application as a matrix of amorphous solid dispersion (ASD) formulations is rarely reported, despite the fact that drugs can adsorb to BT in an amorphous state. The objective of this study was to explore the feasibility of BT as a water-insoluble ASD matrix for enhancing the oral bioavailability of poorly water-soluble drugs, including sorafenib (SF). We prepared a novel BT-based ASD of an SF-BT composite (SFBTC) by adsorbing SF onto BT under acidic conditions using the ionic interaction between cationic SF and negatively charged BT. Scanning electron microscopy (SEM), powder X-ray diffractometry (pXRD), and differential scanning calorimetry (DSC) analyses revealed that SF adsorbed to BT in an amorphous state at SF:BT ratios from 1:3 to 1:10. In pharmacokinetic studies in rats, SFBTC (1:3) significantly improved the oral bioavailability of SF, and the AUClast of SFBTC (1:3) was 3.3-fold higher than that of NEXAVAR®, a commercial product of SF. An in vitro release study under sink conditions revealed that SFBTC (1:3) completely released SF in a pH-dependent manner, while a nonsink condition study indicated the generation of supersaturation under intestinal pH conditions. A kinetic solubility study showed that the release of SFBTC (1:3) followed the diffusion-controlled mechanism, which is a typical characteristic of water-insoluble matrix-based ASDs. The pharmacokinetic studies of drug-BT composites of various drugs belonging to BCS class II indicated that the pKa value of the adsorbed drugs is one of the most important factors determining their dissolution and oral bioavailability. These results suggest that BT could be a promising water-insoluble ASD matrix for improving the oral bioavailability of poorly water-soluble drugs, including SF.

Systematic Screening Study for the Selection of Proper Stabilizers to Produce Physically Stable Canagliflozin Nanosuspension by Wet Milling Method.

One of the crucial approaches to managing the low solubility and weak bioavailability of drugs is via nanocrystal technology. Through this technology, drug particles have an increased solubility and a faster dissolution rate due to high surface free energy, which requires an appropriate stabilizer(s) to prevent instabilities during the manufacturing process and storage of the nanosuspension. This study aimed to establish a scientific predictive system for properly selecting stabilizers or to reduce the attempts on a trial-and-error basis in the wet-milling method. In total, 42 experiments were performed to examine the effect of critical material attributes on the wettability of the drug, the saturation solubility in the stabilizer solutions or combinations thereof and the dynamic viscosity of stabilizer solutions. All data were evaluated by Minitab 19® and an optimization study was performed. The optimized formulation at a certain concentration of stabilizer combination was ground by Dyno Mill® with 0.3 mm beads for one hour. The optimized nanosuspension with a particle size of 204.5 nm was obtained in short milling time and offered 3.05- and 3.51 times better dissolution rates than the marketed drug product (Invokana® 100 mg) in pH 4.5 and pH 6.8 as non-sink conditions, respectively. The formulation was monitored for three months at room temperature and 4 °C. The parameters were 261.30 nm, 0.163, -14.1 mV and 261.50 nm, 0.216 and -17.8 mV, respectively. It was concluded that this approach might indicate the appropriate selection of stabilizers for the wet-milling process.

The Increased Release Kinetics of Quercetin from Superparamagnetic Nanocarriers in Dialysis

The actual cumulative mass of released quercetin from nanoparticles within the dialysis membrane was determined under the influence of external stationary and alternating magnetic fields. We have shown that the control of the release kinetics of quercetin from MNPs, i.e., the distribution of quercetin between the nanoparticles and the suspension within the membrane, can be tuned by the simple combination of stationary and alternating magnetic fields. Under non-sink conditions, the proportion of quercetin in the suspension inside the membrane is increased toward the nanoparticles, resulting in the increased release of quercetin. The results obtained could be applied to the release of insoluble flavonoids in aqueous suspensions in general.

A new modelling approach for dissolution of polydisperse powders

A new modelling approach for dissolution of polydisperse powders is developed within the framework of the classical Noyes–Whitney/Nernst–Brunner analysis. Its distinguishing feature is that the underlying continuous particle-size distribution is retained. Two different but related dependencies of the diffusion-layer thickness on particle size are considered. First, a power-law dependence that interpolates between a thickness that is proportional to (or equals) the particle radius (obtained when the exponent equals 1) and a constant thickness (obtained when the exponent is 0). Second, a piecewise linear function such that the thickness equals the particle radius for sufficiently small particles and is constant for larger ones. The modelling approach is exemplified by consideration of a lognormal particle-size distribution. Highly accurate closed-form expressions for the fraction of dissolved drug are obtained for dissolution under sink conditions (which are exact if the diffusion-layer thickness is radius-independent). Moreover, it is demonstrated that any result derived under sink conditions can be reused to determine the fraction of dissolved/absorbed drug under non-sink conditions, using the concept of a retarded time. Comparison with literature data and experiments are used to validate the modelling approach and to demonstrate its usefulness in a practical context.

Encapsulation and release of hydrocortisone from proliposomes govern vaginal delivery.

Topical preparations of hydrocortisone can be used for the anti-inflammatory treatment of the female genital area. Although the drug is a low-strength corticosteroid, systemic absorption and distribution of the drug are the most common safety risks associated with this therapy. In the current investigation, we elucidate the physicochemical properties of lipid-based drug carrier systems that govern the local bioavailability of hydrocortisone for intravaginal administration. For this purpose, we compared various proliposome formulations with a commercial cream. Depending on the availability of physiological acceptors, encapsulation and drug release from the lipid phase were found to be the most important drivers of drug bioavailability. The high permeability of hydrocortisone leads to rapid transport of the drug across the mucosal cell layer as indicated by experiments using HEC-1-A and CaSki cell monolayer models. Under sink conditions, differences in the release from the liposomes as determined in the Dispersion Releaser were almost negligible. However, under non-sink conditions, the drug release plateaued at levels corresponding to the encapsulation efficiency. After redispersion, all liposomal formulations performed better than the commercial drug product indicating that the encapsulation into the lipid phase is the main driver sustaining the release.

A Simple One-Parameter Percent Dissolved Versus Time Dissolution Equation that Accommodates Sink and Non-sink Conditions via Drug Solubility and Dissolution Volume

In vitro dissolution generally involves sink conditions, so dissolution equations generally do not need to accommodate non-sink conditions. Greater use of biorelevant media, which are typically less able to provide sink conditions than pharmaceutical surfactants, necessitates equations that accommodate non-sink conditions. One objective was to derive an integrated, one-parameter dissolution equation for percent dissolved versus time that accommodates non-sink effects via drug solubility and dissolution volume parameters, including incomplete solubility. A second objective was to characterize the novel equation by fitting it to biorelevant dissolution profiles of tablets of two poorly water-soluble drugs, as well as by conducting simulations of the effect of dose on dissolution profile. The Polli dissolution equation was derived, % ;dissolved=100%left[1-frac{left({{M}_{0}-c}_{s}Vright)}{{M}_{0}-{{c}_{s}Ve}^{{-k}_{d}left(frac{{{M}_{0}-c}_{s}V}{V}right)t}}right], where M0 is the drug dose (mg), cs is drug solubility (mg/ml), V is dissolution volume (ml), and kd is dissolution rate coefficient (ml/mg per min). Maximum allowable percent dissolved was determined by drug solubility and not a fitted extent of dissolution parameter. The equation fit tablet profiles in the presence and absence of sink conditions, using a single fitted parameter, kd, and where solubility ranged over a 1000-fold range. kd was generally smaller when cs was larger. FeSSGF provided relatively small kd values, reflecting FeSSGF colloids are large and slowly diffusing. Simulations showed impact of non-sink conditions, as well as plausible kd values for various cs scenarios, in agreement with observed kd values. The equation has advantages over first-order and z-factor dissolution rate equations. An Excel file for regression is provided.Graphical

Design of Ternary Amorphous Solid Dispersions for Enhanced Dissolution of Drug Combinations.

Using sulfamethoxazole (SMZ) and trimethoprim (TMP) as model drugs, we designed amorphous solid dispersions (ASDs) for the simultaneous solubility enhancement of two active pharmaceutical ingredients (APIs) by exploiting the drug-drug and drug-polymer interactions. In order to make this approach broadly applicable and over a wide dose range, a mixture of SMZ and TMP at weight ratios of 5:1 and 1:5 (w/w) were formulated into ternary ASDs. Depending on the dose ratio of the two drugs, the polymer used was either an aminoalkyl methacrylate copolymer (Eudragit, EDE) or polyacrylic acid. The drug-drug and drug-polymer interactions were characterized to be ionic by infrared and solid-state nuclear magnetic resonance spectroscopy. The interactions resulted in a substantial reduction in molecular mobility, evident from the increase in the structural relaxation time determined by dielectric spectroscopy. The drug-drug interaction resulted in ∼3 orders of magnitude reduction in molecular mobility. The addition of a polymer led to a further decrease in molecular mobility of up to 4 orders of magnitude. The strength of intermolecular interactions was also estimated from the glass transition temperatures of the ASDs obtained by differential scanning calorimetry. The strong intermolecular interactions yielded highly stable ASDs with no evidence of crystallization, both at elevated temperatures and under accelerated storage conditions (40 °C/75% relative humidity; 6 weeks). The dissolution performances of the ASDs were evaluated using the area under the curve (AUC) obtained from the concentration-time profiles under the non-sink condition. SMZ and TMP in their ternary ASDs, when compared with their crystalline counterparts, exhibited up to 6.4- and 4.6-fold increases in AUC, respectively. Importantly, the synchronized release of the two drugs was observed, a desirable attribute in synergistic formulations. A single-phase ternary ASD, stabilized by drug-drug and drug-polymer interactions, is likely responsible for the unique release profile.

Physiologically Based Pharmacokinetic Models Can Be Used to Predict the Unique Nonlinear Absorption Profiles of Vismodegib

Predicting human pharmacokinetics (PK) during the drug discovery phase is valuable to assess doses required to reach therapeutic exposures. For orally administered compounds, however, this can be especially difficult since the absorption process is complex. Vismodegib is a compound with unique nonlinear oral PK characteristics in humans. Oral physiologically-based pharmacokinetic (PBPK) models were built using preclinical in vitro and in vivo data and successfully predicted the oral PK profiles in rats, dogs, and monkeys. Simulated drug exposures (AUC0-inf and Cmax), following oral administration were within 2-fold of observed values for the dog and monkey, and close to 2-fold for the rat, providing validation to the model structure. Adaptation of this oral PBPK model to humans, using human physiological parameters coupled with predicted human PK, resulted in underpredictions of vismodegib exposure following both single and multiple doses. When observed human PK was used to drive the oral PBPK model, oral PK profiles in humans were well predicted with fold errors in predicted vs observed drug exposures being close to 1. Importantly, the oral PBPK model captured the unique nonlinear, non-dose dependent PK of vismodegib at steady-state. The mechanism responsible for nonlinearity was consistent with oral absorption being influenced by nonsink permeation conditions. We introduce a new parameter, the permeation gradient factor, to characterize the effect of nonsink conditions on permeation. Using vismodegib as an example, we demonstrate the value of using oral PBPK models in drug discovery to predict the oral PK of compounds with nonlinear absorption characteristics in human. Significance Statement A physiologically-based pharmacokinetic model was built to demonstrate the value of these models early in the drug discovery stage for the prediction of human PK for compounds with unusual oral pharmacokinetics. In this study, our model could successfully capture the unique steady-state oral pharmacokinetics of our model compound, vismodegib. The mechanism for nonlinearity can be attributed to nonsink permeation conditions in vivo. We introduce the permeation gradient factor as a parameter to assess this effect.

Preparation, characterization, and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs

Rivaroxaban (RIV) is a direct Factor Xa inhibitor anticoagulant, but the oral bioavailability of RIV is estimated to be only 60% due to its poor solubility. The aim of the present study was to improve the solubility and bioavailability of RIV. Five cocrystals—p-hydroxybenzoic acid (HBA), 2,4-dihydroxybenzoic acid (DBA), nicotinamide (NA), isonicotinamide (IA), and succinic acid (SA)—were used as cofomers and were successfully obtained and characterized by powder X-ray diffraction, thermal analysis, and Fourier transform infrared spectra. RIV-DBA and RIV-HBA cocrystals showed obvious improvements in solubility, dissolution (under sink conditions), and intrinsic dissolution rates versus RIV. Moreover, the dissolution of RIV-HBA, RIV-DBA, and RIV-SA cocrystals under non-sink conditions showed obvious “spring and parachute” patterns. The in vitro permeability levels in a Caco-2 cell model of RIV-DBA and RIV-IA cocrystals were significantly improved versus RIV. Pharmacokinetic studies in beagle dogs showed that RIV-DBA and RIV-HBA cocrystals had higher bioavailability than RIV. The enhancements in solubility and bioavailability indicate the potential of RIV cocrystals as a better candidate for the treatment of thrombosis versus RIV.

Non-Effective Improvement of Absorption for Some Nanoparticle Formulations Explained by Permeability under Non-Sink Conditions.

We evaluated the in vitro permeability of nanoparticle formulations of high and low lipophilic compounds under non-sink conditions, wherein compounds are not completely dissolved. The permeability of the highly lipophilic compound, griseofulvin, was improved by about 30% due to nanonization under non-sink conditions. Moreover, this permeability was about 50% higher than that under sink conditions. On the other hand, for the low lipophilic compound, hydrocortisone, there was no difference in permeability between micro-and nano-sized compounds under non-sink conditions. The nanonization of highly lipophilic compounds improves the permeability of the unstirred water layer (UWL), which in turn improves overall permeability. On the other hand, because the rate-limiting step in permeation for the low lipophilic compounds is the diffusion of the compounds in the membrane, the improvement of UWL permeability by nanonization does not improve the overall permeability. Based on this mechanism, nanoparticle formulations are not effective for low lipophilic compounds. To accurately predict the absorption of nanoparticle formulations, it is necessary to consider their permeability under non-sink conditions which reflect in vivo conditions.

Formulation and Processing Strategies which Underpin Susceptibility to Matrix Crystallization in Amorphous Solid Dispersions

Through matrix crystallization, an amorphous solid may transform directly into its more stable crystalline state, reducing the driving force for dissolution. Herein, the mechanism of matrix crystallization in an amorphous solid dispersion (ASD) was probed. ASDs of bicalutamide/copovidone were prepared by solvent evaporation and hot melt extrusion, and sized by mortar and pestle or cryomilling techniques, modulating the level of mechanical activation experienced by the sample. Drug loading (DL) of the binary ASD was varied from 5-50%, and ternary systems were formulated at 30% DL with two surfactants (sodium dodecyl sulfate, Vitamin E TPGS). Imaging of partially dissolved or crystallized compacts by scanning electron microscopy with energy-dispersive X-ray analysis and confocal fluorescence microscopy was performed to investigate pathways of hydration, phase separation, and crystallization. Monitoring drug and polymer release of ASD powder under non-sink conditions provided insight into supersaturation and desupersaturation profiles. Systems at the greatest risk of matrix crystallization had high DLs, underwent mechanical activation, and/or contained surfactant. Systems having greatest resistance to matrix crystallization had rapid and congruent drug and polymer release. This study has implications for formulation and process design of ASDs and risk assessment of matrix crystallization.