Hypromellose Acetate Succinate Research Articles

An Artificial Gut/Absorption Simulator: Understanding the Impact of Absorption on In Vitro Dissolution, Speciation, and Precipitation of Amorphous Solid Dispersions.

Upon dissolution, amorphous solid dispersions (ASDs) of poorly water-soluble compounds can generate supersaturated solutions consisting of bound and free drug species that are in dynamic equilibrium with each other. Only free drug is available for absorption. Drug species bound to bile micelles, polymer excipients, and amorphous and crystalline precipitate can reduce the drug solute's activity to permeate, but they can also serve as reservoirs to replenish free drug in solution lost to absorption. However, with multiple processes of dissolution, absorption, and speciation occurring simultaneously, it may become challenging to understand which processes lead to an increase or decrease in drug solution concentration. Closed, nonsink dissolution testing methods used routinely, in the absence of drug removal, allow only for static equilibrium to exist and obscure the impact of each drug species on absorption. An artificial gut simulator (AGS) introduced recently consists of a hollow fiber-based absorption module and allows mass transfer of the drug from the dissolution media at a physiological rate after tuning the operating parameters. In the present work, ASDs of varying drug loadings were prepared with a BCS-II model compound, ketoconazole (KTZ), and hypromellose acetate succinate (HPMCAS) polymer. Simultaneous dissolution and absorption testing of the ASDs was conducted with the AGS, and simple analytical techniques were utilized to elucidate the impact of bound drug species on absorption. In all cases, a lower amount of crystalline precipitate was formed in the presence of absorption relative to the nonsink dissolution "control". However, formation of HPMCAS-bound drug species and crystalline precipitate significantly reduced KTZ absorption. Moreover, at high drug loading, inclusion of an absorption module was shown to enhance ASD dissolution. The rank ordering of the ASDs with respect to dissolution was significantly different when nonsink dissolution versus AGS was used, and this discrepancy could be mechanistically elucidated by understanding drug dissolution and speciation in the presence of absorption.

The impact of diluents on the compaction, dissolution, and physical stability of amorphous solid dispersion tablets

Amorphous solid dispersion (ASD) is an effective approach for enhancing the solubility, dissolution, and bioavailability of poorly water-soluble drugs. However, these metastable forms can transform into more thermodynamically stable but less soluble crystalline forms. Despite this challenge, research on processing ASDs into solid dosage forms, such as tablets, is lacking. This work aims to fill this gap by investigating the impact of common diluents on the tableting behavior, dissolution, and physical stability of ASDs composed of itraconazole and hypromellose acetate succinate. Four widely used diluents found in commercially available ASD tablets were selected for the study: microcrystalline cellulose (MCC), anhydrous lactose, starch, and mannitol. The performance of ASD tablets varied significantly depending on the diluent used. Tablets prepared with MCC exhibited higher mechanical strength than those formulated using other diluents. ASD tablets containing mannitol and lactose revealed a faster release rate than those composed of MCC or starch. Notably, the study highlighted that the physical stability of ASDs within a tablet is not solely dependent on the amount of sorbed water; crystalline diluents like lactose and mannitol were found to facilitate ASD recrystallization within a tablet. In summary, the study underscores the importance of excipient selection, considering factors such as mechanical strength, dissolution rate, and physical stability of ASD tablets. These findings offer valuable insights into the selection of excipients for downstream ASD tablet development, leading to improved manufacturability, physical stability, and the overall quality of ASD drug products.

Impact of hypromellose acetate succinate and Soluplus® on the performance of β-carotene solid dispersions with the aid of sorbitan monolaurate: In vitro-in vivo comparative assessment

Solid dispersions (SDs) possess the potential to enhance the bioavailability of insoluble active pharmaceutical ingredients (APIs) by effectively converting them into amorphous state. However, SDs have a tendency to recrystallize unless appropriate excipients are employed. The objective of this study was to evaluate the ability of hypromellose acetate succinate HF (HPMCAS-HF) and Soluplus® to inhibit the recrystallization of β-carotene and improve its in vivo bioavailability through the fabrication of ternary β-carotene solid dispersions (SDs) with the aid of specific surfactant. Due to rapid micellization, the dissolution profiles of β-carotene SDs based on HPMCAS-HF/Span 20 (5:5, w/w) or Soluplus®/Span 20 (6:4, w/w) combinations exhibited significant improvement, which were almost 7–10 times higher than β-carotene bulk powder. DSC and PXRD analysis indicated a notable reduction in the crystallinity degree of β-carotene within the SDs. The stability study demonstrated a half-life of β-carotene in the SDs exceeding 30 days. Additionally, the in vivo pharmacokinetics analysis confirmed that the cellulose derivatives/surfactant combinations significantly enhanced the bioavailability of β-carotene by 1.37-fold and 2.3-fold, respectively. Notably, the HPMCAS-HF/Span 20 combination exhibited superior performance. Consequently, the HPMCAS-HF/Span 20 combination held potential for the advancement of an effective drug delivery system for β-carotene.

Can the Oral Bioavailability of the Discontinued Prostate Cancer Drug Galeterone Be Improved by Processing Method? KinetiSol® Outperforms Spray Drying in a Head-to-head Comparison.

Galeterone, a novel prostate cancer candidate treatment, was discontinued after a Phase III clinical trial due to lack of efficacy. Galeterone is weakly basic and exhibits low solubility in biorelevant media (i.e., ~ 2µg/mL in fasted simulated intestinal fluid). It was formulated as a 50-50 (w/w) galeterone-hypromellose acetate succinate spray-dried dispersion to increase its bioavailability. Despite this increase, the bioavailability of this formulation may have been insufficient and contributed to its clinical failure. We hypothesized that reformulating galeterone as an amorphous solid dispersion by KinetiSol® compounding could increase its bioavailability. In this study, we examined the effects of composition and manufacturing technology (Kinetisol and spray drying) on the performance of galeterone amorphous solid dispersions. KinetiSol compounding was utilized to create galeterone amorphous solid dispersions containing the complexing agent hydroxypropyl-β-cyclodextrin or hypromellose acetate succinate with lower drug loads that both achieved a ~ 6 × increase in dissolution performance versus the 50-50 spray-dried dispersion. When compared to a spray-dried dispersion with an equivalent drug load, the KinetiSol amorphous solid dispersions formulations exhibited ~ 2 × exposure in an in vivo rat study. Acid-base surface energy analysis showed that the equivalent composition of the KinetiSol amorphous solid dispersion formulation better protected the weakly basic galeterone from premature dissolution in acidic media and thereby reduced precipitation, inhibited recrystallization, and extended the extent of supersaturation during transit into neutral intestinal media.

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.

Pre-Processing a Polymer Blend into a Polymer Alloy by KinetiSol Enables Increased Ivacaftor Amorphous Solid Dispersion Drug Loading and Dissolution.

This study compares the effects of pre-processing multiple polymers together to form a single-phase polymer alloy prior to amorphous solid dispersion formulation. KinetiSol compounding was used to pre-process a 1:1 (w/w) ratio of hypromellose acetate succinate and povidone to form a single-phase polymer alloy with unique properties. Ivacaftor amorphous solid dispersions comprising either a polymer, an unprocessed polymer blend, or the polymer alloy were processed by KinetiSol and examined for amorphicity, dissolution performance, physical stability, and molecular interactions. A polymer alloy ivacaftor solid dispersion with a drug loading of 50% w/w was feasible versus 40% for the other compositions. Dissolution in fasted simulated intestinal fluid revealed that the 40% ivacaftor polymer alloy solid dispersion reached a concentration of 595 µg/mL after 6 h, 33% greater than the equivalent polymer blend dispersion. Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance revealed changes in the ability of the povidone contained in the polymer alloy to hydrogen bond with the ivacaftor phenolic moiety, explaining the differences in the dissolution performance. This work demonstrates that the creation of polymer alloys from polymer blends is a promising technique that provides the ability to tailor properties of a polymer alloy to maximize the drug loading, dissolution performance, and stability of an ASD.

Enhanced biopharmaceutical performance of brick dust molecule nilotinib via stabilized amorphous nanosuspension using a facile acid-base neutralization approach.

"Brick dust" compounds have high lattice energy as manifested by the poor aqueous solubility and suboptimal bioavailability. Nilotinib being a weakly basic brick dust molecule exhibits erratic and limited absorption during gastrointestinal transit, attributed to pre-absorptive factors like pH-dependent solubility, poor dissolution kinetics, and post-absorptive factors including P-gp-mediated drug efflux. In our study, these problems are addressed holistically by the successful fabrication of amorphous nanosuspension by an acid-base neutralization approach. The nanosuspension was obtained via rapid precipitation of nilotinib in an amorphous form and the generated in situ sodium chloride salt assisted in stabilizing the drug-loaded nanosuspension in a cage of salt and micellar stabilizer. Soluplus® and hypromellose acetate succinate (HPMCAS) were employed as a novel combination of stabilizers. Systematic optimization was carried out by employing the I-optimal method using Design Expert®software with a concentration of HPMCAS and Soluplus®as independent variables and evaluating them for responses viz particle size, polydispersity index (PDI), and zeta potential. The resultant nanosuspension showed a mean particle size of 130.5 ± 1.22nm with a PDI value of 0.27 ± 0.01, and a zeta potential of - 5.21 ± 0.91mV. The nanosuspension was further characterized for morphology, dissolution, and in vivo pharmacokinetics study. X-ray powder diffraction study of the nano-formulation displayed a halo pattern revealing the amorphous form. Stability studies showed that the nanosuspension remained stable at 40°C ± 2°C and 75% RH ± 5% RH for a period of three months. In vitro drug release and solubility study showed threefold and 36-fold enhancement in dissolution and solubility of the nanosuspension. Furthermore, an in vivo pharmacokinetic study in Sprague-Dawley rats following oral administration displayed a 1.46-fold enhancement in the relative bioavailability of the nanosuspension in contrast to neat nilotinib.

Minimization of Acid-Catalyzed Degradation in KinetiSol Processing through HPMCAS Neutralization.

Hypromellose acetate succinate (HPMCAS) is an enteric polymer that has been successfully employed as a carrier in amorphous solid dispersions (ASDs). Deprotonation of succinic acid substituents at intestinal pH levels results in solubilization of the polymer. However, the acidic moieties responsible for favorable pH-dependent solubility can also result in incompatibilities between acid-sensitive drugs and HPMCAS. Solution-state conversion of the carboxylic acid substituents of enteric polymers into carboxylate salts to reduce acid-mediated drug degradation is a demonstrated effective strategy for generating ASDs in enteric polymers. This work aimed to extend the use of a pre-ionized enteric polymer to KinetiSol solvent-free processing to reduce acid- or base-mediated drug degradation during processing. Pre-ionization of HPMCAS was accomplished by reaction with a stoichiometric quantity of sodium carbonate (Na2CO3) delivered as a saturated aqueous solution. The resulting ionized polymer, HPMCAS-Na, was dried thoroughly before processing. Tetrabenazine (TBZ) was chosen as a model drug for its susceptibility to degradation via both acid- and base-catalyzed reaction mechanisms and for its tendency to form a single impurity by these mechanisms. The use of HPMCAS-Na in KinetiSol solid dispersions (KSDs) of TBZ resulted in a 6- to 8-fold reduction of the acid- and base-generated TBZ impurity compared with KSDs formulated with untreated HPMCAS.

3D printing of LEGO® like designs with tailored release profiles for treatment of sleep disorder

3D printed LEGO®-like designs are an attractive approach for the development of compartmental delivery systems due to their potential for dose personalisation through the customisation of drug release profiles. Additive manufacturing technologies such as Fused Deposition Modelling (FDM) are ideal for the printing of structures with complex geometries and various sizes. This study is a paradigm for the fabrication of 3D printed LEGO® -like tablets by altering the design of the modular units and the filament composition for the delivery of different drug substances. By using a combination of placebo and drug loaded compartments comprising of immediate release (hydroxypropyl cellulose) and pH dependant polymers (hypromellose acetate succinate) we were able to customise the release kinetics of melatonin and caffeine that can potentially be used for the treatment of sleep disorders. The LEGO® -like compartments were designed to achieve immediate release of melatonin followed by variable lag times and controlled release of caffeine.

Improving Dissolution Performance and Drug Loading of Amorphous Dispersions Through a Hierarchical Particle Approach

Co-precipitation is an emerging manufacturing strategy for amorphous solid dispersions (ASDs). Herein, the interplay between processing conditions, surface composition, and release performance was evaluated using grazoprevir and hypromellose acetate succinate as the model drug and polymer, respectively. Co-precipitated amorphous dispersion (cPAD) particles were produced in the presence and absence of an additional polymer that was either dissolved or dispersed in the anti-solvent. This additional polymer in the anti-solvent was deposited on the surfaces of the cPAD particles during isolation and drying to create hierarchical particles, which we define here as a core ASD particle with an additional water soluble component that is coating the particle surfaces. The resultant hierarchical particles were characterized using X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, and X-ray photoelectron spectroscopy (XPS). Release performance was evaluated using a two-stage dissolution test. XPS analysis revealed a trend whereby cPAD particles with a lower surface drug concentration showed improved release relative to particles with a higher surface drug concentration, for nominally similar drug loadings. This surface drug concentration could be impacted by whether the secondary polymer was dissolved in the anti-solvent or dispersed in the anti-solvent prior to isolating final dried hierarchical cPAD powders. Grazoprevir exposure in dogs was higher when the hierarchical cPAD was dosed, with ∼1.8 fold increase in AUC compared to the binary cPAD. These observations highlight the important interplay between processing conditions and ASD performance in the context of cPAD particles and illustrate a hierarchical particle design as a successful approach to alter ASD surface chemistry to improve dissolution performance.

Surface Characterization as a Tool for Identifying the Factors Affecting the Dissolution Rate of Amorphous Solid Dispersion Tablets.

An amorphous solid dispersion (ASD) is a commonly used approach to enhancing the dissolution of poorly aqueous soluble drugs. Selecting the desired polymer and drug loading can be time-consuming. Surface properties, such as surface composition and wetting behavior, are essential factors controlling the dissolution of ASD tablets. Thus, our study aims to use surface characterization to understand the factors that affect the dissolution rate of ASD tablets. In this work, we prepared ASDs with itraconazole and hypromellose acetate succinate (HPMCAS) using spray drying. ASDs were prepared using three grades of HPMCAS and different drug loading levels (10%, 30%, and 50%). We prepared ASD tablets with two porosities. For each tablet, contact angles were measured using the Drop Shape Analyzer; surface free energies, disperse, and polar fractions were calculated based on the contact angles. We conducted near-infrared (NIR) and dissolution measurements of ASD tablets. Principal component analysis (PCA) was carried out to investigate the NIR spectra further. The relative PCA scores were reported with other sample properties. A partial least square (PLS) model using NIR scores, tablets' wetting properties, and dissolution rates revealed that water and buffer contact angles, surface free energy, and polar fraction are the most significant factors attributing to the dissolution rate of ASD tablets. This work understood the interplay between the surface properties and the dissolution rate of ASD tablets. Moreover, surface characterization can be the tool to screen the formulation and compaction process of ASD tablets in early development.

Downstream Processing of Itraconazole:HPMCAS Amorphous Solid Dispersion: From Hot-Melt Extrudate to Tablet Using a Quality by Design Approach.

The downstream processing of hot-melt extruded amorphous solid dispersions (ASDs) into tablets is challenging due to the low tabletability of milled ASDs. Typically, the extrudate strand is sized before milling, as the strand cannot be fed directly into the milling system. At the lab scale, the strand can be sized by hand-cutting before milling. For scaling up, pelletizers or chill roll and flaker systems can be used to break strands. Due to the different techniques used, differences in milling and tablet compaction are to be expected. We present a systematic study of the milling and tableting of an extruded ASD of itraconazole with hypromellose acetate succinate (HPMCAS) as a carrier polymer. The strand was sized using different techniques at the end of the extruder barrel (hand-cutting, pelletizer, or chill roll and flaker) before being milled at varying milling speeds with varying screen sizes. The effects of these variables (sizing technology, milling speed, and screen size) on the critical quality attributes (CQAs) of the milled ASD, such as yield, mean particle size (D50), tablet compaction characteristics, and tablet dissolution, were established using response surface methodology. It was found that the CQAs varied according to sizing technology, with chill roll flakes showing the highest percentage yield, the lowest D50, and the highest tabletability and dissolution rate for itraconazole. Pearson correlation coefficient tests indicated D50 as the most important CQA related to tabletability and dissolution. For certain milling conditions, the milling of hand-cut filaments results in similar particle size distributions (PSDs) to the milling of pellets or chill roll flakes.

Downstream processing of spray-dried ASD with hypromellose acetate succinate – Roller compaction and subsequent compression into high ASD load tablets

Despite wide commercial application of hypromellose acetate succinate (HPMCAS) in spray-dried amorphous solid dispersion (ASD) drug products, little information is available in the references on downstream processing of spray-dried dispersions with HPMCAS. Poor flow and high dilution factor are a challenge in formulating spray-dried ASDs into tablets, leaving little space for other excipients facilitating binding and disintegration. Direct compression is not possible due to the poor powder flow of spray-dried ASDs. Moisture has to be avoided due to the plasticizing properties of water on the ASD, resulting in reduced stability of the amorphous state. Thus, dry granulation by roller compaction and subsequent tablet compression is the preferred downstream process. We report the investigation of downstream processing by roller compaction and tablet compression of a high load formulation with 75% of spray-dried amorphous solid dispersion (Nifedipine:HPMCAS 1:2). A head to head comparison of microcrystalline cellulose/croscarmellose (MCC/cl-NaCMC) as binder/disintegrant vs. MCC and low-substituted hydroxypropyl cellulose (L-HPC) as excipient for binding and disintegration showed improved re-workability of the formulation with MCC/L-HPC after roller compaction. Upon transfer to the rotary press, a 45% higher tensile strength of tablets is observed after dry granulation with MCC/L-HPC.

Predicting in vivo performance of fenofibrate amorphous solid dispersions using in vitro non-sink dissolution and dissolution permeation setup

Amorphous solid dispersion (ASD) is emerging as a useful formulation strategy to increase the bioavailability of active pharmaceutical ingredients with poor solubility. In vitro dissolution testing under non-sink conditions has often been used to evaluate the ability of ASDs to generate and maintain supersaturation to predict the in vivo performance. However, such a single compartment dissolution setup can fail to predict the oral bioavailability, due to an interdependence between precipitation and permeation. Hence, the use of two compartment dissolution-permeation setups is emerging. In this study, three ASDs containing fenofibrate as model drug substance were developed using Soluplus®, and Hypromellose Acetate Succinate in two different grades (high and low), respectively. The aim was to compare the use of a small-scale in vitro non-sink dissolution setup and a small-scale in vitro dissolution-permeation setup to predict the in vivo oral exposure of the ASDs in rats. The maximum concentration (Cmax) and area under curve (AUC) obtained in the in vitro studies were used to predict the in vivo rank order of the formulations. The results showed that the two in vitro studies resulted in the same rank order based on both Cmax and AUC. Interestingly, Cmax resulted in a better in vitro/in vivo correlation than the in vitro AUC, and based on the in vitro Cmax, the in vivo rank order was predicted.

Preparation and In Vitro/In Vivo Evaluation of Orally Disintegrating/Modified-Release Praziquantel Tablets.

This study was designed to develop orally disintegrating/sustained-release praziquantel (PZQ) tablets using the hot-melt extrusion (HME) technique and direct compression, and subsequently evaluate their release in in vitro and in vivo pharmacokinetics. For the extrusion process, hypromellose acetate succinate (HPMCAS)-LG was the carrier of pure PZQ, with a standard screw configuration used at an extrusion temperature of 140 °C and a screw rotation speed of 100 rpm. Differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD) and Fourier-transform infrared spectroscopy (FTIR) were performed to characterize the extrudate. Orally disintegrating/sustained-release praziquantel tablets (PZQ ODSRTs) were prepared by direct compression after appropriate excipients were blended with the extrudate. The release amount was 5.10% in pH 1.0 hydrochloric acid at 2 h and over 90% in phosphoric acid buffer at 45 min, indicating the enteric-coating character of PZQ ODSRTs. Compared with the pharmacokinetics of marketed PZQ tablets (Aipuruike®) in dogs, the times to peak (Tmax), elimination half-life (t1/2λ) and mean residence time (MRT) were extended in PZQ ODSRTs, and the relative bioavailability of PZQ ODSRTs was up to 184.48% of that of Aipuruike®. This study suggested that PZQ ODSRTs may have potential for the clinical treatment of parasitosis.

Balancing Solid-State Stability and Dissolution Performance of Lumefantrine Amorphous Solid Dispersions: The Role of Polymer Choice and Drug-Polymer Interactions.

Amorphous solid dispersions (ASDs) are of great interest due to their ability to enhance the delivery of poorly soluble drugs. Recent studies have shown that, in addition to acting as a crystallization inhibitor, the polymer in an ASD plays a role in controlling the rate of drug release, notably in congruently releasing formulations, where both the drug and polymer have similar normalized release rates. The aim of this study was to compare the solid-state stability and release performance of ASDs when formulated with neutral and enteric polymers. One neutral (polyvinylpyrrolidone-vinyl acetate copolymer, PVPVA) and four enteric polymers (hypromellose acetate succinate; hypromellose phthalate; cellulose acetate phthalate, CAP; methacrylic acid-methyl methacrylate copolymer, Eudragit L 100) were used to formulate binary ASDs with lumefantrine, a hydrophobic and weakly basic antimalarial drug. The normalized drug and polymer release rates of lumefantrine-PVPVA ASDs up to 35% drug loading (DL) were similar and rapid. No drug release from PVPVA systems was detected when the DL was increased to 40%. In contrast, ASDs formulated with enteric polymers showed a DL-dependent decrease in the release rates of both the drug and polymer, whereby release was slower than for PVPVA ASDs for DLs < 40% DL. Drug release from CAP and Eudragit L 100 systems was the slowest and drug amorphous solubility was not achieved even at 5% DL. Although lumefantrine-PVPVA ASDs showed fast release, they also showed rapid drug crystallization under accelerated stability conditions, while the ASDs with enteric polymers showed much greater resistance to crystallization. This study highlights the importance of polymer selection in the formulation of ASDs, where a balance between physical stability and dissolution release must be achieved.

Effect of Hypromellose Acetate Succinate Substituents on Miscibility Behavior of Spray-dried Amorphous Solid Dispersions: Flory–Huggins Parameter Prediction and Validation

• Theoretical predictions and validation of miscibility was investigated. • Gibbs-composition phase diagram predicts the composition dependent miscibility. • Substituent ratios have significant effect on miscibility and drug loading. • Higher succinoyl content leads to higher dissolution efficiency. • Non-polar drugs show higher miscibility with HG grade, but low dissolution. This study reports the impact of physicochemical properties of lipophilic drugs such as Fenofibrate (FBT), Itraconazole (ITZ), Efavirenz (EFV) and Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) grades on the miscibility, dissolution, and stability of the spray dried Amorphous Solid Dispersions (ASDs). The miscibility between of the drugs and HPMCAS grades was predicted using solubility parameter-derived Flory-Huggins interaction parameter and later phase diagram was constructed to delineate the composition dependent miscibility. By varying the HPMCAS grade−drug combinations and loadings, the amorphicity of prepared ASDs was analyzed using Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD) and in vitro dissolution experiments were conducted to measure apparent solubility and finally, investigate the interplay between substituent ratio and functionality. Interactions between the drugs and polymeric grades and drug concentration in polymer is crucial in determining the drug precipitation within the ASDs which is further supported by Fourier Transform Infrared Spectroscopy (FTIR). The dissolution efficiency and dissolution rate of the ASDs were dependent on the acetyl-succinoyl ratio in HPMCAS.

Evaluation of the impact of surfactants on miscibility of griseofulvin in spray dried amorphous solid dispersions

The aim of this contribution is to examine the impact of incorporating surfactants into amorphous solid dispersions on solid state miscibility and aqueous solubility of the antifungal drug griseofulvin. Spray dried amorphous solid dispersions of griseofulvin (GF) and hypromellose acetate succinate (HPMCAS) were prepared by spray drying. Three different surfactants of varying ratios between 1 to 5% were used namely the anionic sodium dodecyl sulfate (SDS), the cationic dodecyletrimethylammonium bromide (DTAB) and the non-ionic pluronic (F127). Flory-Huggins model combined with calculations based on Hoffman's equation were used to calculate miscibility and predicted solubility of the amorphous form. The results showed that the prepared solid dispersions exhibited enhanced drug-polymer miscibility reflected by improved thermodynamics of mixing. The highest miscibility was achieved when DTAB was incorporated by which the drug-polymer miscibility was enhanced by approximately 1.5 times. The tendency to recrystallize was calculated using reduced recrystallization parameter and correlated with the measured saturation solubility showing distinct properties which were dependent on the type of surfactant. Saturated solubility of the solid dispersions was compared with micellar solubility and was found to be significantly affected by the presence of the polymer. The glass transition temperature (Tg) decreased significantly upon the addition of surfactants. However, gravimetric analysis showed that solvent content did not exceed 1% which suggests that the shifted Tg was not related to plasticizing effect of residual solvent. Overall, these results suggest potential role for the surfactants in enhancing solid state miscibility when incorporated into the solid dispersions.

Precipitation from amorphous solid dispersions in biorelevant dissolution testing: The polymorphism of regorafenib

Amorphous Solid Dispersions (ASDs) are a major drug formulation technique to achieve higher bioavailability for poorly water-soluble active pharmaceutical ingredients. So far, dissolution tailoring and supersaturation enhancement have been studied in detail, whereas less is known about the importance of formed precipitates with amorphous or crystalline states at the site of drug absorption.Regorafenib monohydrate (RGF MH), a multikinase inhibitor drug categorized as Biopharmaceutics Classification System (BCS) class II compound, was formulated with povidone K25 and hypromellose acetate succinate (HPMCAS) as an ASD. Here, for the first time, the RGF precipitation process as well as the physicochemical properties of the arising precipitates are investigated. The formed precipitates from biorelevant dissolution showed varying drug content and were analyzed offline by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), confocal Raman microscopy (CRM), X-ray powder diffraction (XRPD), and small angle X-ray scattering (SAXS). In addition to different crystalline RGF precipitates, an amorphous co-precipitate of RGF and HPMCAS was identified, which was suppressed in the presence of PVP. Wide angle X-ray scattering (WAXS) and isothermal calorimetry (ITC) were used to track the precipitation process of RGF in-situ. From calorimetric data, the precipitation profile was calculated. RGF forms precipitates in multiple polymorphic states dependent on the environmental conditions, i.e., dissolution media composition and chosen excipients. The engineered formation of defined amorphous structures in-vivo may be a promising future drug formulation strategy.

A differential equation based modelling approach to predict supersaturation and in vivo absorption from in vitro dissolution-absorption system (idas2) data

In vitro dissolution tests are widely used to monitor the quality and consistency of oral solid dosage forms, but to increase the physiological relevance of in vitro dissolution tests, newer systems combine dissolution and permeation measurements. Some of these use artificial membranes while others (e.g., in the in vitro dissolution absorption system 2; IDAS2), utilize cell monolayers to assess drug permeation. We determined the effect of the precipitation inhibitor Hypromellose Acetate Succinate (HPMCAS) on the supersaturation/permeation of Ketoconazole and Dipyridamole in IDAS2 and its effect on their absorption in rats. Thus the main objectives of this study were to determine: (1) whether dissolution and permeation data from IDAS2 could be used to predict rat plasma concentration using an absorption model and (2) whether the effect of the precipitation inhibitor HPMCAS on supersaturation and permeation in IDAS2 was correlated with its effect on systemic absorption in the rat. Predicted drug concentrations in rat plasma, generated using parameters estimated from IDAS2 dissolution/permeation data and a mathematical absorption model, showed good agreement with measured concentrations. While in IDAS2, the prolongation of Ketoconazole’s supersaturation caused by HPMCAS led to higher permeation, which paralleled the higher systemic absorption in rats, Dipyridamole showed no supersaturation and, thus, no effect of HPMCAS in dissolution or permeation in IDAS2 and no effect on Dipyridamole absorption in rats. The ability of IDAS2 to detect supersaturation following a pH-shift supports the potential value of this system for studying approaches to enhance intestinal absorption through supersaturation and the accuracy of plasma concentration predictions in rats suggest the possibility of combining IDAS2 with absorption models to predict plasma concentration in different species.