Amorphous Solid Dispersion Formulation Research Articles

Solid amorphous formulations for enhancing solubility and inhibiting Erlotinib crystallization during gastric-to-intestinal transfer

The objective of this study was to improve the solubility and inhibit the crystallisation during the gastric-to-intestinal transfer of Erlotinib (ERL), a small molecule kinase inhibitor (smKI) compound class, which is classified as class II drug in the Biopharmaceutical Classification System (BCS). A screening approach combining different parameters (solubility in aqueous media, inhibitory effect of drug crystallisation from supersaturated drug solutions) was applied to selected polymers for the development of solid amorphous dispersions of ERL. ERL solid amorphous dispersions formulations were then prepared with 3 different polymers (Soluplus®, HPMC-AS-L, HPMC-AS-H) at a fixed drug: polymer ratio (1:4) by two different production methods (spray drying and hot melt extrusion). The spray-dried particles and cryo-milled extrudates were characterized by thermal properties, shape and particle size, solubility and dissolution behavior in aqueous media. The influence of the manufacturing process on these solid characteristics was also identified during this study. Based on the obtained results, it is concluded that the cryo-milled extrudates of HPMC-AS-L displayed better performance (enhanced solubility, reduced ERL crystallization during the simulated gastric-to-intestinal transfer) and represents a promising amorphous solid dispersion formulation for oral administration of ERL.

In vitro dissolution/permeation tools for amorphous solid dispersions bioavailability forecasting I: Experimental design for PermeaLoop™

Along with the increasing demand for candidate-enabling formulations comes the need for appropriate in vitro bioavailability forecasting. Dissolution/permeation (D/P) systems employing cell-free permeation barriers are increasingly gaining interest, due to their low cost and easy application as passive diffusion bio-predictive profiling in drug product development, as this accounts for nearly 75% of new chemical entities (NCEs) absorption mechanism.To this end, this study comprises theoretical considerations on the design and experimental work towards the establishment and optimization of a PermeaLoop™ based dissolution/permeation assay to simultaneously evaluate the drug release and permeation using Itraconazole (ITZ)-based amorphous solid dispersions (ASD) formulations, with different drug loads, based on a solvent-shift approach. Alternative method conditions were tested such as: donor medium, acceptor medium and permeation barrier were screened using both PermeaPad® and PermeaPlain® 96-well plates. A range of solubilizers, namely Sodium Dodecyl Sulfate, Vitamin E-TPGS and hydroxypropyl-β-cyclodextrin, were screened as possible solubilizing additives to the acceptor medium, while donor medium was varied between blank FaSSIF (phosphate buffer) and FaSSIF. The method optimization also included the ITZ dose selection, being the ITZ single dose (100 mg) considered the most adequate to be used in further experiments to allow the comparison with in vivo studies.In the end, a standardized approach that may be applied to predict the bioavailability of weakly basic poorly soluble drug-based formulations is described, contributing to strengthening the analytical portfolio of in vitro pre-clinical drug product development.

Engineering of 3D printed personalized polypills for the treatment of the metabolic syndrome

Metabolic syndrome is a collection of abnormalities, including at least three of the following insulin resistance, hypertension, dyslipidemia, type 2 diabetes, obesity, inflammation, and non-alcoholic fatty liver disease. 3D printed solid dosage forms have emerged as a promising tool enabling the fabrication of personalized medicines and offering solutions that cannot be achieved by industrial mass production. Most attempts found in the literature to manufacture polypills for this syndrome contain just two drugs. However, most fixed-dose combination (FDC) products in clinical practice required the use of three or more drugs. In this work, Fused deposition modelling (FDM) 3D printing technology coupled with hot-melt extrusion (HME) has been successfully applied in the manufacture of polypills containing nifedipine (NFD), as an antihypertensive drug, simvastatin (SMV), as an antihyperlipidemic drug, and gliclazide (GLZ) as an antiglycemic drug. Hanssen solubility parameters (HSPs) were utilized as predictors to guide the formation of amorphous solid dispersion between drug and polymer to ensure miscibility and enhanced oral bioavailability. The HSP varied from 18.3 for NFD, 24.6 for SMV, and 7.0 for GLZ while the total solubility parameter for the excipient mixture was 27.30.5. This allowed the formation of an amorphous solid dispersion in SMV and GLZ 3D printed tablets compared to NFD which was partially crystalline. Popypill showed a dual release profile combining a faster SMV release (< 6h) with a 24 h sustained release for NDF and GLZ. This work demonstrated the transformation of FDC into dynamic dose-personalized polypills.

The Implications of Drug-Polymer Interactions on the Physical Stability of Amorphous Solid Dispersions.

Amorphous solid dispersions (ASDs) are a formulation and development strategy that can be used to increase the apparent aqueous solubility of poorly water-soluble drugs. Their implementation, however, can be hindered by destabilization of the amorphous form, as the drug recrystallizes from its metastable state. Factors such as the drug-polymer solubility, miscibility, mobility, and nucleation/crystal growth rates are all known to impact the physical stability of an ASD. Non-covalent interactions (NCI) between the drug and polymer have also been widely reported to influence product shelf-life. In this review, the relationship between thermodynamic/kinetic factors and adhesive NCI is assessed. Various types of NCIs reported to stabilize ASDs are described, and their role in affecting physical stability is examined. Finally, NCIs that have not yet been widely explored in ASD formulations, but may potentially impact their physical stability are also briefly described. This review aims to stimulate further theoretical and practical exploration of various NCIs and their applications in ASD formulations in the future.

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.

Tailored ASD destabilization - Balancing shelf life stability and dissolution performance with hydroxypropyl cellulose

Amorphous solid dispersion (ASD) formulations are preferred enabling formulations for poorly water soluble active pharmaceutical ingredients (API) as they reliably enhance the dissolution behavior and solubility. Balancing a high stability against unwanted transformations such as crystallization and amorphous phase separation during storage on the one hand and optimizing the dissolution behavior of the formulation (high supersaturation and maintenance for long time) on the other hand are essential during formulation development. This study assessed the potential of ternary ASDs (one API and two polymers) containing the polymers hydroxypropyl cellulose together with poly(vinylpyrrolidone-co-vinyl acetate) (PVP VA64) or hydroxypropyl cellulose acetate succinate to stabilize the amorphously embedded APIs fenofibrate and simvastatin during storage and to enhance the dissolution performance. Thermodynamic predictions using the PC-SAFT model revealed for each combination of polymers the optimal polymer ratio, maximum API load that is thermodynamically stable as well as miscibility of the two polymers. The stability predictions were validated by three months enduring stability tests, followed by a characterization of the dissolution behavior. The thermodynamically most stable ASDs were found to be the ASDs with deteriorated dissolution performance. Within the investigated polymer combinations, physical stability and dissolution performance opposed each other.

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.

Thermodynamic Modeling of the Amorphous Solid Dispersion-Water Interfacial Layer and Its Impact on the Release Mechanism.

During the dissolution of amorphous solid dispersion (ASD) formulations, the gel layer that forms at the ASD/water interface strongly dictates the release of the active pharmaceutical ingredient (API) and, hence, the dissolution performance. Several studies have demonstrated that the switch of the gel layer from eroding to non-eroding behavior is API-specific and drug-load (DL)-dependent. This study systematically classifies the ASD release mechanisms and relates them to the phenomenon of the loss of release (LoR). The latter is thermodynamically explained and predicted via a modeled ternary phase diagram of API, polymer, and water, and is then used to describe the ASD/water interfacial layers (below and above the glass transition). To this end, the ternary phase behavior of the APIs, naproxen, and venetoclax with the polymer poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) and water was modeled using the perturbed-chain statistical associating fluid theory (PC-SAFT). The glass transition was modeled using the Gordon-Taylor equation. The DL-dependent LoR was found to be caused by API crystallization or liquid-liquid phase separation (LLPS) at the ASD/water interface. If crystallization occurs, it was found that API and polymer release was impeded above a threshold DL at which the APIs crystallized directly at the ASD interface. If LLPS occurs, an API-rich phase and a polymer-rich phase are formed. Above a threshold DL, the less mobile and hydrophobic API-rich phase accumulates at the interface which prevents API release. LLPS is further influenced by the composition and glass transition temperature of the evolving phases and was investigated at 37 °C and 50 °C regarding impact of temperature of. The modeling results and LoR predictions were experimentally validated by means of dissolution experiments, microscopy, Raman spectroscopy, and size exclusion chromatography. The experimental results were found to be in very good agreement with the predicted release mechanisms deduced from the phase diagrams. Thus, this thermodynamic modeling approach represents a powerful mechanistic tool that can be applied to classify and quantitatively predict the DL-dependent LoR release mechanism of PVPVA64-based ASDs in water.

Application of Sucrose Acetate Isobutyrate in Development of Co-Amorphous Formulations of Tacrolimus for Bioavailability Enhancement.

The focus of the present work was to develop co-amorphous dispersion (CAD) formulations of tacrolimus (TAC) using sucrose acetate isobutyrate as a carrier, evaluate by in vitro and in vivo methods and compare its performance with hydroxypropyl methylcellulose (HPMC) based amorphous solid dispersion (ASD) formulation. CAD and ASD formulations were prepared by solvent evaporation method followed by characterization by Fourier transformed infrared spectroscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dissolution, stability, and pharmacokinetics. XRPD and DSC indicated amorphous phase transformation of the drug in the CAD and ASD formulations, and dissolved more than 85% of the drug in 90 min. No drug crystallization was observed in the thermogram and diffractogram of the formulations after storage at 25 °C/60% RH and 40 °C/75% RH. No significant change in the dissolution profile was observed after and before storage. SAIB-based CAD and HPMC-based ASD formulations were bioequivalent as they met 90% confidence of 90-11.1% for Cmax and AUC. The CAD and ASD formulations exhibited Cmax and AUC 1.7-1.8 and 1.5-1.8 folds of tablet formulations containing the drug's crystalline phase. In conclusion, the stability, dissolution, and pharmacokinetic performance of SAIB-based CAD and HPMC-based ASD formulations were similar, and thus clinical performance would be similar.

Corroborating various material-sparing techniques with hot melt extrusion for the preparation of triclabendazole amorphous solid dispersions

Amorphous solid dispersions (ASD) are one of the most adopted technologies for improving the solubility of novel molecules. Formulation of ASDs using solvent free methods such as hot melt extrusion (HME) has been in the spotlight off-lately. However, early-stage formulation development is tricky and a difficult bridge to pass due to limited drug availability. Material-sparing techniques (theoretical & practical) have been used for selecting suitable polymeric carriers for formulating ASDs. However, these techniques have limitations in predicting the effect of process parameters. The objective of this study is to use both theoretical and practical material-sparing techniques to optimize a polymer for the developing Triclabendazole (TBZ) ASDs. Initial screening by theoretical approaches suggested that TBZ is highly miscible with Kollidon®VA64 (VA64) and poorly miscible with Parteck®MXP (PVA). However, results from ASDs prepared using SCFe were opposite to these predictions. ASDs prepared using either technique and both VA64 and PVA showed >200x increase in solubility. Each formulation released >85% of drug in less than 15 mins. Although the thermodynamic phase diagram suggested that VA64 was the ideal polymer for TBZ-ASDs, it has certain limitations in factoring the different elements during melt-processing and hence, practical approaches like SCFe could help in predicting the drug-polymer miscibility for HME processing.

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.

Preparation of a ternary amorphous solid dispersion using hot-melt extrusion for obtaining a stable colloidal dispersion of amorphous probucol nanoparticles

In our previous reports, ternary amorphous solid dispersions (ASDs) of probucol (PBC)/polymer/surfactant were prepared by spray-drying and cryo-grinding, and colloidal dispersions of amorphous PBC nanoparticles were obtained by dispersing the ternary ASD into water. In this study, hot-melt extrusion, which is a practical method for preparing ASD formulations, was utilized to obtain ternary ASDs and colloidal dispersions of amorphous PBC nanoparticles. Polyvinylpyrrolidone K12 (PVP) with a relatively low Tg (below 100 °C) was used as a polymer, while poloxamer P407 (P407), which is chemically stable during the hot-melt extrusion process, was utilized as a surfactant. Ternary ASDs were successfully produced with high weight ratios of PVP and P407. A hydrogen bond between the PBC hydroxyl proton and PVP carbonyl oxygen in the ternary ASD was detected using solid-state NMR spectroscopy, suggesting that amorphous PBC was stabilized mainly by PVP. Stable colloidal dispersions of amorphous PBC nanoparticles were obtained from the PBC/PVP/P407 ASD at a weight ratio of 1:4:2. The mean particle size was below 200 nm and the amorphous state of PBC remained stable upon storage at 25 °C for 14 d. Solution-state 1H NMR and zeta-potential measurements suggested that P407 mainly stabilized the colloidal dispersion of amorphous PBC nanoparticles by steric hindrance at the solid/liquid interface. The findings of this study demonstrate that hot-melt extrusion can form practical ternary ASDs that provide colloidal dispersion of amorphous drug nanoparticles. Thus, this study advocates for the use of hot-melt extrusion in the design of an amorphous formulation for a variety of poorly water-soluble drugs.

Development of an Amorphous Solid Dispersion Formulation for Mitigating Mechanical Instability of Crystalline Form and Improving Bioavailability for Early Phase Clinical Studies.

In this work, an amorphous solid dispersion (ASD) formulation was systematically developed to simultaneously enhance bioavailability and mitigate the mechanical instability risk of the selected crystalline form of a development drug candidate, GDC-0334. The amorphous solubility advantage calculation was applied to understand the solubility enhancement potential by an amorphous formulation for GDC-0334, which showed 2.7 times theoretical amorphous solubility advantage. This agreed reasonably well with the experimental solubility ratio between amorphous GDC-0334 and its crystalline counterpart (∼2 times) in buffers of a wide pH range. Guided by the amorphous solubility advantage, ASD screening was then carried out, focusing on supersaturation maintenance and dissolution performance. It was found that although the type of polymer carrier did not impact ASD performance, the addition of 5% (w/w) sodium dodecyl sulfate (SDS) significantly improved the GDC-0334 ASD dissolution rate. After ASD composition screening, stability studies were conducted on selected ASD powders and their hypothetical tablet formulations. Excellent stability of the selected ASD prototypes with or without tablet excipients was observed. Subsequently, ASD tablets were prepared, followed by in vitro and in vivo evaluations. Similar to the effect of facilitating the dissolution of ASD powders, the added SDS improved the disintegration and dissolution of ASD tablets. Finally, a dog pharmacokinetic study confirmed 1.8 to 2.5-fold enhancement of exposure by the developed ASD tablet over the GDC-0334 crystalline form, consistent with the amorphous solubility advantage of GDC-0334. A workflow of developing an ASD formulation for actual pharmaceutical application was proposed according to the practice of this work, which could provide potential guidance for ASD formulation development in general for other new chemical entities.

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

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

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

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

Effect of Span 20 Feeding Zone in the Twin Screw Extruder on the Properties of Amorphous Solid Dispersion of Ritonavir

A ternary amorphous solid dispersion (ASD) system consisting of drug/polymer/surfactant is receiving increased attention to improve the oral bioavailability of poorly water-soluble drugs. The effect of polymers has been extensively studied, while the impact of surfactants has not yet to be studied to the same extent. Challenging questions to be answered are whether the surfactants should be added with the drug or separately and the resulting differences between the two operating processes. By adjusting the liquid feeding zone for Span 20 in the hot-melt twin screw extruder equipment, we investigated the effect of Span 20 on the properties of the polyvinylpyrrolidone/vinyl acetate (PVPVA)-based ASD formulations of ritonavir. We found that with the delayed feeding positions of Span 20 in the twin screw extruder, the ability of the ternary ASDs to maintain the supersaturation of the milled extrudates was observed to be significantly enhanced. Furthermore, adding surfactant after a thorough mixing of polymer and drug could decrease the molecular mobility of ternary ASD formulations. In addition, the effects of Span 20 on the complex viscosity and structure of PVPVA were also investigated. The delayed addition of Span 20 could improve the complex viscosity of PVPVA, thus leading to the drug precipitation inhibition. In conclusion, the delayed addition of Span 20 in the twin screw extruder and prolonging the mixing time of the drug and polymer may be critical to the maintenance of supersaturation.

Real-time in situ X-ray micro-computed tomography study of the effect of impurities on the crystallization of amorphous nifedipine

Controlling the physical stability of noncrystalline active pharmaceutical ingredients remains a major challenge in the development of amorphous formulations such as amorphous solid-dispersion (ASD) formulations. To establish new evaluation and formulation strategies, the spatial distribution of the crystal phase in bulk amorphous nifedipine (NFD) was investigated as a model. The crystallization of amorphous NFD and the effect of a deliberately added impurity were investigated using powder X-ray diffraction (PXRD), differential scanning calorimetry and real-time in situ X-ray micro-computed tomography (X-ray CT). The stability data of amorphous samples, i.e., NFD and a mixture of NFD with an oxidative degradation product of NFD, impurity A (Imp A), at a weight ratio of 90:10, presented as percent amorphous remaining, suggests that Imp A accelerates the bulk crystal growth of NFD. Real-time in situ X-ray CT results showed surface-enhanced crystal growth and cavity formation in solid NFD samples. Moreover, the crystals were heterogeneous in density. These results suggest that Imp A affects the physical stability of the amorphous NFD. X-ray CT equipped with a heating unit can aid in-situ evaluation and assessment of physicochemical properties and physical stability of amorphous samples and formulations.

A Comparative Study between A Protein Based Amorphous Formulation and Other Dissolution Rate Enhancing Approaches: A Case Study with Rifaximin.

Amorphous solid dispersions (ASDs) based on proteins as co-formers have previously shown promising potential to improve the solubility and bioavailability of poorly water-soluble drugs. In particular, whey proteins have shown to be promising co-formers and amorphous stabilizers in ASD formulations, including at high drug loading. In this study, the feasibility of the whey protein β-lactoglobulin (BLG) as a co-former in ASDs was compared to the more traditional ASD co-formers based on synthetic polymers (hydroxypropyl methylcellulose acetate succinate and Eudragit® L) as well as to a nanocrystalline formulation. The poorly water-soluble drug rifaximin (RFX) was chosen as the model drug. All drug/co-former formulations were prepared as fully amorphous ASDs by spray drying at 50% (w/w) drug loading. The BLG-based ASD had the highest glass transition temperature and showed a faster dissolution rate and higher drug solubility in three release media with different pH values (1.2, 4.5, and 6.5) compared to the polymer-based ASDs and the nanocrystalline RFX. In conclusion, BLG is a promising co-former and amorphous stabilizer of RFX in ASD formulations, superior to the selected polymer-based ASD systems or the nanocrystalline formulation.

The role of surfactants in preserving the stability of amorphous solid dispersions: A review

In recent years among various formulation strategies, amorphous solid dispersions (ASDs) has gained tremendous recognition for improving the solubility of poorly soluble drug substances. Among various manufacturing strategies, hot melt extrusion (HME), spray drying, kinetisol, and electrospinning are the most widely employed for developing ASDs. Despite the improving solubility and bioavailability, the stability of ASDs is the major problem haunting the pharmaceutical industries. Various factors, such as miscibility, the solubility of the drug in polymer, drug-polymer interactions, glass transition temperature, hygroscopicity, and storage conditions, determine the stability of ASDs. The poor stability of amorphous drugs also limits the drug loading capacity, resulting in an increased volume of the dosage form affecting patient compliance. Apart from the physical stability of ASDs, solution-mediated recrystallization of the drug when present in a supersaturated state is another factor affecting the quality and performance of the formulations. In recent years incorporation of surfactants to hinder solution-mediated recrystallization of drugs, thereby improving the stability and performance of ASD formulations, is being most widely investigated. The incorporation of surfactant in the HME process will also act as a plasticizer, thereby allowing the process to be carried at lower temperatures. This review article mainly focuses on the role of surfactants in ASD systems and recent advancements. Still, research is warranted to understand the mechanism of surfactants and to establish screening criteria.

Stability and intrinsic dissolution of vacuum compression molded amorphous solid dispersions of efavirenz

In this study, the stability and intrinsic dissolution of vacuum compression molded (VCM) amorphous solid dispersions (ASDs) of efavirenz (EFV) were investigated in relation to its solubility limits in seven polymers determined by the melting point depression (MPD) method. The extrapolated solubility limits of EFV at 22 °C ranged from 3 to 68% (w/w) with PVOH being the only polymer suggesting immiscibility with EFV according to both MPD and Hansen solubility parameters (HSPs). All ASDs with EFV loadings below or close to their calculated solubility limit did not show any signs of crystallization upon conditioning for 7 months at either 22 or 37 °C and 23 or 75% relative humidity. However, all ASDs with EFV loading above the solubility limit crystallized at high humidity, while the ASDs with cellulose derived carrier polymers proved kinetically stable at low humidity over 7 months. While the EFV intrinsic dissolution rates from the VCM ASDs were partly depending on the polymer dissolution rate, no correlation was observed between EFV matrix crystallization and its miscibility in the polymer. Altogether, the observations of the study underline the importance of combining preformulation miscibility determination and dissolution studies to rationally decide on both stability and viability of ASD formulations.