Performance Of Amorphous Solid Dispersions Research Articles

Amorphous solid dispersions of triclabendazole: Keeping the supersaturated drug solution using poloxamers

The dissolution performance of amorphous solid dispersions often leads to the formation of supersaturated drug solutions. However, in many cases, the drugs can recrystallize from those solutions and precipitate. Thus, this study evaluates whether two selected poloxamers, as carriers of amorphous solid dispersions, could avoid the recrystallization and further precipitation of the hydrophobic triclabendazole. Different systems were prepared by the melting method and then characterized in solid and liquid states. The findings indicated that the drug solubility increased more than twenty times, from 0.3 μg/mL (raw drug) to 3.53 μg/mL and 7.28 μg/mL in the presence of P188 and P237, respectively. A similar finding was observed for the drug dissolution, and P188 and P237 increased the drug dissolution to 90 and 100 %, respectively. This study also confirmed that P237 was more effective than P188 in avoiding drug precipitation. As seen by X-ray diffraction analysis, an almost complete amorphization of the drug was observed by increasing the ratio of the poloxamers. Thus, these findings help to understand the dissolution behavior and supersaturated state of triclabendazole from amorphous solid dispersions, which could be applied to other hydrophobic drugs.

Characterizing Phase Separation of Amorphous Solid Dispersions Containing Imidacloprid.

Amorphous-Amorphous phase separation (AAPS) is an important phenomenon that can impede the performance of amorphous solid dispersions (ASDs). The purpose of this study was to develop a sensitive approach relying on dielectric spectroscopy (DS) to characterize AAPS in ASDs. This includes detecting AAPS, determining the size of the active ingredient (AI) discrete domains in the phase-separated systems, and accessing the molecular mobility in each phase. Using a model system consisting of the insecticide imidacloprid (IMI) and the polymer polystyrene (PS), the dielectric results were further confirmed by confocal fluorescence microscopy (CFM). The detection of AAPS by DS was accomplished by identifying the decoupled structural (α-)dynamics of the AI and the polymer phase. The α-relaxation times corresponding to each phase correlated reasonably well with those of the pure components, implying nearly complete macroscopic phase separation. Congruent with the DS results, the occurrence of the AAPS was detected by means of CFM, making use of the autofluorescent property of IMI. Oscillatory shear rheology and differential scanning calorimetry (DSC) detected the glass transition of the polymer phase but not that of the AI phase. Furthermore, the otherwise undesired effects of interfacial and electrode polarization, which can appear in DS, were exploited to determine the effective domain size of the discrete AI phase in this work. Here, stereological analysis of CFM images probing the mean diameter of the phase-separated IMI domains directly stayed in reasonably good agreement with the DS-based estimates. The size of phase-separated microclusters showed little variation with AI loading, implying that the ASDs have presumably undergone AAPS upon manufacturing. DSC provided further support to the immiscibility of IMI and PS, as no discernible melting point depression of the corresponding physical mixtures was detected. Moreover, no signatures of strong attractive AI-polymer interactions could be detected by mid-infrared spectroscopy within this ASD system. Finally, dielectric cold crystallization experiments of the pure AI and the 60 wt % dispersion revealed comparable crystallization onset times, hinting at a poor inhibition of the AI crystallization within the ASD. These observations are in harmony with the occurrence of AAPS. In conclusion, our multifaceted experimental approach opens new venues for rationalizing the mechanisms and kinetics of phase separation in amorphous solid dispersions.

Amorphous Solid Dispersions: Role of the Polymer and Its Importance in Physical Stability and In Vitro Performance.

Amorphous solid dispersions stabilized by one or more polymer(s) have been widely used for delivering amorphous drugs with poor water solubilities, and they have gained great market success. Polymer selection is important for preparing robust amorphous solid dispersions, and considerations should be given as to how the critical attributes of a polymer can enhance the physical stability, and the in vitro and in vivo performances of a drug. This article provides a comprehensive overview for recent developments in the understanding the role of polymers in amorphous solid dispersions from the aspects of nucleation, crystal growth, overall crystallization, miscibility, phase separation, dissolution, and supersaturation. The critical properties of polymers affecting the physical stability and the in vitro performance of amorphous solid dispersions are also highlighted. Moreover, a perspective regarding the current research gaps and novel research directions for better understanding the role of the polymer is provided. This review will provide guidance for the rational design of polymer-based amorphous pharmaceutical solids with desired physicochemical properties from the perspective of physical stability and in vitro performance.

How rotational speed of planetary ball mill and polymer load influence the performance and water vapor sorption in solid dispersions composed of tadalafil and soluplus

The presence of residual water may deteriorate the performance of amorphous solid dispersions prepared by ball milling, affecting molecular mobility, crystallinity, particle size and finally, the drug dissolution rate. As the stability of these metastable systems depend on both formulation and process variables, the aim of this study was to assess for the first time, the impact that the polymer load and the rotational speed applied upon high energy ball milling could have on the performance of binary co-milled solid dispersions composed of tadalafil (a hydrophobic crystalline drug) and Soluplus (an amphiphilic, hygroscopic amorphous polymer). Each of these variables was tested at three levels. Scanning electron microscopy, laser diffraction and X-ray powder diffraction were used to analyze morphology, particle size distribution and crystallinity of ball milled formulations respectively. Dissolution studies were also carried out. Advanced tools of applied physics, namely solid state 1H NMR and relaxometry were used to assess the structure and water mobility upon gaseous phase hydration on storage. It was shown that both tested variables determined the particle size of the formulation. When the rotational speed of 400 rpm was used, all solid dispersion were XRD-amorphous, but to ensure the immediate release of tadalafil its micellar solubilization in Soluplus was necessary. While the formulation was exposed to water vapor, the hydration level increased with an increasing polymer load as well. Hence, the rotational speed governed the space available for the adsorption of water molecules and their organization in a monolayer or multilayers. Such behavior may have impact on the kinetics of the amorphous drug recrystallization, and finally deteriorate its dissolution.

Impact of structural relaxation on mechanical properties of amorphous polymers

Fusion based methods, such as hot-melt extrusion, are a common way of preparing amorphous solid dispersions. Since the amorphous glass, however, is not in a configurational equilibrium, the molecular arrangement of the obtained material can differ in dependence of the preparation conditions. Although the changes in the configuration of an amorphous material, which are commonly referred to as structural relaxation or physical aging, are well investigated, the impact on mechanical properties of amorphous solid dispersions have widely been neglected so far. The presented study investigated copovidone as a model polymer commonly used in amorphous solid dispersions and revealed that structural relaxation was already introduced into the polymer during hot-melt extrusion while its degree was cooling rate dependent. The degree of structural relaxation significantly affected the mechanical properties of copovidone as assessed by diametral compression tests, macroindentation and nanoindentation. An increase in Young’s modulus and indentation hardness was observable with a higher degree of structural relaxation, which, during tablet compression, translated into tablets with significantly lower tensile strength. Furthermore, evaluation of the force-displacement curves during tablet compression revealed a decreased proportion of irreversible deformation with higher degree of structural relaxation correlating well with the increased indentation hardness during macroindentation. Thus, understanding structural relaxation and its impact on material properties is of utmost importance to assess the processability and compaction performance of amorphous solid dispersions in dependence of their preparation conditions and thermal history.

The tangential flow absorption model (TFAM) – A novel dissolution method for evaluating the performance of amorphous solid dispersions of poorly water-soluble actives

There is a substantial demand for absorptive dissolution tests, as single vessel dissolution experiments were originally not designed for testing supersaturating systems. Current approaches suffer from inadequate mass transfer of the dissolved active from the dissolution site, discrepancies in the fluid volume compared to in vivo intestinal fluid volumes or the dilution of functional excipients.In this work a novel dissolution apparatus was developed that enables adjustable mass transfer of the active through a membrane, while retaining the functional polymeric excipients at the dissolution site. Using this setup the dissolution behavior of various spray dried amorphous solid dispersions containing carbamazepine, hydrochlorothiazide and ketoconazole as model actives at intermediate and high supersaturation levels was evaluated. Compared to non-absorptive dissolution experiments, differences in the concentration-time profiles were noted. The experiments with a high supersaturation of ketoconazole revealed a concentration decrease over time under absorptive conditions. Additionally, it was observed that the difference between “spring” as well as “spring and parachute” formulations was less pronounced with increasing drug efflux. Further, the apparatus was also tested with Fasted State Simulated Intestinal Fluid as dissolution medium and results were compared to phosphate buffer pH6.8. As major benefits of the new TFAM apparatus the easy experimental procedure and sample preparation for drug concentration measurements using spectroscopy in the permeate, without the necessity for additional filtration and/or centrifugation to remove precipitated drug molecules, could be highlighted. This TFAM approach seems to be a promising tool for identifying formulations for amorphous solid dispersions with optimal in vitro performance.

Investigation of Drug–Polymer Miscibility, Molecular Interaction, and Their Effects on the Physical Stabilities and Dissolution Behaviors of Norfloxacin Amorphous Solid Dispersions

This study investigated the drug–polymer miscibility, intermolecular interaction, physical stability, and dissolution performance of amorphous solid dispersions (ASDs) of norfloxacin (NFX) with pol...

Amorphous solid dispersions of ketoprofen and poly-vinyl polymers prepared via electrospraying and spray drying: A comparison of particle characteristics and performance

The purpose of this work was to compare the particle characteristics and dissolution performance of amorphous solid dispersions (ASDs) of ketoprofen and vinyl-pyrrolidone based polymers prepared using electrospraying and spray drying methods. Solution characteristics (surface tension, viscosity and conductivity) were determined for ethanolic solutions containing different vinyl-pyrrolidone based polymers (PVP and PVPVA) and different ketoprofen to polymer mass ratios. The only statistically significant difference in solution properties between PVP and PVPVA systems was electrical conductivity. The higher conductivity in PVP-containing solutions resulted in smaller, more spherical particles than the equivalent formulations prepared with PVPVA when processed via electrospraying. Electrospraying resulted in powders with higher specific surface area, smaller mean particle size, and narrower particle size distribution relative to the spray-dried material. Amorphisation of ketoprofen via both processes was confirmed using pXRD, DSC and FTIR. Although the specific surface area of the electrosprayed powder was higher than the equivalent spray-dried system, this did not translate into a faster dissolution rate at pH 1.2 but did lead to a faster surface moisture adsorption rate at various relative humidities. The flowability of the powder produced via the electrospraying process is poor compared to the equivalent powder produced via spray drying, which may cause challenges in downstream processing. While the ASD powder produced via electrospraying had a smaller particle size and narrower size distribution compared to equivalent spray-dried ASD, further refinement in terms of a final formulation is needed to translate this benefit into an improved dissolution rate in the case of ketoprofen.

Miniaturized Measurement of Drug-Polymer Interactions via Viscosity Increase for Polymer Selection in Amorphous Solid Dispersions.

Drug-polymer interactions have a substantial impact on stability and performance of amorphous solid dispersions (ASD) but are difficult to analyze. Whereas there are many screening methods described for polymer selection based for example on glass forming ability, drug-polymer miscibility, supersaturation, or inhibition of recrystallization, the distinct detection of physico-chemical interactions mostly lacks miniaturized techniques. This work presents an interaction screening assessing the relative viscosity increase between highly concentrated polymer solutions with and without the model drug ketoconazole (KTZ). The fluorescent molecular rotor 9-(2-carboxy-2-cyanovinyl)julolidine was added to the solutions in a miniaturized setup in μL-scale. Due to its environment-sensitive emission behavior, the integrated fluorescence intensity can be used as a viscosity dye within this screening approach (FluViSc). Differences in relative viscosity increases through addition of KTZ were proposed to rank polymers regarding KTZ-polymer interactions. Absolute viscosities were measured with a cone-plate rheometer as a complimentary method and supported the results acquired by the FluViSc. Solid-state nuclear magnetic resonance (ss-NMR) relaxation time measurements and Raman spectroscopy were utilized to investigate drug-polymer interactions at a molecular level. Whereas Raman spectroscopy was not suited to reveal KTZ-polymer interactions, ss-NMR relaxation time measurements differentiated between the selected polymeric carriers hydroxypropylmethylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidone vinyl acetate 60:40 (PVP-VA64). Interactions were detected for HPMCAS/KTZ ASD while there was no hint for interactions between KTZ and PVP-VA64. These results were in correlation with the FluViSc. The findings were correlated with the dissolution performance of ASD and found to be predictive for supersaturation and inhibition of precipitation during dissolution.

Insight into Amorphous Solid Dispersion Performance by Coupled Dissolution and Membrane Mass Transfer Measurements.

The tendency of highly supersaturated solutions of poorly water-soluble drugs to undergo liquid-liquid phase separation (LLPS) into drug-rich and water-rich phases when the concentration exceeds the amorphous solubility, for example, during dissolution of some amorphous solid dispersions, is thought to be advantageous from a bioavailability enhancement perspective. Recently, we have developed a high surface area, flow-through absorptive dissolution testing apparatus that enables fast mass transfer providing more in vivo relevant conditions and time frames for formulation testing. Using this apparatus, the absorption behaviors of solutions with different extents of supersaturation below and above the amorphous solubility were evaluated. In addition, simultaneous dissolution-absorption testing of amorphous solid dispersions (ASDs) with varying drug loadings and polymer types was carried out to study and distinguish the absorption behavior of ASDs that do or do not undergo LLPS. When compared with closed-compartment dissolution testing, a significant influence of the absorptive compartment on the dissolution rate of ASDs, particularly at high drug loadings, was observed. The formation of drug-rich nanodroplets, generated by both solvent-addition and ASD dissolution, resulted in a higher amount of drug transferred across the membrane. Moreover, the mass transfer was further enhanced with increasing concentration above the amorphous solubility, thereby showing correlation with an increase in the number of drug-rich particles. The importance of including an absorptive compartment in dissolution testing is highlighted in this study, enabling coupling of dissolution to membrane transport, and providing a more meaningful comparison between different formulations.

New Strategies for Improving the Development and Performance of Amorphous Solid Dispersions.

The understanding of amorphous solid dispersions has grown significantly in the past decade. This is evident from the number of approved commercial amorphous solid dispersion products. While amorphous formulation is considered an enabling technology, it has become the norm for formulating poorly soluble compounds. Despite this success, improvements can still be made that enable early development formulation decisions, to develop a rationale for selecting a manufacturing process, to overcome degradation and phase separation during processing, to help achieve physical stability during storage, and to optimize dissolution behavior. The purpose of this literature review is to present recently reported strategies for improving the development and performance of ASDs. The benefits and limitations of each strategy as well as recent relevant case studies will be presented in this review. The strategies are presented from three different aspects: (a) prediction techniques that enable formulation decisions, (b) manufacturing considerations that help produce physically and chemically stable ASDs, and

Importance of in vitro dissolution conditions for the in vivo predictability of an amorphous solid dispersion containing a pH-sensitive carrier

The present study investigated the influence of in vitro dissolution conditions on the in vivo predictability of an amorphous solid dispersion of celecoxib (CCX) in the pH-sensitive polymer Eudragit® S 100. Different doses of a 25:75w/w% CCX:Eudragit® S 100 amorphous solid dispersion (CCX:EUD) were investigated. During in vitro dissolution a significant effect of the pH of the dissolution media on the release of CCX was observed. In fasted state simulated intestinal fluid (FaSSIF) pH 6.5, the release of CCX from the amorphous solid dispersion was comparable to that of crystalline CCX and lower than that of amorphous CCX whereas in FaSSIF pH 7.4, the release was significantly increased compared to both crystalline and amorphous CCX. With a 3-fold increase in the exposure of CCX:EUD compared to crystaline CCX. The in vivo data also suggested that Eudragit® S 100 was suitable as a carrier in amorphous solid dispersions of CCX. In vitro-in vivo correlation demonstrated that the in vitro data obtained in FaSSIF pH 7.4 was more predictive for the in vivo performance than that obtained in FaSSIF pH 6.5. Consequently, the findings of this study underline that when predicting the in vivo performance of amorphous solid dispersions with pH-sensitive polymers, it is imperative that the in vitro dissolution conditions are carefully considered.

Effect of micro-environment modification and polymer type on the in-vitro dissolution behavior and in-vivo performance of amorphous solid dispersions

This study investigates the effects of micro-environment modification and polymer type on the in-vitro dissolution behavior and in-vivo performance of micro-environment pH modifying solid dispersions (pHM-SD) for the poorly water-soluble model drug Toltrazuril (TOL). Various pHM-SDs were prepared using Ca(OH)2 as a pH-modifier in hydrophilic polymers, including polyethylene glycol 6000 (PEG6000), polyvinylpyrrolidone k30 (PVPk30) and hydroxypropyl methylcellulose (HPMC). Based on the results of physicochemical characterizations and in-vitro dissolution testing, the representative ternary (Ca(OH)2:TOL:PEG6000/HPMC/PVPk30=1:8:24, w/w/w) and binary (TOL:PVPk30=1:3, w/w) solid dispersions were selected and optimized to perform in-vivo pharmacokinetic study. The micro-environment pH modification improved the in-vitro water-solubility and in-vivo bioavailability of parent drug TOL. Furthermore, the addition of alkalizers not only enhanced the release and absorption of prototype drug, but also promoted the generation of active metabolites, including toltrazuril sulfoxide (TOLSO) and toltrazuril sulfone (TOLSO2). The in-vitro dissolution profiles and in-vivo absorption, distribution and metabolism behaviors of the pHM-SDs varied with polymer type. Moreover, in-vivo bioavailability of three active pharmaceutical ingredients increased with an increase in in-vitro dissolution rates of the drug from the pHM-SDs prepared with various polymers. Therefore, a non-sink in-vitro dissolution method can be used to predict the in-vivo performance of pHM-SDs formulated with various polymers with trend consistency. In-vitro and in-vivo screening procedures revealed that the pHM-SD composed of Ca(OH)2, TOL and PVPk30 at a weight ratio of 1:8:24, of which the safety was adequately proved via histopathological examination, may be a promising candidate for providing better clinical outcomes.

Effect of polymer type and drug dose on the in vitro and in vivo behavior of amorphous solid dispersions

This study investigated the non-sink in vitro dissolution behavior and in vivo performance in rats of celecoxib (CCX) amorphous solid dispersions with polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) at different drug doses. Both in vitro and in vivo, the amorphous solid dispersions with the hydrophilic polymers PVP and HPMC led to higher areas under both, the in vitro dissolution and the plasma concentration–time curves (AUC) compared to crystalline and amorphous CCX for all doses. In contrast, the amorphous solid dispersion with the hydrophobic polymer PVA showed a lower AUC both in vitro and in vivo than crystalline CCX. For crystalline CCX and CCX:PVA, the in vitro AUC was limited by the low solubility of the drug and the slow release of the drug from the hydrophobic polymer, respectively. For the supersaturating formulations, amorphous CCX, CCX:PVP and CCX:HPMC, the in vitro performance was mainly dependent on the dissolution rate and precipitation/crystallization inhibition of the polymer. As expected, the crystallization tendency increased with increasing dose, and therefore the in vitro AUCs did not increase proportionally with dose. Even though the in vivo AUC for all formulations increased with increasing dose, the relative bioavailability decreased significantly, indicating that the supersaturating formulations also crystallized in vivo and that the absorption of CCX was solubility-limited. These findings underline the importance of evaluating relevant in vitro doses, in order to rationally assess the performance of amorphous solid dispersions and avoid confusion in early in vivo studies.

Influence of polymer molecular weight on in vitro dissolution behavior and in vivo performance of celecoxib:PVP amorphous solid dispersions

In this study, the influence of the molecular weight of polyvinylpyrrolidone (PVP) on the non-sink in vitro dissolution and in vivo performance of celecoxib (CCX):PVP amorphous solid dispersions were investigated. The dissolution rate of CCX from the amorphous solid dispersions increased with decreasing PVP molecular weight and crystallization inhibition was increased with increasing molecular weight of PVP, but reached a maximum for PVP K30. This suggested that the crystallization inhibition was not proportional with molecular weight of the polymer, but rather there was an optimal molecular weight where the crystallization inhibition was strongest.Consistent with the findings from the non-sink in vitro dissolution tests, the amorphous solid dispersions with the highest molecular weight PVPs (K30 and K60) resulted in significantly higher in vivo bioavailability (AUC0–24h) compared with pure amorphous and crystalline CCX.A linear relationship between the in vitro and in vivo parameter AUC0–24h indicated that the simple non-sink in vitro dissolution method used in this study could be used to predict the in vivo performance of amorphous solid dispersion with good precision, which enabled a ranking between the different formulations. In conclusion, the findings of this study demonstrated that the in vitro and in vivo performance of CCX:PVP amorphous solid dispersions were significantly controlled by the molecular weight of the polymer.

Investigating the Dissolution Performance of Amorphous Solid Dispersions Using Magnetic Resonance Imaging and Proton NMR.

We have investigated the dissolution performance of amorphous solid dispersions of poorly water-soluble bicalutamide in a Kollidon VA64 polymeric matrix as a function of the drug loading (5% vs. 30% bicalutamide). A combined suite of state-of-the-art analytical techniques were employed to obtain a clear picture of the drug release, including an integrated magnetic resonance imaging UV-Vis flow cell system and H-NMR. Off-line H-NMR was used for the first time to simultaneously measure the dissolution profiles and rates of both the drug and the polymer from a solid dispersion. MRI and H-NMR data showed that the 5% drug loading compact erodes linearly, and that bicalutamide and Kollidon VA64 are released at approximately the same rate from the molecular dispersion. For the 30% extrudate, data indicated a slower water ingress into the compact which corresponds to a slower dissolution rate of both bicalutamide and Kollidon VA64.

Drug-polymer-water interaction and its implication for the dissolution performance of amorphous solid dispersions.

The in vitro dissolution mechanism of an amorphous solid dispersion (ASD) remains elusive and highly individualized, yet rational design of ASDs with optimal performance and prediction of their in vitro/in vivo performance are very much desirable in the pharmaceutical industry. To this end, we carried out comprehensive investigation of various ASD systems of griseofulvin, felodipine, and ketoconazole, in PVP-VA or HPMC-AS at different drug loading. Physiochemical properties and processes related to drug-polymer-water interaction, including the drug crystallization tendency in aqueous medium, drug-polymer interaction before and after moisture exposure, supersaturation of drug in the presence of polymer, polymer dissolution kinetics, etc., were characterized and correlated with the dissolution performance of ASDs at different dose and different drug/polymer ratio. It was observed that ketoconazole/HPMC-AS ASD outperformed all other ASDs in various dissolution conditions, which was attributed to the drug's low crystallization tendency, the strong ketoconazole/HPMC-AS interaction and the robustness of this interaction against water disruption, the dissolution rate and the availability of HPMC-AS in solution, and the ability of HPMC-AS in maintaining ketoconazole supersaturation. It was demonstrated that all these properties have implications for the dissolution performance of various ASD systems, and further quantification of them could be used as potential predictors for in vitro dissolution of ASDs. For all ASDs investigated, HPMC-AS systems performed better than, or at least comparably with, their PVP-VA counterparts, regardless of the drug loading or dose. This observation cannot be solely attributed to the ability of HPMC-AS in maintaining drug supersaturation. We also conclude that, for fast crystallizers without strong drug-polymer interaction, the only feasible option to improve dissolution might be to lower the dose and the drug loading in the ASD. In this study, we implemented an ASD/water Flory-Huggins parameter plot, which might assist in revealing the physical nature of the drug-polymer interaction. We also introduced supersaturation parameter and dissolution performance parameter as two quantitative measurements to compare the abilities of polymers in maintaining drug supersaturation, and the dissolution performance of various solid dispersions, respectively.

The incorporation of low-substituted hydroxypropyl cellulose into solid dispersion systems

While the use of amorphous solid dispersions to improve aqueous solubility is well documented, little consideration has traditionally been given to the finished dosage form. The objective of this study was to evaluate the dissolution performance of amorphous solid dispersions containing a dispersed superdisintegrant with binding properties. KinetiSol® dispersing was used to thermally process hypromellose acetate succinate-based compositions containing the drug substance nifedipine (NIF) and a highly compressible grade of low-substituted hydroxypropyl cellulose (New Binder Disintegrants; NBD-grade). Solid-state analysis demonstrated that compositions were rendered amorphous during processing. Tablets containing intra-dispersion NBD were found to exhibit non-sink dissolution performance similar to milled intermediate, demonstrating excellent disintegration characteristics. Conversely, tablets without intra-dispersion NBD were found to release significantly less NIF during dissolution analysis due to particle agglomeration. It was determined that compressibility and particle wetting increased as the level of intra-dispersion NBD increased.

Real time Raman imaging to understand dissolution performance of amorphous solid dispersions

We have employed for the first time Raman spectroscopic imaging along with multi-variate curve resolution (MCR) analysis to investigate in real time and in-situ the dissolution mechanisms that underpin amorphous solid dispersions, with data being collected directly from the dosage form itself. We have also employed a novel rotating disk dissolution rate (RDDR) methodology to track, through the use of high-performance liquid chromatography (HPLC), the dissolution trends of both drug and polymer simultaneously in multi-component systems. Two formulations of poorly water-soluble felodipine in a polymeric matrix of copovidone VA64 which have different drug loadings of 5% and 50% w/w were used as models with the aim of studying the effects of increasing the amount of active ingredient on the dissolution performance. It was found that felodipine and copovidone in the 5% dispersion dissolve with the same dissolution rate and that no Raman spectral changes accompanied the dissolution, indicating that the two components dissolve as single entity, whose behaviour is dominated by water-soluble copovidone. For the 50% drug-loaded dispersion, partial RDDR values of both felodipine and copovidone were found to be extremely low. MCR Raman maps along with classical Raman/X-ray powder diffraction (XRPD) characterisation revealed that after an initial loss of copovidone from the extrudate the drug re-crystallises, pointing to a release dynamics dependent on the low water solubility and high hydrophobicity of felodipine. Raman imaging revealed different rates of transition from amorphous to crystalline felodipine at different locations within the dosage form.

Assessing the performance of amorphous solid dispersions

The characterization and performance of stable amorphous solid dispersion systems were evaluated in 40 research papers reporting active pharmaceutical ingredient (API) dissolution and bioavailability from various systems containing polymers. The results from these studies were broadly placed into three categories: amorphous dispersions that improved bioavailability (∼82% of the cases), amorphous dispersions possessing lower bioavailability than the reference material (∼8% of the cases), and amorphous dispersions demonstrating similar bioavailabilities as the reference material (∼10% of the cases). A comparative analysis of these studies revealed several in vitro and in vivo variables that could have influenced the results. The in vitro factors compared primarily centered on dissolution testing and equipment, content and amount of dissolution media, sink or nonsink conditions, agitation rates, media pH, dissolution characteristics of the polymer, and dispersion particle size. The in vivo factors included reference materials used for bioavailability comparisons, animal species utilized, fasting versus fed conditions, and regional differences in gastrointestinal (GI) content and volume. On the basis of these considerations, a number of recommendations were made on issues ranging from the assessment of physical stability of API-polymer dispersions to in vivo GI physiological factors that require consideration in the performance evaluation of these systems.