Non-sink Dissolution Research Articles

The effect of some acrylic polymers on dissolution of celecoxib solid dispersion formulations

Objective The purpose of the present study was firstly to identify the effectiveness of Eudragit® polymers (Eudragit® RL, RS, L100-55, L100, S100 and E100) in inhibition of celecoxib precipitation from buffer solutions (pH = 6.8). Furthermore, the influence of Eudragit® polymers on non-sink dissolution behavior of celecoxib from solid dispersions was investigated. Methods Solid dispersions were prepared by the rotary evaporation method. In vitro dissolution studies, FT-IR and differential scanning calorimetry were employed to characterize the formulations. Results The results revealed that Eudragit® E100, L100 and S100 inhibited precipitation of celecoxib efficiently. It is understood that crystallization during the dissolution of solid dispersions could happen through crystallization from solid matrix following contact with the dissolution medium or from the supersaturated solution produced following dissolution. The supersaturated drug concentrations attained from the dissolution of Eudragit®-celecoxib solid dispersions were almost similar, suggesting that crystallization from solid matrix did not occur readily. However, only solid dispersions containing efficient crystallization inhibitor polymers were able to maintain the supersaturated solution up to the end of the dissolution run. Conclusion Results revealed that the principal mechanism of attaining supersaturated solution of celecoxib from solid dispersions was related to crystallization inhibition from solution not from solid matrix.

Surfactant-free amorphous solid dispersion with high dissolution for bioavailability enhancement of hydrophobic drugs: a case of quercetin

At present, saccharides as hydrophilic matrixes, have been gradually used in amorphous solid dispersions (ASD) for dispersing poorly water-soluble drugs without surfactants. In this study, an amorphous chitosan oligosaccharide (COS) was applied as a water-soluble matrix to form surfactant-free ASD via the ball milling to vitrify quercetin (QUE) and enhance the dissolution and bioavailability. Solid-state characterization (DSC, XRPD, FTIR, SEM and PLM) and physical stability assessments verified that the prepared ASDs showed excellent physical stability with complete amorphization due to potential interactions between QUE and COS. In vitro sink dissolution tests suggested all QUE-COS ASDs (w:w, 1:1, 1:2 and 1:4) significantly enhanced the dissolution rate of QUE. Meanwhile, in vitro non-sink dissolution exhibited that the maximum supersaturated concentration ranged from 112.62 to 138.00 µg/mL for all QUE-COS ASDs, which was much higher than that of pure QUE. Besides, the supersaturation of QUE-COS ASD kept for at least 24 h. In rat pharmacokinetics, the oral bioavailability of QUE-COS ASDs showed 1.64 ∼ 2.25 times increase compared to the pure QUE (p < .01). Hence, the present study confirms the amorphous COS could be applied as a promising hydrophilic matrix in QUE-COS ASDs for enhancing dissolution performance and bioavailability of QUE.

Elucidating the effect of crystallization on drug release from amorphous solid dispersions in soluble and insoluble carriers.

The development of amorphous solid dispersions (ASDs) is one way to overcome the bioavailability challenges of poorly water-soluble active pharmaceutical ingredients (APIs). An important consideration with ASD systems is that crystallization can occur during preparation, storage, and dissolution, thus reducing their bioavailability advantage. Currently, it is unclear whether the dissolution characteristics of the polymer carrier affects the dissolution performance of ASDs with intrinsic crystallization. Our aim was to differentiate the impact of a minor amount of intrinsic crystallinity (up to 10%) within soluble and insoluble carriers on ASD performance, using the area under the curve (AUC) values of non-sink dissolution profiles as a measure of dissolution performance that can inform in vivo bioavailability. In order to discern such differences, itraconazole (ITZ) ASDs were prepared by Hot Melt Extrusion (HME) with 50% (w/w) drug loading. PVP K12 and HPMCAS were used as the soluble and insoluble carriers in pH 1.2 dissolution media, respectively. Dissolution was also conducted in pH 6.8 buffer, wherein HPMCAS becomes soluble, to cross-validate experimental observations. Crystalline content was determined by differential scanning calorimetry (DSC) prior to dissolution. Soluble polymers differed from insoluble polymers in that crystals formed during processing and storage were released during dissolution which can undergo further growth causing a sharp decline in drug concentration in the dissolution medium. This led to a significant decrease in the AUC for soluble ASDs containing intrinsic crystallinity. In contrast, insoluble polymer carriers did not release the intrinsically formed crystals and the impact of subsequent crystal growth on dissolution performance was minimal for insoluble ASD systems. Furthermore, physical mixtures with spiked crystallinity were only found to reflect the dissolution performance of soluble ASDs exhibiting intrinsic crystallinity. Thus, in considering the impact of intrinsic crystallinity on ASD performance, the nature of the polymeric carrier in terms of solubility characteristics needs to be taken into account as there is significantly more variation in AUC with soluble carriers than insoluble carriers exhibiting intrinsic crystallinity.

Effects of Coformer and Polymer on Particle Surface Solution-Mediated Phase Transformation of Cocrystals in Aqueous Media.

The purpose of the present study was to investigate the effect of the coformer difference on particle surface solution-mediated phase transformation (PS-SMPT) during cocrystal particle dissolution in aqueous media in the absence and presence of polymers. SMPT can occur either in the bulk phase or at the particle surface because drug molecules can be supersaturated at the dissolving cocrystal surface, as well as in the bulk phase. Previously, bulk phase SMPT has been primarily investigated in formulation development. However, little is known about the effects of coformers and polymers on PS-SMPT of cocrystals. In this study, six carbamazepine (CBZ) cocrystals were used as model cocrystals (malonic acid (MAL), succinic acid (SUC), glutaric acid (GLA), adipic acid (ADP), saccharin (SAC), and nicotinamide (NCT); nonsink dissolution tests were performed with or without a precipitation inhibitor (hydroxypropyl methylcellulose (HPMC)) at pH 6.5. The residual particles were analyzed by powder X-ray diffraction, differential scanning calorimetry, polarized light microscopy (PLM), and scanning electron microscopy. Real-time PLM was used to directly observe rapid PS-SMPT. In the absence of HPMC, supersaturation was not observed in the bulk phase for all cocrystals. All cocrystals rapidly transformed to CBZ dihydrate aggregates via PS-SMPT (mostly within 1 min). In contrast, in the presence of 0.1% HPMC, supersaturation was observed for CBZ-SUC, CBZ-ADP, CBZ-SAC, and CBZ-NCT but not for CBZ-MAL and CBZ-GLA. The cocrystals with lower solubility coformers tended to induce higher supersaturation in the bulk phase. The PS-SMPT of CBZ-SUC, CBZ-ADP, and CBZ-SAC was slowed down by HPMC. By suppressing PS-SMPT, the cocrystals exhibited its supersaturation potential, depending on the properties of each coformer. To take advantage of the supersaturation potential of cocrystals to improve oral drug absorption, it is important to suppress particle surface SMPT in addition to bulk phase SMPT.

In Vivo Performance of Innovative Polyelectrolyte Matrices for Hot Melt Extrusion of Amorphous Drug Systems.

Hot melt extrusion of amorphous systems has become a pivotal technology to cope with challenges of poorly water-soluble drugs. Previous research showed that small molecular additives with targeted molecular interactions enabled introduction of a polyelectrolyte matrix into hot melt extrusion that would otherwise not be possible to process due to the unfavorable properties upon heating of the pure polymer. Carboxymethyl cellulose sodium (NaCMC) with lysine or alternatively meglumine led to modified polymeric matrices that showed adequate processability by hot melt extrusion and yielded stable amorphous formulations. The investigated formulations, including fenofibrate as a model drug, were characterized by attenuated total reflectance Fourier transform infrared spectroscopy, differential scanning calorimetry, and viscosity measurements after aqueous dispersion. Further biopharmaceutical assessment started with biorelevant nonsink dissolution testing followed by a pharmacokinetic in vivo study in rats. The in vitro assessment showed superiority of the lysine-containing formulation in the extent of in vitro supersaturation and overall drug release. In accordance with this, the in vivo study also demonstrated increased exposure of the amorphous formulations and in particular for the system containing lysine. In summary, the combination of polyelectrolytes with interacting additives presents a promising opportunity for the formulation of poorly water-soluble drugs.

Impact of HPMCAS on the Dissolution Performance of Polyvinyl Alcohol Celecoxib Amorphous Solid Dispersions.

Amorphous solid dispersions (ASDs) have been proven to increase the bioavailability of poorly soluble drugs. It is desirable that the ASD provide a rapid dissolution rate and a sufficient stabilization of the generated supersaturation. In many cases, one polymer alone is not able to provide both features, which raises a need for reasonable polymer combinations. In this study we aimed to generate a rapidly dissolving ASD using the hydrophilic polymer polyvinyl alcohol (PVA) combined with a suitable precipitation inhibitor. Initially, PVA and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were screened for their precipitation inhibitory potential for celecoxib in solution. The generated supersaturation in presence of PVA or HPMCAS was further characterized using dynamic light scattering. Binary ASDs of either PVA or HPMCAS (at 10% and 20% drug load) were prepared by hot-melt extrusion and solid-state analytics were conducted using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and fourier-transformed infrared spectroscopy (FT-IR). The non-sink dissolution studies of the binary ASDs revealed a high dissolution rate for the PVA ASDs with subsequent precipitation and for the HPMCAS ASDs a suppressed dissolution. In order to utilize the unexploited potential of the binary ASDs, the PVA ASDs were combined with HPMCAS either predissolved or added as powder and also formulated as ternary ASD. We successfully generated a solid formulation consisting of the powdered PVA ASD and HPMCAS powder, which was superior in monophasic non-sink dissolution and biorelevant biphasic dissolution studies compared to the binary and ternary ASDs.

Comparison of induction methods for supersaturation: Amorphous dissolution versus solvent shift

Simple solvent shift is often used to induce supersaturation and investigate precipitation kinetics in early drug development as a substitute for amorphous dissolution. This study develops and compares a small-scale non-sink amorphous dissolution method to a solvent shift method as induction methods for supersaturation of the model drugs albendazole, felodipine and tadalafil with respect to the maximum dissolved drug concentration, and the solid form of the precipitate. The study also investigates the effect of pre-dispersed precipitation inhibitors (hydroxypropyl methyl cellulose (HPMC) or polyvinylpyrrolidone (PVP)) on tadalafil supersaturation induced by both amorphous dissolution and solvent shift with respect to maximum dissolved drug concentration, precipitation rate and solid form of the precipitate. The maximum drug concentrations achieved through solvent shift were 15.9, 208 and 108 µg/mL for albendazole, felodipine and tadalafil, respectively. Pre-dispersing 0.1% (w/v) HPMC or PVP, increased the maximum concentration by solvent shift of tadalafil to 180 µg/mL, for both polymers. Dissolution of up to 90 mg albendazole, 120 mg felodipine and 8.9 mg tadalafil could yield a maximum dissolved drug concentration of 76.1%, 87.9% and 102.5%, respectively, of the corresponding solvent shift maximum concentration. The maximum concentration achieved through amorphous dissolution of tadalafil with HPMC or PVP present in the dissolution medium was 87.1% and 88.7%, respectively of the solvent shift maximum concentration. Dissolution of 2 mg amorphous tadalafil with and without pre-dispersed polymer gave the same rank order of onset of precipitation as for the solvent shift method. The solid form of precipitate was the same for albendazole, felodipine, tadalafil and tadalafil with PVP for both methods. For tadalafil with HPMC, the precipitate was amorphous following solvent shift, but crystalline after amorphous dissolution. Overall, this study shows that the maximum concentration achievable through amorphous dissolution can be estimated when performing solvent shift and the precipitation inhibition of excipients assessed via solvent shift can be used to predict the effect on precipitation using amorphous dissolution.

Processing of Polyvinyl Acetate Phthalate in Hot-Melt Extrusion-Preparation of Amorphous Solid Dispersions.

The preparation of amorphous solid dispersions (ASDs) is a suitable approach to overcome solubility-limited absorption of poorly soluble drugs. In particular, pH-dependent soluble polymers have proven to be an excellently suitable carrier material for ASDs. Polyvinyl acetate phthalate (PVAP) is a polymer with a pH-dependent solubility, which is as yet not thoroughly characterized regarding its suitability for a hot-melt extrusion process. The objective of this study was to assess the processability of PVAP within a hot-melt extrusion process with the aim of preparing an ASD. Therefore, the influence of different process parameters (temperature, feed-rate) on the degree of degradation, solid-state and dissolution time of the neat polymer was studied. Subsequently, drug-containing ASDs with indomethacin (IND) and dipyridamole (DPD) were prepared, respectively, and analyzed regarding drug content, solid-state, non-sink dissolution performance and storage stability. PVAP was extrudable in combination with 10% (w/w) PEG 3000 as plasticizer. The dissolution time of PVAP was only slightly influenced by different process parameters. For IND no degradation occurred in combination with PVAP and single phased ASDs could be generated. The dissolution performance of the IND-PVAP ASD at pH 5.5 was superior and at pH 6.8 equivalent compared to commonly used polymers hydroxypropylmethylcellulose acetate succinate (HPMCAS) and Eudragit L100-55.

Evolution of supersaturation from amorphous solid dispersions in water-insoluble polymer carriers: Effects of swelling capacity and interplay between partition and diffusion.

The use of water-insoluble carriers for amorphous solid dispersions (ASDs) has attracted more recent interest as the kinetic solubility profiles (KSP) from these systems can achieve a more sustained level of supersaturation when compared with ASDs based on water-soluble polymers. However, the effect of swelling capacity of water-insoluble carriers on the resulting KSP of ASDs has not been fully explored in terms of their achievable degree and extent of drug supersaturation. Thus, the objective of this study is to compare kinetic solubility profiles of ASDs based on commercially available water-insoluble carriers in order to bridge this knowledge gap and provide fundamental information important to the design of ASDs based on water-insoluble carriers. This was achieved by comparing the KSP from non-sink dissolution studies of ASDs of two model poorly-water soluble drugs, indomethacin (IND) and posaconazole (PCZ) based on commercially available water-insoluble carriers with different equilibrium water swelling such as fully hydrolyzed (physically crosslinked) poly (vinyl alcohol) (PVA), Eudragit RS PO, as well as chemically crosslinked PHEMA hydrogels . Our results show that the higher the swelling capacity of the water-insoluble carrier, the faster the rate of supersaturation generation, and the shorter the sustained supersaturation due to drug precipitation. The interplay of particle size, total dose and the swelling capacity was also shown to be an essential aspect when tailoring the supersaturation generation from water-insoluble polymer-based ASDs. The importance of the swelling feature was confirmed using firstly different polymer carriers (PVA, Eudragit RS PO, and PHEMA) and then polymer samples of identical composition and drug loading but with different swelling capacities (e.g., PVA, physically crosslinked to different degrees). Furthermore, a large drug partitioning value between the polymer carrier and dissolution medium was found to limit the extent of drug release or supersaturation buildup from these ASDs. Finally, the existence of electrostatic polymer-drug interactions realized from our molecular dynamic simulations supports the observed impact of the large partitioning of the model drug IND between the polymer ED RS PO and the dissolution medium, thereby leading to a lower degree of supersaturation generation (or slower drug release) from this ASD.

Amorphous solid dispersions containing residual crystallinity: Influence of seed properties and polymer adsorption on dissolution performance

The solubility advantage of amorphous solid dispersions (ASDs) is contingent upon supersaturation being generated and maintained. If crystals are present within an ASD, these crystals directly result in lost solubility advantage, and may also seed crystal growth leading to desupersaturation. The goal of this study was to evaluate the impact of residual crystals on ASD supersaturation profiles. Indomethacin-copovidone (PVPVA) ASDs with different levels of residual crystallinity were manufactured by hot melt extrusion (HME). PVPVA at 5 and 50 µg/mL was found to be a highly effective nucleation and crystal growth inhibitor of indomethacin at high supersaturation. Evidence of polymer adsorption onto indomethacin crystals was observed by atomic force microscopy and scanning electron microscopy. HME ASDs containing 0–25% residual crystallinity demonstrated lost solubility advantage, along with minimal desupersaturation during non-sink dissolution testing. While bulk seeds did not properly represent the impact of residual crystals, extensive polymer adsorption onto residual seed crystals resulted in poisoned crystal growth, limiting the potential dissolution performance consequences. Several risk factors related to the presence of residual crystallinity were identified: polymeric crystal growth inhibition effectiveness, seed properties, and supersaturation conditions.

Effect of buffer capacity on dissolution and supersaturation profiles of pioglitazone hydrochloride

The purpose of the present study was to investigate the effect of buffer capacity (β) on the dissolution, supersaturation, and precipitation (DSP) profiles of a salt form drug. The DSP of pioglitazone HCl (PIO–HCl, pKa = 5.8, intrinsic solubility = 0.4 μg/mL) was investigated under a non-sink condition (30 mg in 500 mL) in phosphate and maleate buffers with various β (2–32 mM/ΔpH) at pH 6.5. Precipitation from the bulk solution was investigated by a pH-shift method (pH 3.0 to 6.5). The slurry pH was measured to assess the solid surface pH. As β was increased, the degree of supersaturation in the non-sink dissolution test decreased from 25 to less than 3. The PIO-HCl particles transformed to the free base (PIO-FB) while retaining the outer shape of the initial particles. In the pH-shift precipitation test, β did not affect the precipitation of PIO-FB, and the shape of precipitant was different from that in the dissolution tests. The pH of the PIO-HCl slurry increased from 0.9 to 1.6 as β increased. In conclusion, buffer capacity had a marked impact on the PIO-HCl DSP profile. PIO-HCl transformed to PIO-FB before dissolving into the bulk phase.

Absorptive Dissolution Testing: An Improved Approach to Study the Impact of Residual Crystallinity on the Performance of Amorphous Formulations

Amorphous solid dispersions typically improve the oral bioavailability of poorly soluble drugs. However, residual crystallinity is always a concern, in terms of potential impact on the product stability and performance. Consequently, in vitro tools that allow biorelevant assessment of residual crystallinity are of interest. The goal of the present study was to use absorptive dissolution testing to evaluate the impact of different levels of crystallinity in an amorphous formulation on membrane mass transport kinetics and supersaturation-time profiles. Partial crystallinity was induced in commercially available tacrolimus formulations by exposure to moderate temperature and high relative humidity. A hollow fiber membrane was coupled to a dissolution vessel to create an absorptive dissolution testing apparatus, and concentration-time profiles were simultaneously monitored during dissolution (donor compartment) and after absorption across the membrane (receiver compartment). The coupled dissolution-absorption measurements indicated that residual crystallinity impacted the absorption profiles in a manner that depended on the volume of fluid used for the dissolution measurement. A high percentage of residual crystallinity hampered the drug release from the formulation. Higher supersaturation in nonsink dissolution conditions improved mass transfer rates; however, the presence of seed crystals led to rapid desupersaturation. Further systematic studies to delineate the interplay between the rate of absorption and desupersaturation revealed that for a given dissolution rate, the crystallization rate would supersede the absorption rate only at high supersaturations. Thus, seeds have a lower impact on absorption when the overall supersaturation generated is lower. This study underscores the importance of considering competing physical processes when evaluating amorphous formulations. A further consideration highlighted is that different fluid volumes may impact the absorption profile for supersaturating dosage forms. Absorptive dissolution testing appears to be a potentially valuable tool to mechanistically investigate amorphous solid dispersion formulation release and phase behavior under more biorelevant conditions.

Involvement of metabolism-permeability in enhancing the oral bioavailability of curcumin in excipient-free solid dispersions co-formed with piperine

Curcumin (CUR) has gained increasing interest worldwide due to multiple biological activities. However, the therapeutic application remains limited because of its low aqueous solubility, intestinal metabolism and poor membrane permeability. In present study, an excipient-free CUR solid dispersion co-formed with piperine (PIP), the absorption enhancer involving metabolism-permeability, was successfully prepared by melting and quench cooling (co-amorphous CUR-PIP). The co-amorphous CUR-PIP exhibited superior performance in non-sink dissolution compared with crystalline and amorphous CUR, and showed physically stable at least 3 months, attributing to the strong molecular interactions between CUR and PIP as evaluated by FTIR spectra. Furthermore, the combination of PIP with CUR in the co-amorphous formulation could inhibit the glucuronidation of CUR, as exhibited in the in vitro assay of rat intestinal microsomes. The co-amorphous CUR-PIP would also exhibit higher gastrointestinal membrane permeability of CUR, as confirmed by Papp of CUR in Caco-2 model. After administration of co-amorphous CUR-PIP, the AUC of CUR significantly increased by 2.16- and 1.92-fold those in crystalline and amorphous CUR, respectively. This study demonstrates that the developed co-amorphous CUR-PIP can enhance the bioavailability of CUR by increasing its dissolution, inhibiting metabolic processes, and facilitating membrane permeability.

Mechanism of Supersaturation Suppression in Dissolution Process of Acidic Drug Salt.

Supersaturable active pharmaceutical ingredients (sAPI), such as salts, cocrystals, and amorphous solids, can form supersaturated solutions after dissolving in the gastrointestinal fluids. However, there are cases in which supersaturation is not observed in an in vitro nonsink dissolution test. The purpose of the present study was to investigate the mechanisms of supersaturation suppression in the dissolution process of acidic drug salts. Diclofenac sodium (DCF Na, p Ka = 4.0) was employed as a model drug. DCF Na APIs and tablets (25 mg, 0.08 mmol) showed little or no supersaturation at pH 1.2 (compendial paddle apparatus, 500 mL, 50 rpm). However, marked supersaturation was observed at pH 2.0 and 3.0. The liquid-liquid phase separation (LLPS) of DCF free acid (FA) was observed in the surrounding of the DCF Na particles immediately after contact with acidic media. Particularly at pH 1.2, the surface of DCF Na was immediately covered with the liquid (oil) layer of DCF FA. The DCF FA liquid layer started to crystallize within several minutes. The LLPS concentration of DCF FA (0.30 mM) was twice as high as the theoretical maximum concentration after the complete dissolution of DCF Na in the dissolution test (0.16 mM). In addition, in the bulk phase precipitation test at 0.16 mM, rapid concentration reduction was not observed within 1 h in the bulk media. Taken together, these results suggest that the LLPS (and subsequent crystallization) of DCF FA on the surface of DCF Na particles rather than in the bulk medium is more likely to have suppressed the supersaturation from DCF Na.

Surfactant-free solid dispersion of BCS class IV drug in an amorphous chitosan oligosaccharide matrix for concomitant dissolution in vitro - permeability increase

Saccharides have been applied as a water-soluble matrix for dispersing hydrophobic drugs homogeneously without the need to use surfactants in amorphous solid dispersions (ASD). Up to now, concomitant permeability improvement of BCS Class IV drug by such matrices have not been much appreciated. Herein, an amorphous chitosan oligosaccharide (COS) was used as matrix to prepare surfactant-free ASD of BCS class IV drug by the ball milling method, with curcumin (CUR) as a model drug. The DSC, XRPD, FTIR and physical stability experiments indicated that CUR was in an amorphous state with high physical stability and exhibited potential interactions with COS in the ASD. Non-sink dissolution in vitro studies showed the maximum dissolution concentration of all CUR-COS ASD (CUR and COS at weight ratios of 1:1, 1:2 and 1:4) reached ranging from 97.85 to 101.21 μg/mL, far above that of pure CUR. The supersaturated concentration remained for at least 24 h under non-sink condition. Caco-2 cell model revealed that, compared to the pure CUR group, the apparent permeability coefficients were increased by 1.72–4.44-fold in all three CUR-COS ASD, which was mainly attributed to opening the tight junctions of Caco-2 cells by COS. The pharmacokinetic study showed that all CUR-COS ASD groups exhibited significant enhancements in AUC0-∞, with 1.55–3.01-fold that of pure CUR (p < 0.01). Tmax of CUR was shortened after oral administration of all three ASD. The current study demonstrates the amorphous COS could be used as a promising matrix in ASD for enhancing the oral bioavailability of BCS class IV drug by improving dissolution behavior and membrane permeability.

Melt-based screening method with improved predictability regarding polymer selection for amorphous solid dispersions

The predictability of preformulation screening tools for polymer selection in amorphous solid dispersions (ASD) regarding supersaturation and precipitation was systematically examined. The API-polymer combinations were scaled up by means of hot-melt extrusion and spray-drying to verify the predictions. As there were discrepancies between a solvent-based screening and performance of ASD, a new screening tool with improved predictability at minimal investments of time and material is presented. The method refinement resulted in a better correlation between the screening and ASD prototypes.So far, a purely solvent-based screening was used which consisted of film casting by rapid solvent evaporation. This approach was improved by applying a heating step after film casting. Four representative polymers were tested with two different model active pharmaceutical ingredients (API) under non-sink dissolution conditions. Polyvinylpyrrolidone (PVP) based polymers showed no benefit towards pure API in the solvent-based screening but good supersaturation as ASD formulations. The extrudates with the cellulose derivatives hydroxypropylmethylcellulose acetate succinate (HPMCAS) and cellulose acetate phthalate (CAP) showed lower supersaturation than predicted by the solvent-based screening but performed especially well as spray-dried dispersions (SDD).False negative results for PVP-co-vinyl acetate (PVP-VA64) could be avoided by using the new melt-based screening. Furthermore, comparing the results from the two different screening methods allowed predicting the performance of extrudates vs. SDD with cellulose derivatives as polymeric excipients.

Population Balance Model for Simulation of the Supersaturation–Precipitation Behavior of Drugs in Supersaturable Solid Forms

We developed a simulation method to describe in vitro drug concentration−time profiles under supersaturated conditions. In a nonsink dissolution test of carbamazepine polymorphic form III (CBZIII), a model supersaturable solid, the concentration of carbamazepine reached a supersaturated state against its dihydrate form (CBZDH). After a certain period, de-supersaturation due to the precipitation of CBZDH was observed. In the simulation of this typical dissolution−precipitation profile, the precipitation process of CBZDH was simulated by a population balance model in which the rates of primary/secondary nucleation and growth of CBZDH were considered. Six rate constants in the precipitation model were determined from de-supersaturation profiles in unseeded isothermal crystallization experiments of CBZDH. The dissolution process of CBZIII was modeled on the basis of its dissolution profile under a sink condition. The simulated concentration versus time curves satisfactorily reproduced the characteristics of dissolution, supersaturation, and precipitation behavior of the model drug. The presented method will enable rational design of formulations and accurate prediction of the oral absorbability of drugs in supersaturable solid forms.

Combined Effects of Supersaturation Rates and Doses on the Kinetic-Solubility Profiles of Amorphous Solid Dispersions Based on Water-Insoluble Poly(2-hydroxyethyl methacrylate) Hydrogels.

Under nonsink dissolution conditions, the kinetic-solubility profiles of amorphous solid dispersions (ASDs) based on soluble carriers typically exhibit so-called "spring-and-parachute" concentration-time behaviors. However, the kinetic-solubility profiles of ASDs based on insoluble carriers (including hydrogels) are known to show sustained supersaturation during nonsink dissolution through a matrix-regulated diffusion mechanism by which the supersaturation of the drug is built up gradually and sustained over an extended period without any dissolved polymers acting as crystallization inhibitors. Despite previous findings demonstrating the interplay between supersaturation rates and total doses on the kinetic-solubility profiles of soluble amorphous systems (including ASDs based on dissolution-regulated releases from soluble polymer carriers), the combined effects of supersaturation rates and doses on the kinetic-solubility profiles of ASDs based on diffusion-regulated releases from water-insoluble carriers have not been investigated previously. Thus, the objective of this study is to examine the impacts of total doses and supersaturation-generation rates on the resulting kinetic-solubility profiles of ASDs based on insoluble hydrogel carriers. We employed a previously established ASD-carrier system based on water-insoluble-cross-linked-poly(2-hydroxyethyl methacrylate) (PHEMA)-hydrogel beads and two poorly water soluble model drugs: the weakly acidic indomethacin (IND) and the weakly basic posaconazole (PCZ). Our results show clearly for the first time that by using the smallest-particle-size fraction and a high dose (i.e., above the critical dose), it is indeed possible to significantly shorten the duration of sustained supersaturation in the kinetic-solubility profile of an ASD based on a water-insoluble hydrogel carrier, such that it resembles the spring-and-parachute dissolution profiles normally associated with ASDs based on soluble carriers. This generates sufficiently rapid initial supersaturation buildup above the critical supersaturation, resulting in more rapid precipitation. Above this smallest-particle-size range, the matrix-diffusion-regulated nonlinear rate of drug release gets slower, which results in a more modest rate of supersaturation buildup, leading to a maximum supersaturation below the critical-supersaturation level without appreciable precipitation. The area-under-the-curve (AUC) values of the in vitro kinetic-solubility concentration-time profiles were used to correlate the corresponding trends in dissolution enhancement. There are observed monotonic increases in AUC values with increasing particle sizes for high-dose ASDs based on water-insoluble hydrogel matrixes, as opposed to the previously reported AUC maxima at some intermediate supersaturation rates or doses in soluble amorphous systems, whereas in the case of low-dose ASDs (i.e., below the critical dose levels), crystallization would be negligible, leading to sustained supersaturation with all particle sizes (i.e., eventually reaching the same maximum supersaturation) and the smallest particle size reaching the maximum supersaturation the fastest. As a result, the smallest particle sizes yield the largest AUC values in the case of low-dose ASDs based on water-insoluble hydrogel matrixes. In addition to probing the interplay between the supersaturation-generation rates and total doses in ASDs based on insoluble hydrogel carriers, our results further support the fact that through either increasing the hydrogel-particle size or lowering the total dose to achieve maximum supersaturation still below the critical-supersaturation level, it is possible to avoid drug precipitation so as to maintain sustained supersaturation.

Effects of tablet formulation and subsequent film coating on the supersaturated dissolution behavior of amorphous solid dispersions

The effects of tablet preparation and subsequent film coating with amorphous solid dispersion (ASD) particles that were composed of a drug with poor water solubility and hydrophilic polymers were investigated. ASD particles were prepared with a drug and vinylpyrrolidone–vinyl acetate copolymer (PVPVA) or polyvinylpyrrolidone (PVP) at a weight ratio of 1:1 or 1:2 using a melt extrusion technique. Tablets were prepared by conventional direct compression followed by pan coating. A mathematical model based on the Noyes–Whitney equation assuming that stable crystals precipitated at the changeable surface area of the solid–liquid interface used to estimate drug dissolution kinetics in a non-sink dissolution condition. All the ASD particles showed a maximum dissolution concentration approximately ten times higher than that of the crystalline drug. The ASD particles with PVPVA showed higher precipitation rate with lower polymer ratio, while PVP did not precipitate within 960 min regardless of the polymer ratio, suggesting the ASD particles of 1:1 drug:PVPVA (ASD-1) were the most unstable among the ASD particles considered. The dissolution of a core tablet with ASD-1 showed less supersaturation and a much higher precipitation rate than those of ASD-1 particles. However, a film-coated tablet or core tablet with a trace amount of hydroxypropylmethylcellulose (HPMC) showed a similar dissolution profile to that of the ASD-1 particles, indicating HPMC had a remarkable precipitation inhibition effect. Overall, these results suggest that tablet preparation with ASD may adversely affect the maintenance of supersaturation; however, this effect can be mitigated by adding an appropriate precipitation inhibitor to the formulation.

In Situ Salt Formation during Melt Extrusion for Improved Chemical Stability and Dissolution Performance of a Meloxicam-Copovidone Amorphous Solid Dispersion.

As the pipeline for poorly soluble compounds continues to grow, drug degradation during melt extrusion must be addressed. We present a novel method for stabilizing a thermally labile drug substance while preserving its physical stability and even improving its dissolution performance. In a previous study, we found that incorporating meglumine during extrusion of meloxicam results in chemical stabilization that cannot be achieved using process optimization alone. The purpose of this study is to understand the mechanism behind this stabilization and its impact on the performance of a meloxicam-Kollidon VA64 amorphous solid dispersion. The meloxicam concentration was maintained at 10% (w/w) for blends with and without meglumine. The optimal meglumine blend contained an equimolar amount of meloxicam to meglumine with the remainder consisting of Kollidon VA64. Both formulations were processed with optimized extrusion conditions and analyzed by HPLC for purity. Meglumine at a 1:1 molar ratio with meloxicam results in 100% purity of meloxicam after melt extrusion. Solid-state NMR revealed a proton transfer between the meloxicam and meglumine indicating an in situ salt formation. During non-sink dissolution, the meglumine ASD enables meloxicam to maintain supersaturatation (≅50 times more than meloxicam free acid) for >7.25 h. The ASD without meglumine began precipitating 2.25 h following the pH shift. The ASDs were placed at 40 °C/75% RH for 6 months, and their stability was assessed. No significant chemical degradation, recrystallization, or significant moisture uptake was observed after six months' storage at 40 °C/75% RH.