Polyvinylpyrrolidone-vinyl Acetate Research Articles

Delaying the First Nucleation Event of Amorphous Solid Dispersions Above the Polymer Overlap Concentration (c*): PVP and PVPVA in Posaconazole

A thorough understanding of effects of polymers on crystallization of amorphous drugs is essential for rational design of robust amorphous solid dispersion (ASD), since crystallization of the amorphous drug negates their solubility advantage. In this work, we measured the first nucleation time (t0, time to form the first critical nucleus in fresh liquid/glass) in posaconazole (POS)/polyvinylpyrrolidone vinyl acetate (PVPVA) and POS/polyvinylpyrrolidone (PVP K25) ASDs and showed that the polymer overlap concentration (c*, concentration above which adjacent polymer chains begin to contact) is critical in controlling crystallization of ASDs. When polymer concentration c < c*, t0 of POS ASDs is approximately equal to that of the neat amorphous POS, but it increases significantly when c > c*. This observation supports the view that the effective inhibitory effect of crystallization in ASDs above c* is primarily correlated with delay in the first nucleation event. Our finding is useful in efficient polymer selection and performance prediction of high drug loaded ASD formulations.

Impact of Polyvinylpyrrolidone-Vinyl Acetate Copolymer and Sodium Starch Glycolate Excipients on Phenolic Extraction from Red Clover: Enhancing Biological Activity and Antioxidant Potential.

Adding certain excipients during the extraction process can enhance the concentration of target compounds, leading to potentially increased biological properties of the plant extract. This study explores the impact of PVP/VAC and SSG excipients on red clover bud extracts, aiming to enhance their concentration of target compounds and, consequently, their biological properties. The antioxidative potential was evaluated using DPPH, ABTS, and FRAP methods, and the chemical profile was determined using mass spectrometry. Antibacterial activity against various strains was determined through the minimal inhibitory concentration (MIC) method. The results revealed that the excipient-enriched samples exhibited significantly elevated antioxidant activities as well as phenolic and flavonoid contents compared to control samples. Notably, sample V1E3 demonstrated the highest antioxidant potential, with 52.48 ± 0.24 mg GAE/g dw (phenolic content), 463 ± 6.46 μg TE/g dw (ABTS), 12.81 ± 0.05 μg TE/g dw (DPPH), and 29.04 ± 1.16 mg TE/g dw (post-column ABTS). The highest flavonoid content was found in the S1E3 sample-24.25 ± 0.17 mg RU/g dw. Despite the increased antioxidant potential, no significant variance in antimicrobial activity was noted between the test samples and controls. This implies that excipients may hold the potential to enhance the biological properties of red clover extracts for pharmaceutical applications. These findings contribute valuable insights into optimizing extraction processes for improved functionality and application of plant-derived compounds in therapeutic formulations.

Understanding the Influence of API Conformations on Amorphous Dispersion Formation Potential Predictions using the R3m Molecular Descriptor.

The R3m molecular descriptor (R-GETAWAY third-order autocorrelation index weighted by the atomic mass) has previously been shown to encode molecular attributes that appear to be physically and chemically relevant to grouping diverse active pharmaceutical ingredients (API) according to their potential to form persistent amorphous solid dispersions (ASDs) with polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA). The initial R3m dispersibility model was built by using a single three-dimensional (3D) conformation for each drug molecule. Since molecules in the amorphous state will adopt a distribution of conformations, molecular dynamics simulations were performed to sample conformations that are probable in the amorphous form, which resulted in a distribution of R3m values for each API. Although different conformations displayed R3m values that differed by as much as 0.4, the median of each R3m distribution and the value predicted from the single 3D conformation were very similar for most structures studied. The variability in R3m resulting from the distribution of conformations was incorporated into a logistic regression model for the prediction of ASD formation in PVPVA, which resulted in a refinement of the classification boundary relative to the model that only incorporated a single conformation of each API.

A multifaceted approach for grading of polymers for the development of stable amorphous solid dispersion of Riluzole

The current work involves grading three widely used polymers for preparing a kinetically and thermodynamically stable amorphous solid dispersion (ASD) of a neuroprotective drug Riluzole (RLZ) by evaluating the drug-polymer interactions. Polymers were screened based on their chemical interaction with RLZ and their ability to inhibit the crystallization of the drug. Detailed computational studies were performed to quantify the non-covalent interactions between RLZ and the modelled structures of polymers; polyacrylic acid (PAA), polyvinylpyrrolidone vinyl acetate (PVP VA), and hydroxypropyl methyl cellulose acetate succinate (HPMC AS) for calculating the interaction energies of drug-polymer complexes. Experimental characterization of drug-polymer complexes through analytical techniques further validated the formation of the drug-polymer complexes. The results indicated that RLZ interacts with the polymers in the order PAA > PVP VA > HPMC AS, giving an insight into the stability of drug-polymer complexes. In vitro dissolution study also showed higher dissolution profile of RLZ with PAA. Further, the drug-polymer miscibility was determined by employing Flory-Huggins theory and stability in accordance with Gibbs free energy of mixing and phase diagram. This work presented a multi-technique approach for the grading of polymers in search of a stable ASD of the poorly water-soluble drug RLZ.

Development and Evaluation of Amorphous Solid Dispersion of Riluzole with PBPK Model to Simulate the Pharmacokinetic Profile.

In the current work, screening of polymers viz. polyacrylic acid (PAA), polyvinyl pyrrolidone vinyl acetate (PVP VA), and hydroxypropyl methyl cellulose acetate succinate (HPMC AS) based on drug-polymer interaction and wetting property was done for the production of a stable amorphous solid dispersion (ASD) of a poorly water-soluble drug Riluzole (RLZ). PAA showed maximum interaction and wetting property hence, was selected for further studies. Solid state characterization studies confirmed the formation of ASD with PAA. Saturation solubility, dissolution profile, and in vivo pharmacokinetic data of the ASD formulation were generated in rats against its marketed tablet Rilutor. The RLZ:PAA ASD showed exponential enhancement in the dissolution of RLZ. Predicted and observed pharmacokinetic data in rats showed enhanced area under curve (AUC) and Cmax in plasma and brain with respect to Rilutor. Furthermore, a physiologically based pharmacokinetic (PBPK) model of rats for Rilutor and RLZ ASD was developed and then extrapolated to humans where physiological parameters were changed along with a biochemical parameter. The partition coefficient was kept similar in both species. The model was used to predict different exposure scenarios, and the simulated data was compared with observed data points. The PBPK model simulated Cmax and AUC was within two times the experimental data for plasma and brain. The Cmax and AUC in the brain increased with ASD compared to Rilutor for humans showing its potential in improving its biopharmaceutical performance and hence enhanced therapeutic efficacy. The model can predict the RLZ concentration in multiple compartments including plasma and liver.

Revisiting Supersaturation of a Biopharmaceutical Classification System IIB Drug: Evaluation via a Multi-Cup Dissolution Approach and Molecular Dynamic Simulation.

As a subclass of the biopharmaceutical classification system (BCS) class II, basic drugs (BCS IIB) exhibit pH-dependent solubility and tend to generate supersaturation in the gastrointestinal tract, leading to less qualified in vitro-in vivo correlation (IVIVC). This study aims to develop a physiologically based multi-cup dissolution approach to improve the evaluation of the supersaturation for a higher quality of IVIVC and preliminarily explores the molecular mechanism of supersaturation and precipitation of ketoconazole affected by Polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA) and hydroxypropyl methyl-cellulose (HPMC). The concentration of ketoconazole in each cup of the dynamic gastrointestinal model (DGIM) was measured using fiber optical probes. Molecular interactions between ketoconazole and PVPVA or HPMC were simulated by Materials Studio. The results demonstrated that PVPVA and HPMC improved and maintained the supersaturation of ketoconazole. PVPVA exhibited superior precipitation inhibitory effect on ketoconazole molecule aggregation due to slightly stronger van der Waals forces as well as unique electrostatic forces, thereby further enhancing in vitro drug absorption, which correlated well with in vivo drug absorption. Compared with a conventional dissolution apparatus paddle method, the DGIM improved the mean prediction error through the IVIVC from 19.30% to 9.96%, reaching the qualification criteria. In conclusion, the physiologically based multi-cup dissolution approach enables improved evaluation of supersaturation in gastrointestinal transportation of BCS IIB drug ketoconazole, enabling screening screen precipitation inhibitors and achieving qualified IVIVC for drug formulation studies.

Mechanoactivation as a Tool to Assess the Autoxidation Propensity of Amorphous Drugs.

Mechanoactivation has attracted considerable attention in the pharmaceutical sciences due to its ability to generate amorphous materials and solid-state synthetic products without the use of solvent. Although some studies have reported drug degradation during milling, no studies have systematically investigated the use of mechanoactivation in predicting drug degradation in the solid state. Thus, this work explores the autoxidation of drugs in the solid state by comilling amorphous mifepristone (MFP):polyvinylpyrrolidone vinyl acetate (PVPVA) and amorphous olanzapine (OLA):PVPVA. MFP was amorphized by ball milling and OLA by quench cooling techniques. Subsequently, comilling the amorphous drugs in the presence of a 10-fold weight ratio of PVPVA (the excipient containing reactive free radicals) was performed at several milling frequencies to identify the kinetics of mechano-autoxidation over milling durations. Overall, milling led to the degradation of up to 5% drug in the solid state. The autoxidation mechanism was confirmed by performing a stress study in the solution at 50 °C for 5 h, by using a 10 mM azo-bis(isobutyronitrile) (AIBN) as a stressing agent. By deconvoluting the effect of milling frequency and the energy on the extent and kinetics of milling-induced autoxidation of amorphous drugs, it was possible to fit an extended Arrhenius model that allowed extrapolation of mechanoactivated degradation rates (Km) to zero milling frequencies. Further, the autoxidation rates of drugs stored at high temperatures were observed to follow an Arrhenius behavior. A good degree of agreement was observed between the model predictions obtained by mechanoactivation (Km) to the reaction rates observed under accelerated temperatures. Additionally, the impact of adding an antioxidant (e.g., butylated hydroxytoluene) to the mixture during comilling was also examined. This study can be helpful in evaluating the stability of amorphous solids stored in accelerated (non-hermetic) conditions, in screening solid-state autoxidation propensity of drugs, and for the rational selection of antioxidants.

Investigating and Comparing the Applicability of the R3m Molecular Descriptor and Solubility Parameter Estimation Approaches in Predicting Dispersion Formation Potential of APIs in a Random Co-Polymer Polyvinylpyrrolidone Vinyl Acetate and its Homopolymer

Evaluation of different amorphous solid dispersion carrier matrices is enabled by active pharmaceutical ingredient (API) structure-based predictions. This study compares the utility of Hansen Solubility Parameters with the R3m molecular descriptor for identifying dispersion polymers based on the structure of the drug molecule. Twelve API-polymer combinations (4 APIs and 3 interrelated polymers) were used to test each approach. Co-solidified mixtures containing 75% API were prepared by melt-quenching. Phase behavior was evaluated and classified using differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, and hot stage microscopy. Observations of dispersion behavior were compared to predictions made using the Hansen Solubility Parameter and R3m. The solubility parameter approach misclassified the dispersion behavior of 1 API-polymer combination and also did not produce definite predictions in 3 out of 12 of the API-polymer combinations. In contrast, R3m classifications of dispersion behavior were correct in all but two cases, with one misclassification and one ambiguous prediction. The solubility parameters best classify dispersion behavior when specific drug-polymer intermolecular interactions are present, but may be less useful otherwise. Ultimately, these two methods are most effectively used together, as they are based on distinct features of the same molecular structure.

Implications of Coexistent Halogen and Hydrogen Bonds in Amorphous Solid Dispersions on Drug Solubility, Miscibility, and Mobility.

Specific noncovalent drug-polymer interactions were analytically identified using Raman and Fourier transform infrared spectroscopy for amorphous solid dispersions (ASD) formed between either chlorpropamide or tolbutamide and polyvinylpyrrolidone vinyl acetate random copolymer (PVPVA). Spectral changes in the C-Cl stretching vibrations due to changes in the electronic environment of the Cl atom confirmed halogen bond formation in chlorpropamide-PVPVA ASDs, the extent of which was established to be inversely related to the concentration of the drug using 2D correlation spectroscopy analysis. Hydrogen bonding between the secondary amide of each drug and the pyrrolidone carbonyl of the copolymer was also confirmed in all dispersions. Implications of coexistent interactions were investigated for drug-polymer solubility, mixing free energy, and molecular mobility relative to tolbutamide, which only formed hydrogen bonds with PVPVA. Chlorpropamide had a higher solubility, a larger negative mixing free energy, and lower mobility in PVPVA relative to tolbutamide. These thermodynamic and kinetic differences demonstrate the significance of halogen bond formation even when hydrogen bonding is present.

Combining lipid based drug delivery and amorphous solid dispersions for improved oral drug absorption of a poorly water-soluble drug.

Two widely applied enabling drug delivery approaches, self-nanoemulsifying drug delivery systems (SNEDDS) and amorphous solid dispersions (ASD), were combined, with the aim of enhancing physical stability, solubilization and absorption of the model drug ritonavir. Ritonavir was loaded at a concentration above its saturation solubility (Seq) in the SNEDDS (superSNEDDS, 250% of Seq). An ASD of ritonavir with polyvinylpyrrolidone-vinyl acetate copolymers (Kollidon® VA64) was prepared by ball milling. Relevant control formulations, which include conventional SNEDDS (90% of Seq), superSNEDDS with a physical mix of Kollidon® VA64 and ritonavir (superSNEDDS+PM) and an aqueous suspension of ritonavir were used. A pharmacokinetic (PK) study in rats was performed to assess the relative bioavailability of ritonavir after oral administration. This was followed by evaluating the formulations in a novel two-step in vitro lipolysis model simulating rat gastric and intestinal conditions. The addition of a ritonavir containing ASD to superSNEDDS increased the degree of supersaturation from 250% to 275% Seq in the superSNEDDS and the physical stability (absence of drug recrystallization) of the system from 48h to 1month under ambient conditions. The PK study in rats displayed significantly higher Cmax and AUC0-7h (3-fold increase) and faster Tmax for superSNEDDS+ASD compared to the conventional SNEDDS whilst containing 3 times less lipid than the latter. Furthermore, superSNEDDS+ASD were able to keep the drug solubilised during in vitro lipolysis to the same degree as the conventional SNEDDS. These findings suggest that dissolving an ASD in a superSNEDDS can contribute to the development of novel oral delivery systems with increased bioavailability for poorly water-soluble drugs.

Application of Twin-Screw Melt Granulation to Overcome the Poor Tabletability of a High Dose Drug.

Pharmaceutical tablet manufacturing has seen a paradigm shift toward continuous manufacturing and twin-screw granulation-based technologies have catalyzed this shift. Twin-screw granulator can simultaneously perform unit operations like mixing, granulation, and drying of the granules. The present study investigates the impact of polymer concentration and processing parameters of twin-screw melt granulation, on flow properties and compaction characteristics of a model drug having high dose and poor tabletability. Acetaminophen (AAP) and polyvinylpyrrolidone vinyl acetate (PVPVA) were used as a model drug (90-95% w/w) and polymeric binder (5-10%w/w), respectively, for the current study. Feed rate (~650-1150g/h), extruder screw speed (150-300rpm), and temperature (60-150°C) were used as processing variables. Results showed the reduction in particle size of drug in the extrudates (D90 of 15-25μm from ~80μm), irrespective of processing condition, while flow properties were a function of polymer concentration. Overall, good flowability of the products and their tablets with optimum tensile strength can be obtained through using high polymer concentration (i.e., 10% w/w), lower feed rate (~650g/h), lower extruder screw speed (150rpm), and higher processing temperatures (up to 120°C). The findings from the current study can be useful for continuous manufacturing of tablets of high dose drugs with minimal excipient loading in the final dosage form.

Supersaturated amorphous solid dispersions of celecoxib prepared in situ by microwave irradiation

This study investigated the ability of in situ amorphisation using microwave irradiation in order to prepare highly supersaturated ASDs, i.e. ASDs with drug loads higher than the saturation solubility in the polymer at ambient temperature. For this purpose, compacts containing the crystalline drug celecoxib (CCX) and polyvinylpyrrolidone (PVP), polyvinylpyrrolidone—vinyl acetate copolymer (PVP/VA), or polyvinyl acetate (PVAc), were prepared at drug loads between 30 and 90 % w/w. Sodium dihydrogen phosphate (NaH2PO4) monohydrate was included in all compacts, as a source of water, to facilitate the dielectric heating of the compacts upon dehydration during microwave irradiation. After processing, the samples were analysed towards their solid state using X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC). Complete amorphisation of CCX was achieved across all the investigated polymers and with a maximal drug load of 90, 80, and 50 % w/w in PVP, PVP/VA, and PVAc, respectively. These drug loads corresponded to a 2.3-, 2.4-, and 10.0-fold supersaturation in the investigated polymers at ambient temperature. However, dissolution experiments with the in situ prepared ASDs in fasted state simulated intestinal fluid (FaSSIF), showed a lower initial drug release (0–2 h) compared to equivalent physical mixtures of crystalline CCX and polymers or crystalline CCX alone. The lower drug release rate was explained by the fusion of individual drug and polymer particles during microwave irradiation and, subsequently, a lack of disintegration of the monolithic ASDs. Nevertheless, supersaturation of CCX in FaSSIF was achieved with the in situ amorphised ASDs with PVP and PVP/VA, albeit only after 3–24 h. Overall, the present study confirmed that it is feasible to prepare supersaturated ASDs in situ. However, in the current experimental setup, the monolithic nature of the resulting ASDs is considered a limiting factor in the practical applicability of this preparation method, due to limited disintegration and the associated negative effect on the drug release.

Prediction and Construction of Drug-Polymer Binary System Thermodynamic Phase Diagram in Amorphous Solid Dispersions (ASDs).

Amorphous solid dispersion (ASD) has been well known as a potential strategy to improve the bioavailability and dissolution performance of poorly water-soluble drugs. The primary concern of this approach is the long-term stability of the amorphous drug in the solid dispersion. Accurate prediction and detection of the solubility and miscibility of drug in polymeric binary system will be a milestone to the development of ASDs. In this investigation, a method based on Flory-Huggins (F-H) theory was proposed to predict and calculate the solubility and miscibility of the drug in polymeric matrix and construct the phase diagram to identify the relevance between drug loading and temperature for ASDs development. Indomethacin (Indo) was chosen as the model drug, and polyvinyl pyrrolidone vinyl acetate (Kollidon® VA 64) was used as a polymeric carrier for the ASD systems. Physical mixtures were prepared with different drug loadings (10 to 90%) and analyzed by differential scanning calorimetry (DSC). The interaction parameter χ was calculated for physical mixtures by the melting point depression and solubility parameter contribution methods. The phase diagram was constructed to investigate the impact of other parameters like drug loading, processing temperature, and Gibbs free energy of mixing (ΔGmix). For further validation, formulations were developed using HME to verify the accuracy of the phase diagram and to guide in the hot-melt extrusion (HME) process design space and optimization.

Interpreting the Physicochemical Meaning of a Molecular Descriptor Which Is Predictive of Amorphous Solid Dispersion Formation in Polyvinylpyrrolidone Vinyl Acetate.

A molecular descriptor known as R3m (the R-GETAWAY third-order autocorrelation index weighted by the atomic mass) was previously identified as capable of grouping members of an 18-compound library of organic molecules that successfully formed amorphous solid dispersions (ASDs) when co-solidified with the co-polymer polyvinylpyrrolidone vinyl acetate (PVPva) at two concentrations using two preparation methods. To clarify the physical meaning of this descriptor, the R3m calculation is examined in the context of the physicochemical mechanisms of dispersion formation. The R3m equation explicitly captures information about molecular topology, atomic leverage, and molecular geometry, features which might be expected to affect the formation of stabilizing non-covalent interactions with a carrier polymer, as well as the molecular mobility of the active pharmaceutical ingredient (API) molecule. Molecules with larger R3m values tend to have more atoms, especially the heavier ones that form stronger non-covalent interactions, generally, more irregular shapes, and more complicated topology. Accordingly, these molecules are more likely to remain dispersed within PVPva. Furthermore, multiple linear regression modeling of R3m and more interpretable descriptors supported these conclusions. Finally, the utility of the R3m descriptor for predicting the formation of ASDs in PVPva was tested by analyzing the commercially available products that contain amorphous APIs dispersed in the same polymer. All of these analyses support the conclusion that the information about the API geometry, size, shape, and topological connectivity captured by R3m relates to the ability of a molecule to interact with and remain dispersed within an amorphous PVPva matrix.

Artemisinin Cocrystals for Bioavailability Enhancement. Part 1: Formulation Design and Role of the Polymeric Excipient.

Artemisinin (ART) is a most promising antimalarial agent, which is both effective and well tolerated in patients, though it has therapeutic limitations due to its low solubility, bioavailability, and short half-life. The objective of this work was to explore the possibility of formulating ART cocrystals, i.e., artemisinin-orcinol (ART-ORC) and artemisinin-resorcinol (ART2-RES), as oral dosage forms to deliver ART molecules for bioavailability enhancement. This is the first part of the study, aiming to develop a simple and effective formulation, which can then be tested on an appropriate animal model (i.e., mouse selected for in vivo study) to evaluate their preclinical pharmacokinetics for further development. In the current work, the physicochemical properties (i.e., solubility and dissolution rate) of ART cocrystals were measured to collect information necessary for the formulation development strategy. It was found that the ART solubility can be increased significantly by its cocrystals, i.e., 26-fold by ART-ORC and 21-fold by ART2-RES, respectively. Screening a set of polymers widely used in pharmaceutical products, including poly(vinylpyrrolidone), hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose acetate succinate, based on the powder dissolution performance parameter analysis, revealed that poly(vinylpyrrolidone)/vinyl acetate (PVP-VA) was the most effective crystallization inhibitor. The optimal concentration of PVP-VA at 0.05 mg/mL for the formulation was then determined by a dissolution/permeability method, which represented a simplified permeation model to simultaneously evaluate the effects of a crystallization inhibitor on the dissolution and permeation performance of ART cocrystals. Furthermore, experiments, including surface dissolution of single ART cocrystals monitored by Raman spectroscopy, scanning electron microscopy and diffusion properties of ART in solution measured by 1H and diffusion-ordered spectroscopy nuclear magnetic resonance spectroscopy, provided insights into how the excipient affects the ART cocrystal dissolution performance and bioavailability.

Solvent-Assisted Hot Melt Extrusion of a Thermally Labile, High Melting Point Compound

Molecular dispersions are a highly effective method of increasing bioavailability for a poorly soluble active pharmaceutical ingredient (API) and can be prepared on a large scale by hot melt extrusion (HME). Processing thermally labile active pharmaceutical ingredients (APIs) via HME is generally more difficult, with operating temperatures limited to below that of the API melting point. API melting is considered essential to facilitate the formation of a fully homogeneous amorphous system. Processing below the melting point renders the system much more susceptible to residual crystalline content; hence, HME is not suitable for APIs which degrade upon melting. In the following work, meloxicam (MEL) was used as a model API, possessing properties of high melting temperature and thermal lability. In this proof of concept work, a modified HME method, termed solvent-assisted HME, was used to overcome this issue and prepare an amorphous solid dispersion using HME, wherein a solvent was incorporated in the formulation blend during extrusion and removed post-processing. Formulations containing 10%wt meloxicam (MEL) and 90%wt polyvinylpyrrolidone vinyl acetate (PVPVA) copolymer were extruded using a twin-screw extruder at temperatures below the melting point of MEL. Dimethylformamide (DMF) solvent was added directly into the extruder barrel through a liquid addition port, resulting in extrudate products having a higher conversion of API to the amorphous form. The incorporation of solvent allowed a significant reduction in processing temperatures due to its increased mobility, while also driving the conversion of the API to its amorphous form. The solvent was successfully reduced through a secondary drying step using a vacuum oven. This advancement has demonstrated the potential for thermally labile APIs to be processed via HME expanding the applications of this technology.

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

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

Amorphous Solid Dispersions Containing Residual Crystallinity: Competition Between Dissolution and Matrix Crystallization.

Crystallinity in an amorphous solid dispersion (ASD) may negatively impact dissolution performance by causing lost solubility advantage and/or seeding crystal growth leading to desupersaturation. The goal of the study was to evaluate underlying dissolution and crystallization mechanisms resulting from residual crystallinity contained within bicalutamide (BCL)/polyvinylpyrrolidone vinyl acetate copolymer (PVPVA) ASDs produced by hot melt extrusion (HME). In-line Raman spectroscopy, polarized light microscopy, and scanning electron microscopy were used to characterize crystallization kinetics and mechanisms. The fully amorphous ASD (0% crystallinity) did not dissolve completely, and underwent crystallization to the metastable polymorph (form 2), initiating in the amorphous matrix at the interface of the amorphous solid with water. Under non-sink conditions, higher extents of supersaturation were achieved because dissolution initially proceeded unhindered prior to nucleation. ASDs containing residual crystallinity had markedly reduced supersaturation. Solid-mediated crystallization (matrix crystallization) consumed the amorphous solid, growing the stable polymorph (form 1). Under sink conditions, both the fully amorphous ASD and crystalline physical mixture achieve faster release than the ASDs containing residual crystallinity. In the latter systems, matrix crystallization leads to highly agglomerated crystals with high relative surface area. Solution-mediated crystallization was not a significant driver of concentration loss, due to slow crystal growth from solution in the presence of PVPVA. The high risk stemming from residual crystallinity in BCL/PVPVA ASDs stems from (1) fast matrix crystallization propagating from crystal seeds, and (2) growth of the stable crystal form. This study has implications for dissolution performance outcomes of ASDs containing residual crystallinity.

Aqueous Dissolution and Dispersion Behavior of Polyvinylpyrrolidone Vinyl Acetate-based Amorphous Solid Dispersion of Ritonavir Prepared by Hot-Melt Extrusion with and without Added Surfactants.

In this study, the lack of complete drug release from amorphous solid dispersions (ASDs), as observed in most published reports, was investigated. ASDs with 20% ritonavir were prepared by HME using polyvinylpyrrolidone vinyl acetate (PVPVA) alone and in combination with 10% poloxamer 407 or Span 20 as carriers. It was established by the film casting technique that ritonavir was molecularly dispersed in formulations, and accelerated stability testing confirmed that extrudates were physically stable. Dissolution of ASDs (100-mg ritonavir equivalent) was performed in 250mL 0.01N HCl (pH 2), pH 6.8 phosphate buffer and FeSSIF-V2. Drug concentrations were measured by filtration through 0.45-μm pores and in unfiltered media; the latter gave total amounts of drug present in dissolution media, both as solution and dispersion. Because of low solubility, ritonavir did not dissolve completely in aqueous media. Rather, it formed supersaturated solutions, and the excess drug dispersed in the oily amorphous form with low particle sizes that could crystallize with time. Due to higher drug solubility, the dissolved drug in FeSSIF-V2 was much higher than that in the phosphate buffer. Complete drug release could be observed by accounting for drug both in solution and as phase-separated dispersion. Thus, the present study provides a complete picture of invitro drug dissolution and dispersion from ASDs.

Frequency and waveform dependence of alternating current electrospinning and their uses for drug dissolution enhancement.

The effect of different frequencies and waveforms was investigated for the first time on alternating current electrospinning (ACES). PVPVA64, a polyvinylpyrrolidone-vinyl acetate copolymer was selected for the experiments as an important matrix for amorphous solid dispersions but never processed with ACES. It has been proved that ACES could be operated in a wide range of frequencies (40-250Hz) and using different waveforms (sinusoidal, square, triangle, saw tooth) without significant changes in fiber morphology. Nevertheless, deterioration of the fiber formation process could be also observed especially at high frequencies. The developed PVPVA64-based fibers containing small amounts of additives (polyethylene oxide (PEO) and sodium dodecyl sulfate (SDS)) served as an excellent carrier for spironolactone (SPIR), a poorly soluble antihypertensive drug. As a result of the amorphously dispersed SPIR and the large surface area of the AC electrospun fibers immediate drug release could be achieved.