Polyvinylpyrrolidone-vinyl Acetate Research Articles

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.

Binary polymeric amorphous carvedilol solid dispersions: In vitro and in vivo characterization

Binary polymeric amorphous carvedilol solid dispersions were prepared using solvent method by varying solvent type, polymer type and carvedilol to polymer ratio in order to assess the influence of these factors and maximize carvedilol dissolution rate. Low and high molecular weight polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer were used as polymeric carriers in carvedilol to polymer ratios 1:1, 1:2 or 1:4, while absolute ethanol or acetone were used as solvents. Hard gelatin capsules were prepared with carvedilol solid dispersion and lactose monohydrate, mannitol or microcrystalline cellulose. FTIR and PXRD were used to detect carvedilol crystallinity and identify carvedilol-polymer interactions and carvedilol polymorphs. These techniques confirmed carvedilol transition to amorphous state and suggested that hydrogen bonds were formed between carvedilol and polymer molecules. Carvedilol dissolution rate was significantly higher from solid dispersions with higher carvedilol to polymer ratio and solid dispersions prepared using the solvent in which the polymer was more soluble. Solid dispersion with polyvinylpyrrolidone-vinyl acetate copolymer in 1:4 ratio in absolute ethanol displayed the highest carvedilol dissolution rate with 91.78% carvedilol dissolved in the first 30 min. Capsules prepared with the selected solid dispersion and microcrystalline cellulose as diluent displayed the highest carvedilol dissolution rate, with 93.43% carvedilol dissolved within the first 30 min. Carvedilol bioavailability was significantly increased by formulating solid dispersions, while the analysis of serum biochemical parameters excluded damage on liver and kidney function and the lipid profile of animals exposed to investigated drug delivery system.

Development of a Resveratrol Nanosuspension Using the Antisolvent Precipitation Method without Solvent Removal, Based on a Quality by Design (QbD) Approach.

The purpose of this study was to develop a resveratrol nanosuspension with enhanced oral bioavailability, based on an understanding of the formulation and process parameters of nanosuspensions and using a quality by design (QbD) approach. Particularly, the antisolvent method, which requires no solvent removal and no heating, is newly applied to prepare resveratrol nanosuspension. To ensure the quality of the resveratrol nanosuspensions, a quality target product profile (QTPP) was defined. The particle size (z-average, d90), zeta potential, and drug content parameters affecting the QTPP were selected as critical quality attributes (CQAs). The optimum composition obtained using a 3-factor, 3-level Box–Behnken design was as follows: polyvinylpyrrolidone vinyl acetate (10 mg/mL), polyvinylpyrrolidone K12 (5 mg/mL), sodium lauryl sulfate (1 mg/mL), and diethylene glycol monoethyl ether (DEGEE, 5% v/v) at a resveratrol concentration of 5 mg/mL. The initial particle size (z-average) was 46.3 nm and the zeta potential was −38.02 mV. The robustness of the antisolvent process using the optimized composition conditions was ensured by a full factorial design. The dissolution rate of the optimized resveratrol nanosuspension was significantly greater than that of the resveratrol raw material. An in vivo pharmacokinetic study in rats showed that the area under the plasma concentration versus time curve (AUC0–12h) and the maximum plasma concentration (Cmax) respectively, than those of the resveratrol raw material. Therefore, the prepara values of the resveratrol nanosuspension were approximately 1.6- and 5.7-fold higher,tion of a resveratrol nanosuspension using the QbD approach may be an effective strategy for the development of a new dosage form of resveratrol, with enhanced oral bioavailability.

Effect of Moisture Sorption on Free Volume and Relaxation of Spray Dried Dispersions: Relation to Drug Recrystallization

The effect of vapor sorption on the free volume of drug-polymer spray-dried dispersions (SDDs) was investigated, along with the crystallization propensity of drug molecules in SDDs after exposure to humidity. Subsequently, the correlation of free volume change and relaxation time with drug recrystallization was examined. Four polymers, including polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, hydroxypropyl cellulose, and hydroxypropyl methylcellulose acetate succinate, and 2 drugs (indomethacin and ketoconazole) were selected for preparing SDDs. Free volume data of the exposed SDDs were obtained with positron annihilation lifetime spectroscopy, while the relaxation time was measured using a TA rheometer. Additionally, the crystallization propensity of active pharmaceutical ingredients (APIs) in the exposed SDDs was assessed using both polarized light microscopy and powder X-ray diffraction, followed by relating API crystallization inclination with expansion of holes and relaxation time. Finally, Cohen and Turnbull molecular transport model, along with its extensions by Vrentas and Duda, was qualitatively utilized for interpreting the recrystallization propensity of API molecules. In conclusion, API recrystallization is closely related to free volume change upon moisture sorption and relaxation time, but system dependent; overall, drug-hydroxypropyl methylcellulose acetate succinate SDDs appear physically stable against recrystallization due to less increase in free volume.

Preparation, Characterization and Prevention of Auto-oxidation of Amorphous Sirolimus by Encapsulation in Polymeric Films Using Hot Melt Extrusion.

Sirolimus (SIR) is a macrocyclic lactone antibiotic and used therapeutically as a potent immunosuppressant for prophylaxis of kidney transplant rejection. The development of an oral dosage form is challenging because of very poor aqueous solubility (2.6µg/ml). The oral bioavailability of SIR is only 15-20 % and is affected by food and other drugs. The main reasons for low bioavailability are intestinal degradation by enzymes especially by cytochrome P4503A4, efflux by P-glycoprotein and hepatic first-pass metabolism. The main objective was to prepare a mouth dissolving film dosage form of amorphous SIR to improve dissolution. Crystalline SIR was transformed to its form amorphous by milling for 2 h at room temperature. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and powder x-ray diffraction (PXRD) were used for characterisation. The stability of amorphous SIR was studied at 4°C and 40°C/75% RH. Amorphous SIR was formulated as oral films by melt extrusion with polyvinylpyrrolidone- vinyl acetate (PVP-VA), Soluplus® and hydroxypropyl cellulose (HPC) as carriers. The films were characterized for drug content, physical state, dissolution profile and stability at 4°C and 40°C/75% RH. The PRXD and DSC confirmed the conversion of crystalline SIR to amorphous form by milling. The solubility of amorphous SIR was several folds higher than its crystalline form, but amorphous SIR was highly unstable at all tested temperatures (4° and 40°C). The extruded films exhibited higher dissolution and stability compared to milled SIR powder alone, but the process of extrusion had some detrimental effect on the chemical stability of amorphous SIR. The film formulations showed a significant improvement in the storage stability of the amorphous form of SIR and the solubility advantage of the amorphous form was evident in the dissolution testing. The oral films can potentially improve the bioavailability of SIR by absorption through the buccal mucosa.

Effect of Spray-Dried Particle Morphology on Mechanical and Flow Properties of Felodipine in PVP VA Amorphous Solid Dispersions

Amorphous solid dispersions (ASDs) are commonly used to enhance the oral absorption of drugs with solubility or dissolution rate limitations. Although the ASD formulation is typically constrained by physical stability and in vivo performance considerations, ASD particles can be engineered using the spray-drying process to influence mechanical and flow properties critical to tableting. Using the ASD formulation of 20% w/w felodipine dispersed in polyvinyl pyrrolidone vinyl acetate, spray-drying atomization and drying conditions were tuned to achieve 4 different powders with varying particle properties. The resulting particles ranged in volume moment mean diameter from 4 to 115 μm, bulk density from 0.05 to 0.38 g cm−3, and morphologies of intact, collapsed, and fractured hollow spheres. Powder flowability by shear cell ranged from poor to easy flowing, whereas mechanical property tests suggested all samples will produce strong tablets at reasonable solid fractions and compression pressures. In addition, Hiestand dynamic tableting indices showed excellent dynamic bonding for 3 powders, and low viscoelasticity with high brittleness for all powders. This work demonstrates the extent spray-dried ASD particle morphologies can be engineered to achieve desired powder flow and mechanical properties to mitigate downstream processing risks and increase process throughput.

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.

Influence of mechanical and thermal energy on nifedipine amorphous solid dispersions prepared by hot melt extrusion: Preparation and physical stability

Hot melt extrusion (HME) has been used to prepare solid dispersions, especially molecularly dispersed amorphous solid dispersions (ASDs) for solubility enhancement purposes. The energy generated by the extruder in the form of mechanical and thermal output enables the dispersion and dissolution of crystalline drugs in polymeric carriers. However, the impact of this thermal and mechanical energy on ASD systems remains unclear. We selected a model ASD system containing nifedipine (NIF) and polyvinylpyrrolidone vinyl acetate (PVP/VA 64) to investigate how different types of energy input affect the preparation and physical stability of ASDs. Formulations were prepared using a Leistritz Nano-16 extruder, and we varied the screw design, barrel temperature, screw speed, and feed rate to control the mechanical and thermal energy input. Specific mechanical energy (SME) was calculated to quantitate the mechanical energy input, and the thermal energy was estimated using barrel temperature. We find that both mechanical and thermal energy inputs affect the conversion of crystalline NIF into an amorphous form, and they also affect the level of mixing and the degree of homogeneity in NIF ASDs. However, for small size extruders (e.g., Leistritz Nano-16), thermal energy is more efficient than mechanical energy in preparing NIF ASDs that have better stability.

Formulation and clinical investigation of optimized vinpocetine lyoplant-tabs: new strategy in development of buccal solid dosage form.

BackgroundThis work aimed to develop a new solid dosage formulation of vinpocetine (VPN) in the form of buccal freeze-dried pullulan-based tablets (lyoplant-tabs) loaded with physically modified drug binary system.MethodsDifferent polyvinyl pyrrolidone (PVP) grades were studied to prepare an efficient VPN binary system characterized by enhanced equilibrium saturation solubility, solubilization efficiency, thermodynamic stability, and permeation through oral mucosal cell lines. The concentrations of pullulan and swelling-aid polymer that affect the quality attributes of lyoplant-tabs were optimized. Clinical pharmacokinetics study on human volunteers for the optimized lyoplant-tabs compared to marketed product was accomplished.ResultsA promising drug binary system with polyvinyl pyrrolidone vinyl acetate (PVP-VA64) utilizing the lyophilization technique was developed. Solid-state characterization confirmed transformation of VPN completely into the amorphous form. The concentrations of pullulan and swelling-aid polymer were significantly affecting the characteristics of the tablets. Compared to the commercial VPN tablets, pullulan-based buccal tablets demonstrated enhancement in the studied pharmacokinetic parameters with positive impact on the drug bioavailability.ConclusionThese VPN lyoplant-tabs containing lyophilized PVP-VA64-VPN binary system can be considered as an alternative to currently available marketed tablets; however, further preclinical investigations using large number of volunteers are required.

Thermodynamic and kinetic evaluation of the impact of polymer excipients on storage stability of amorphous itraconazole

Two pharmaceutical polymers with high glass transition temperatures (Tg > 100 °C), polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), have been assessed for their impact on the storage stability of itraconazole (ITZ) amorphous solid dispersions (ASDs). The results showed that the inhibitory effect of PVPVA on the recrystallization of amorphous ITZ was highly sensitive to surrounding relative humidity (RH), especially at RH above 60%. In contrast, amorphous ITZ in HPMCAS matrix exhibited much stronger resistance to recrystallization even under high RH conditions, reflecting the superior crystallization-inhibitory effect of HPMCAS. While the ITZ loads in the two polymers far exceeded the respective thermodynamic solubility limits, both ASD systems remained physically stable over an extended storage period at RH ≤ 60%. Kinetics rather than thermodynamics dictate the physical stability of ITZ ASDs. Crystallization of ITZ in ASDs appears to involve a complex interplay of multiple factors, including polymer type, glass transition temperatures (Tgs) of drug and polymer, crystallization tendency of amorphous drug, and storage conditions. Specifically, with respect to the impact of polymer type, HPMCAS is particularly effective for maintaining the storage stability of ITZ ASDs, which can be attributed to its higher Tg and lower hydrophilicity.

Characterization of the Partition Rate of Ibuprofen Across the Water-Octanol Interface and the Influence of Common Pharmaceutical Excipients

This work reports the measurement of the partition rate of a model drug, ibuprofen (IBU), from aqueous solutions into octanol in the absence and presence of common pharmaceutical excipients including glucose, lactose, maltoheptaose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone–vinyl acetate, hydroxypropyl methylcellulose AS, sodium dodecyl sulfate, Tween 80, and sodium taurocholate at varying concentrations. This attempts to assess the kinetic aspect of IBU partitioning across the water-octanol interface by applying a mechanistic model and to characterize the interfacial resistance. A significant reduction in Pi across the water-octanol interface was observed with extremely low concentration of the selected excipients in the aqueous media. These results reveal the presence of a surface excess of adsorbed excipients at the water-octanol interface. The retardation of the Pi of IBU was found to be sensitive to (1) the molecular weight or the degree of polymerization of these excipients, (2) the hydrodynamic condition of the experimental method, and (3) the pH of the aqueous media. Retardation of the Pi of IBU in the presence of excipients observed in this study is proposed by a steric obstruction mechanism through the adsorbed surface excess layer of excipients located at the water-octanol interface.

On-demand manufacturing of immediate release levetiracetam tablets using pressure-assisted microsyringe printing

Fast and accurate manufacturing of individually tailored solid dosage forms is one of the main challenges for personalized medicine. The use of 3D printers has recently been studied to determine their suitability for personalized drug manufacturing.In the current work, formulations free of organic solvents were developed for a pressure-assisted microsyringe printing method (PAM). The water soluble polymer polyvinyl alcohol-polyethylene glycol graft copolymer (PVA-PEG) was used as matrix, while levetiracetam (LEV) was used as model drug. Furthermore, the influence of a second polymer, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-PVAc) on the properties of the printed tablets was investigated. Tablets were printed using a 3D-Bioplotter. The printed formulations were analyzed regarding mass variation, friability and thickness. Furthermore, the disintegration behavior and dissolution profile were analyzed. Investigations of the dissolution profiles of printed tablets show that an immediate release of the API could be achieved. For tablets with PVA-PEG the drug is released completely within 10 min while the additional use of PVP-PVAc leads to a slightly delay with a complete release within 20 min. The same trend is observed regarding the disintegration time of printed tablets. Tablets with PVA-PEG disintegrated within 95 ± 10 s while tablets with additional PVP-PVAc disintegrated within 130 ± 20 s.Friability of <0.5% indicate that the used PAM printing method provides tablets without loss of structural integrity during handling. Furthermore, it could be shown that the production of tablets with a good content uniformity using a 3D Bioplotter is suitable.

Orally Disintegrating Tablets Containing Melt Extruded Amorphous Solid Dispersion of Tacrolimus for Dissolution Enhancement.

In order to improve the aqueous solubility and dissolution of Tacrolimus (TAC), amorphous solid dispersions of TAC were prepared by hot melt extrusion with three hydrophilic polymers, Polyvinylpyrrolidone vinyl acetate (PVP VA64), Soluplus® and Hydroxypropyl Cellulose (HPC), at a drug loading of 10% w/w. Molecular modeling was used to determine the miscibility of the drug with the carrier polymers by calculating the Hansen Solubility Parameters. Powder X-ray diffraction and differential scanning calorimetry (DSC) studies of powdered solid dispersions revealed the conversion of crystalline TAC to amorphous form. Fourier transform Infrared (FTIR) spectroscopy results indicated formation of hydrogen bond between TAC and polymers leading to stabilization of TAC in amorphous form. The extrudates were found to be stable under accelerated storage conditions for 3 months with no re-crystallization, indicating that hot melt extrusion is suitable for producing stable amorphous solid dispersions of TAC in PVP VA64, Soluplus® and HPC. Stable solid dispersions of amorphous TAC exhibited higher dissolution rate, with the solid dispersions releasing more than 80% drug in 15 min compared to the crystalline drug giving 5% drug release in two hours. These stable solid dispersions were incorporated into orally-disintegrating tablets in which the solid dispersion retained its solubility, dissolution and stability advantage.

Combining an In Vitro Kinetic Model with a Physiologically-Based Pharmacokinetic Model to Assess the Potential In Vivo Fate of Polyvinyl Pyrrolidone-Vinyl Acetate Copolymers.

To understand hydrolysis and alcoholysis of polyvinylpyrrolidone-co-vinylacetate (PVPVA) during formulation and storage, elucidate the reaction mechanism, establish an intrinsic kinetic model, and apply this model coupled with GastroPlus™ modeling to predict the amount of PVPVA degradation in vivo. The experimental approach includes the detection of the polymer reaction by solution nuclear magnetic resonance (NMR) and the measurement of reaction product concentration via gas chromatography (GC). The theoretical approach includes the establishment of the intrinsic kinetic model and the application of GastroPlus™ to predict the degree of PVPVA degradation. The kinetic model established is a first order reaction between PVPVA and 2-propanol (IPA) or water under an acidic condition. The application of this kinetic model shows that between 1.7 and 6.8mg of degradant is formed in the GI tract for a 850mg dose of PVPVA. The results from this application provide valuable input for process development and the risk analysis of the degradation of PVPVA.

Differential scanning calorimetry isothermal hold times can impact interpretations of drug-polymer dispersability in amorphous solid dispersions

Differential scanning calorimetry (DSC) is a commonly employed analytical technique for the analysis and characterization of amorphous solid dispersions. However, steps typical of standard temperature programs can alter the material in situ. Data for two active pharmaceutical ingredients are detailed, wherein isothermal hold times, traditionally employed to remove thermal history and/or residual solvent, were observed to impact the observed dispersability of the compounds in polyvinylpyrrolidone vinyl-acetate copolymer (PVPva). Re-crystallized tolbutamide was observed to re-dissolve in PVPva, while terfenadine was observed to crystallize during the isothermal hold period. Exposing co-solidified drug-polymer mixtures to temperature changes and experimental hold times can potentially confound correct categorization of dispersability, particularly when DSC is used as the lone characterization technique. This work illustrates the importance of using a combination of techniques to improve the certainty of conclusions made with respect to the true, initial physical state of a co-solidified mixture.

Modeling and Prediction of Drug Dispersability in Polyvinylpyrrolidone-Vinyl Acetate Copolymer Using a Molecular Descriptor

The expansion of a novel in silico model for the prediction of the dispersability of 18 model compounds with polyvinylpyrrolidone-vinyl acetate copolymer is described. The molecular descriptor R3m (atomic mass weighted 3rd-order autocorrelation index) is shown to be predictive of the formation of amorphous solid dispersions at 2 drug loadings (15% and 75% w/w) using 2 preparation methods (melt quenching and solvent evaporation using a rotary evaporator). Cosolidified samples were characterized using a suite of analytical techniques, which included differential scanning calorimetry, powder X-ray diffraction, pair distribution function analysis, polarized light microscopy, and hot stage microscopy. Logistic regression was applied, where appropriate, to model the success and failure of compound dispersability in polyvinylpyrrolidone-vinyl acetate copolymer. R3m had combined prediction accuracy greater than 90% for tested samples. The usefulness of this descriptor appears to be associated with the presence of heavy atoms in the molecular structure of the active pharmaceutical ingredient, and their location with respect to the geometric center of the molecule. Given the higher electronegativity and atomic volume of these types of atoms, it is hypothesized that they may impact the molecular mobility of the active pharmaceutical ingredient, or increase the likelihood of forming nonbonding interactions with the carrier polymer.

Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissolution.

The aim of this research was to study the interplay of solid and solution state phase transformations during the dissolution of ritonavir (RTV) amorphous solid dispersions (ASDs). RTV ASDs with polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) were prepared at 10-50% drug loading by solvent evaporation. The miscibility of RTV ASDs was studied before and after exposure to 97% relative humidity (RH). Non-sink dissolution studies were performed on fresh and moisture-exposed ASDs. RTV and polymer release were monitored using ultraviolet-visible spectroscopy. Techniques including fluorescence spectroscopy, confocal imaging, scanning electron microscopy (SEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC) and nanoparticle tracking analysis (NTA) were utilized to monitor solid and the solution state phase transformations. All RTV-PVP and RTV-PVPVA ASDs underwent moisture-induced amorphous-amorphous phase separation (AAPS) on high RH storage whereas RTV-HPMCAS ASDs remained miscible. Non-sink dissolution of PVP- and PVPVA-based ASDs at low drug loadings led to rapid RTV and polymer release resulting in concentrations in excess of amorphous solubility, liquid-liquid phase separation (LLPS) and amorphous nanodroplet formation. High drug loading PVP- and PVPVA-based ASDs did not exhibit LLPS upon dissolution as a consequence of extensive AAPS in the hydrated ASD matrix. All RTV-HPMCAS ASDs led to LLPS upon dissolution. RTV ASD dissolution is governed by a competition between the dissolution rate and the rate of phase separation in the hydrated ASD matrix. LLPS was observed for ASDs where the drug release was polymer controlled and only ASDs that remained miscible during the initial phase of dissolution led to LLPS. Techniques such as fluorescence spectroscopy, confocal imaging and SEM were useful in understanding the phase behavior of ASDs upon hydration and dissolution and were helpful in elucidating the mechanism of generation of amorphous nanodroplets.