Polyvinylpyrrolidone-vinyl Acetate Research Articles

Surface properties and surface free energy of cellulosic etc mucoadhesive polymers

The paper presents the sorption and wettability properties for several mucoadhesive polymers (Carbopol 974P NF (carbomer polymer; carboxy polymethylene), Noveon AA-1, (polycarbophil; acrylic acid polymer crosslinked with divinyl glycol) HPMC (hypromellose; cellulose 2-hydroxyethyl methyl ester) and HEC (cellulose 2-hydroxyethyl ether) and a film-forming polymer Kollidon VA 64 (polyvinylpyrrolidone-vinyl acetate copolymer)) commonly used in controlled drug delivery systems. Moreover, the surface energy of powders was determined using the data obtained according to the three types of experimental investigation. The contact angle measurements for powders were performed according to the Washburn method and using the capillary rise technique. Whereas the sessile drop method was performed on the compressed discs of mucoadhesive polymers. For the surface characterization the IGC technique was also applied. The results obtained by different methods, for both: wettability and surface energies, were compared and correlated. The presented study showed significant differences in the morphology and surface properties of mucoadhesion polymers considered. It was confirmed that for the accurate quantification of the free surface energy (and its components), for mucoadhesive polymers considered, not only the IGC in finite concentration, but also the Washburn method should be used.

An investigation into the factors governing the degree of dissolution enhancement of solid dispersion for poorly soluble drugs

AbstractSolid dispersion (SD) formulation has attracted much attention due to its potential in enhancing dissolution performances of poorly soluble active pharmaceutical ingredients (API). Recently, a review on dissolution performances of SDs classifies the improvement into 3 categories, where 82 % of the studies showed improved bioavailability, 8 % showed reduced bioavailability and 10 % revealed similar bioavailability as compared to pure APIs. This indicates the inconsistent degrees of dissolution improvement of poorly soluble APIs in SD. Although a few factors related to the choice of carriers have been suggested to contribute to the dissolution improvement, however, the underlying factor determining the discrepancy in the degree of dissolution improvement remains in vague. It is hypothesized that the API contributes to the degree of dissolution improvement of SD. Hence, the factor of amorphous solubility advantage of API which leads to the different degrees of dissolution enhancement of SD is investigated in this research. Polyvinylpyrrolidone vinyl acetate (PVPVA)-based SD is prepared with three poorly soluble APIs. Physicochemical properties of SD were characterized using infrared spectroscopy, differential scanning calorimetry (DSC) and X-ray powder diffraction. The dissolution efficiency of each SD was calculated and compared to physical mixture and pure API. Theoretical amorphous solubility advantage for each API was calculated using the thermal properties obtained from DSC. The calculated values were found to be correlating well with the dissolution enhancement of the respective SDs. Hence, this theoretical approach can be utilized as an initial screening tool of API candidates in SD formulation during early pharmaceutical development.

Lubricant-Induced Crystallization of Itraconazole From Tablets Made of Electrospun Amorphous Solid Dispersion

Investigation of downstream processing of nanofibrous amorphous solid dispersions to generate tablet formulation is in a quite early phase. Development of high speed electrospinning opened up the possibility to study tableting of electrospun solid dispersions (containing polyvinylpyrrolidone-vinyl acetate and itraconazole [ITR] in this case). This work was conducted to investigate the influence of excipients on dissolution properties and the feasibility of scaled-up rotary press tableting. The dissolution rates from tablets proved to be mainly composition dependent. Magnesium stearate acted as a nucleation promoting agent (providing an active hydrophobic environment for crystallization of ITR) hindering the total dissolution of ITR. This crystallization process proved to be temperature dependent as well. However, the extent of dissolution of more than 95% was realizable when a less hydrophobic lubricant, sodium stearyl fumarate (soluble in the medium), was applied. Magnesium stearate induced crystallization even if it was put in the dissolution medium next to proper tablets. After optimization of the composition, scaled-up tableting on a rotary press was carried out. Appropriate dissolution of ITR from tablets was maintained for 3 months at 25°C/60% relative humidity. HPLC measurements confirmed that ITR was chemically stable both in the course of downstream processing and storage.

Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole

This study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance.

Microencapsulation of lutein extracted from marigold flowers (Tagetes erecta L.) using full factorial design

Lutein (LUT), is one of the most important carotenoids having prominent antioxidant activity. However, its use is limited due to poor solubility and instability under adverse conditions. LUT was microencapsulated with soluble polymers using spray drying to improve its solubility and bioavailability. Maltodextrin (polysaccharide base) and copovidone (polyvinyl pyrrolidone vinyl acetate based copolymer) were evaluated as hydrophilic carriers for encapsulation of LUT. Design of Experiments (DOE) was utilized and microencapsulation process was optimized using full factorial design. Copovidone proved to be better carrier compared to maltodextrin and showed enhanced dissolution and antioxidant characteristics of LUT. Microencapsulated LUT powder was characterized by dissolution study, DSC, XRD and SEM. This study can be used as a guideline for optimization of microencapsulation of similar bio-actives with hydrophilic carriers to improve solubility and subsequent bioavailability.

Detailed stability investigation of amorphous solid dispersions prepared by single-needle and high speed electrospinning

In this research the long-term stability (one year) of amorphous solid dispersions (ASDs) prepared by high speed electrospinning was investigated at 25°C/60% relative humidity (RH) (closed conditions) and 40°C/75% RH (open conditions). Single needle electrospinning and film casting were applied as reference technologies. Itraconazole (ITR) was used as the model API in 40% concentration and the ASDs consisted of either one of the following polymers as a comparison: polyvinylpyrrolidone-vinyl acetate 6:4 copolymer (no hydrogen bonds between API and polymer) and hydroxypropyl methylcellulose (possible hydrogen bonds between oxo or tertiary nitrogen function of API and hydroxyl moiety of polymer). DSC, XRPD and dissolution characteristics of samples at 0, 3 and 12 months were investigated. In addition, Raman maps of certain electrospun ASDs were assessed to investigate crystallinity. A new chemometric method, based on Multivariate Curve Resolution-Alternating Least Squares algorithm, was developed to calculate the spectrum of amorphous ITR in the matrices and to determine the crystalline/amorphous ratio of aged samples. As it was expected ITR in single needle electrospun SDs was totally amorphous at the beginning, in addition hydroxypropyl methylcellulose could keep ITR in this form at 40°C/75% RH up to one year due to the hydrogen bonds and high glass transition temperature of the SD. In polyvinylpyrrolidone-vinyl acetate matrix ITR remained amorphous at 25°C/60% RH throughout one year. Materials prepared by scaled-up, high throughput version of electrospinning, which is compatible with pharmaceutical industry, also gained the same quality. Therefore these ASDs are industrially applicable and with an appropriate downstream process it would be possible to bring them to the market.

Investigation of drug-excipient interactions in lapatinib amorphous solid dispersions using solid-state NMR spectroscopy.

This study investigated the presence of specific drug-excipient interactions in amorphous solid dispersions of lapatinib (LB) and four commonly used pharmaceutical polymers, including Soluplus, polyvinylpyrrolidone vinyl acetate (PVPVA), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and hydroxypropylmethylcellulose phthalate (HPMCP). Based on predicted pKa differences, LB was hypothesized to exhibit a specific ionic interaction with HPMCP, and possibly with HPMCAS, while Soluplus and PVPVA were studied as controls without ionizable functionality. Thermal studies showed a single glass transition (Tg) for each dispersion, in close agreement with predicted values for Soluplus, PVPVA, and HPMCAS systems. However, the Tg values of LB-HPMCP solid dispersions were markedly higher than predicted values, indicating a strong intermolecular interaction between LB and HPMCP. (15)N solid-state NMR provided direct spectroscopic evidence for protonation of LB (i.e., salt formation) within the HPMCP solid dispersions. (1)H T1 and (1)H T1ρ relaxation studies of the dispersions supported the ionic interaction hypothesis, and indicated multiple phases in the cases of excess drug or polymer. In addition, the dissolution and stability behavior of each system was examined. Both acidic polymers, HPMCAS and HPMCP, effectively inhibited the crystallization of LB on accelerated stability, likely owing to beneficial strong intermolecular hydrogen and/or specific ionic bonds with the acidic polymers. Soluplus and PVPVA showed poor physical properties on stability and subsequently poor crystallization inhibition.

The fate of ritonavir in the presence of darunavir

This study was the first investigation into the potential of a fixed dose combination of ritonavir and darunavir in the form of dispersible powders prepared by spray drying. A common polymer (hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyvinylpyrrolidone-vinyl acetate 64) was formulated with either ritonavir or darunavir or a combination of ritonavir and darunavir. The influence of these polymers on the supersaturation level of ritonavir and darunavir was investigated. The concentration levels of ritonavir and darunavir during these tests dropped instantly to a plateau which could be considered as amorphous solubility. Besides, the presence of darunavir always decreased the supersaturation level of ritonavir and vice versa no matter which polymers were used. Moreover, the rate and extent of release of both ritonavir and darunavir from ternary spray-dried powders were less than the releases from binary spray-dried powders. Intermolecular interaction between ritonavir and darunavir was ruled out by 1H NMR study which means that the decrease in supersaturation level or release must be at least partially attributed to the mediated solvent process. In order to restrict the mutual influence between darunavir and ritonavir, a complex of both ritonavir and darunavir with (2-hydroxypropyl)-β-cyclodextrin was prepared and improved the dissolution rate of both ritonavir and darunavir.

Hydroxypropyl cellulose stabilizes amorphous solid dispersions of the poorly water soluble drug felodipine

Overcoming the low oral bioavailability of many drugs due to their poor aqueous solubility is one of the major challenges in the pharmaceutical industry. The production of amorphous solid dispersions (ASDs) of these drugs using hydrophilic polymers may significantly improve their solubility. However, their storage stability and the stability of their supersaturated solutions in the gastrointestinal tract upon administration are unsolved problems. We have investigated the potential of a low viscosity grade of a cellulosic polymer, hydroxypropyl cellulose (HPC-SSL), and compared it with a commonly used vinyl polymer, polyvinylpyrrolidone vinyl acetate (PVP-VA), for stabilizing the ASDs of a poorly water soluble drug, felodipine. The ASDs were produced using hot melt mixing and stored under standard and accelerated stability conditions. The ASDs were characterized using differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy. Drug dissolution and partitioning rates were evaluated using single- and biphasic dissolution studies. The ASDs displayed superior drug dissolution and partitioning as compared to the pure crystalline drug, which might be attributed to the formation of a drug–polymer molecular dispersion, amorphous conversion of the drug, and drug–polymer hydrogen bonding interactions. Late phase separation and early re-crystallization occurred at lower and higher storage temperatures, respectively, for HPC-SSL ASDs, whereas early phase separation, even at low storage temperatures, was noted for PVP-VA ASDs. Consequently, the partitioning rates for ASDs dispersed in HPC-SSL were greater than those of PVP-VA at lower and room temperature storage, whereas the performance of both of the ASDs was similar when stored at higher temperatures.

Combined use of crystalline sodium salt and polymeric precipitation inhibitors to improve pharmacokinetic profile of ibuprofen through supersaturation.

To maximize the pharmacological effect of a pain reliever such as ibuprofen, early onset of action is critical. Unfortunately, the acidic nature of ibuprofen minimizes the amount of drug that can be solubilized under gastric conditions and would be available for immediate absorption upon entry into the intestine. Although the sodium salt of ibuprofen has higher solubility, rapid conversion from the salt to the poorly soluble free acid phase occurs under gastric conditions. Therefore, the combination of the highly soluble sodium salt form of ibuprofen with polymers was evaluated as an approach to prolong supersaturation of ibuprofen during the disproportionation of the salt. Binary combinations of ibuprofen sodium with polymers resulted in the identification of several formulations that demonstrated high degrees and extended durations of supersaturation during in vitro dissolution experiments. These formulations included HPMC, polyvinyl pyrrolidone-vinyl acetate copolymer (PVP-VA64), methylcellulose (MC), and hydroxypropyl cellulose (HPC). The in vitro supersaturation observed with these ibuprofen-polymer formulations translated to an increase in Cmax and an earlier Tmax for the PVP-VA64, MC, and HPC formulations relative to ibuprofen only controls when administered orally to rats under fasted conditions. Based on these observations, combining ibuprofen sodium with polymers such as PVP-VA64, MC, or HPC is a viable formulation approach to prolong supersaturation in the stomach and enable an optimized pharmacokinetic profile in vivo where rapid onset of action is desired.

Oral absorption of atorvastatin solid dispersion based on cellulose or pyrrolidone derivative polymers

The objectives of this study were to investigate the effects of hydrophilic polymer on the supersaturation and oral absorption of amorphous atorvastatin calcium. Solid dispersions of atorvastatin calcium were prepared by a supercritical antisolvent (SAS) process. The solid dispersion with polyvinylpyrrolidone vinyl acetate (PVP VA64) achieved a higher degree and extent of supersaturation than the dispersions prepared with water-soluble polymers such as hydroxypropylmethyl cellulose (HPMC) and polyvinylpyrrolidone (PVP K30). The absorption of atorvastatin in rats was markedly increased when atorvastatin was orally administered in a PVP VA64 solid dispersion due to enhanced supersaturation and dissolution properties. Therefore, the oral absorption of atorvastatin calcium increased with the degree of supersaturation of solid dispersions prepared using an SAS process.

Analysis of a Nanocrystalline Polymer Dispersion of Ebselen Using Solid-State NMR, Raman Microscopy, and Powder X-ray Diffraction

Nanocrystalline drug-polymer dispersions are of significant interest in pharmaceutical delivery. The purpose of this work is to demonstrate the applicability of methods based on two-dimensional (2D) and multinuclear solid-state NMR (SSNMR) to a novel nanocrystalline pharmaceutical dispersion of ebselen with polyvinylpyrrolidone-vinyl acetate (PVP-VA), after initial characterization with other techniques. A nanocrystalline dispersion of ebselen with PVP-VA was prepared and characterized by powder X-ray diffraction (PXRD), confocal Raman microscopy and mapping, and differential scanning calorimetry (DSC), and then subjected to detailed 1D and 2D SSNMR analysis involving ¹H, ¹³C, and ⁷⁷Se isotopes and ¹H spin diffusion. PXRD was used to show that dispersion contains nanocrystalline ebselen in the 35-60 nm size range. Confocal Raman microscopy and spectral mapping were able to detect regions where short-range interactions may occur between ebselen and PVP-VA. Spin diffusion effects were analyzed using 2D SSNMR experiments and are able to directly detect interactions between ebselen and the surrounding PVP-VA. The methods used here, particularly the 2D SSNMR methods based on spin diffusion, provided detailed structural information about a nanocrystalline polymer dispersion of ebselen, and should be useful in other studies of these types of materials.

Prediction of the Thermal Phase Diagram of Amorphous Solid Dispersions by Flory–Huggins Theory

Miscibility of drug and polymer is one of the key parameters in amorphous formulation design. The purpose of this work is to provide a theoretical approach to evaluate miscibility between drug and polymer in amorphous solid dispersions. The model system is indomethacin and polyvinylpyrrolidone-vinyl acetate copolymer. The Flory-Huggins (F-H) interaction parameter, χ, of drug and polymer was estimated at different temperatures by two methods: melting point depression of drug in various polymer ratios at the melting temperature, and Hildebrand and Scott solubility parameter calculation at 25°C. The simplified first-order relation between the F-H interaction parameter and temperature was established. This allows the construction of a temperature-composition phase diagram of a two-component amorphous system. The spinodal curve was generated and provides an insight into the thermodynamic stability of an amorphous solid dispersion at various temperatures. The predicted stability of the model system was compared with the experimental data. The merits and deficiency of the proposed approach were fully discussed.

Informatics calibration of a molecular descriptors database to predict solid dispersion potential of small molecule organic solids

The use of a novel, in silico method for making an intelligent polymer selection to physically stabilize small molecule organic (SMO) solid compounds formulated as amorphous molecular solid dispersions is reported. 12 compounds (75%, w/w) were individually co-solidified with polyvinyl pyrrolidone:vinyl acetate (PVPva) copolymer by melt-quenching. Co-solidified products were analyzed intact using differential scanning calorimetry (DSC) and the pair distribution function (PDF) transform of powder X-ray diffraction (PXRD) data to assess miscibility. Molecular descriptor indices were calculated for all twelve compounds using their reported crystallographic structures. Logistic regression was used to assess correlation between molecular descriptors and amorphous molecular solid dispersion potential. The final model was challenged with three compounds. Of the 12 compounds, 6 were miscible with PVPva ( i.e. successful formation) and 6 were phase separated ( i.e. unsuccessful formation). 2 of the 6 unsuccessful compounds exhibited detectable phase-separation using the PDF method, where DSC indicated miscibility. Logistic regression identified 7 molecular descriptors correlated to solid dispersion potential ( α = 0.001). The atomic mass-weighted third-order R autocorrelation index (R3m) was the only significant descriptor to provide completely accurate predictions of dispersion potential. The three compounds used to challenge the R3m model were also successfully predicted.

Scientific Opinion on the safety of polyvinylpyrrolidone‐vinyl acetate copolymer for the proposed uses as a food additive

The Panel on Food Additives and Nutrient Sources added to Food provides a scientific opinion on the use of polyvinylpyrrolidone-vinyl acetate (PVP/VA) copolymer in food supplements. PVP/VA copolymer is poorly absorbed orally and largely excreted intact in the faeces. No genotoxicity data are available. Both a 28-day and a 90-day feeding study with PVP/VA copolymer in the rat, revealed a NOAEL of 1000 mg/kg bw/day (highest dose tested). Oral administration of PVP/VA copolymer to male/female rats for 24 months and to male/female dogs for 52 weeks revealed NOAELs of 2800 mg/kg bw/day and 2500 mg/kg bw/day respectively (highest doses tested). No reproductive or developmental toxicity data are available. The exposure to PVP/VA copolymer from its use in food supplements and in pharmaceuticals is 23.4 mg/kg bw/day (adult high consumers) and 16 mg/kg bw/day (child high consumers). The toxicological database was too limited to derive an ADI. From the given range of NOAELs and the intake of PVP/VA copolymer, a Margin of Safety (MOS) varying from 43 to 120 for adults and from 63 to 175 for children can be calculated. These MOS are considered sufficient given the lack of absorption of PVP/VA, the fact that the NOAELs were the highest doses tested and that exposure estimates are based on worst case assumptions. From the maximum residual levels of VA, Margins of Exposure (MOE) of > 106 were calculated. The MOE for hydrazine were above 10000. The Panel concluded that the residual levels of hydrazine (up to a maximum of 1.0 mg/kg in the final product) are unlikely to be of safety concern, but considered it would be prudent to lower the level of hydrazine as far as reasonably achievable. The Panel concluded that the use of PVP/VA copolymer in solid food supplements as a binding/coating agent is unlikely to be of safety concern at the proposed uses.

Structural Interpretation in Composite Systems Using Powder X-ray Diffraction: Applications of Error Propagation to the Pair Distribution Function

To develop a method for drawing statistical inferences from differences between multiple experimental pair distribution function (PDF) transforms of powder X-ray diffraction (PXRD) data. The appropriate treatment of initial PXRD error estimates using traditional error propagation algorithms was tested using Monte Carlo simulations on amorphous ketoconazole. An amorphous felodipine:polyvinyl pyrrolidone:vinyl acetate (PVPva) physical mixture was prepared to define an error threshold. Co-solidified products of felodipine:PVPva and terfenadine:PVPva were prepared using a melt-quench method and subsequently analyzed using PXRD and PDF. Differential scanning calorimetry (DSC) was used as an additional characterization method. The appropriate manipulation of initial PXRD error estimates through the PDF transform were confirmed using the Monte Carlo simulations for amorphous ketoconazole. The felodipine:PVPva physical mixture PDF analysis determined ±3σ to be an appropriate error threshold. Using the PDF and error propagation principles, the felodipine:PVPva co-solidified product was determined to be completely miscible, and the terfenadine:PVPva co-solidified product, although having appearances of an amorphous molecular solid dispersion by DSC, was determined to be phase-separated. Statistically based inferences were successfully drawn from PDF transforms of PXRD patterns obtained from composite systems. The principles applied herein may be universally adapted to many different systems and provide a fundamentally sound basis for drawing structural conclusions from PDF studies.

In situ formation of nanoparticles upon dispersion of melt extrudate formulations in aqueous medium assessed by asymmetrical flow field-flow fractionation

In recent years melt extrudates (e.g. Meltrex ®) have proven to be a promising formulation tool for poorly water-soluble and poorly bioavailable drugs. During the hot-melt extrusion process solid dispersions are formed. For several of these formulations improved bioavailabilities have been reported; the mechanism behind, however is still not very well understood. The aim of this study was to investigate whether solid dispersions prepared by melt extrusion upon dispersion in aqueous medium form particles and/or supramolecular assemblies. The formulation investigated here contained the human immunodeficiency virus (HIV) protease inhibitors lopinavir and ritonavir, polyvinylpyrrolidone–vinyl acetate copolymer (Kollidon ® VA64), sorbitan monolaurate (Span ® 20) and hydrophilic fumed silica (Aerosil ® 200). The aqueous dispersions originating from both, API-containing and placebo formulation were investigated using photon correlation spectroscopy (PCS) and asymmetrical flow field-flow fractionation (AsFlFFF) with subsequent online multi-angle light-scattering (MALS) particle size analysis. The content of both APIs in the AsFlFFF-fractions was quantified using high performance liquid chromatography–mass spectrometry. PCS indicated sub-micron particles. AsFlFFF revealed the co-existence of up to three different types of colloidal to nanoparticulate assemblies in the aqueous dispersions. Even though a complete resolution of the composition of the sub-fractions could not be achieved, the following types could be clearly distinguished: The first fraction eluting from AsFlFFF, appears to be colloidal polymer. Only marginal amounts of the APIs were found associated with the polymer. Secondly, API-rich nanoparticles eluted. Thirdly, nanoparticulate assemblies assigned to sorbitan monolaurate and/or hydrophilic fumed silica were identified. A limited amount of drug was found associated with this fraction. Using AsFlFFF–MALS the size of particles in fractions could be determined. From this experience AsFlFFF is regarded as promising technique for investigation of particles/structures originating during dispersion of melt extrudates in aqueous medium in terms of size and type of nanoparticles and their API-content.

In vitro and in vivo evaluation of fenofibrate solid dispersion prepared by hot-melt extrusion

Objective: This article aimed to develop fenofibrate solid dispersion with high bioavailability using hot-melt extrusion and compare the difference of Eudragit® E100 and polyvinylpyrrolidone-vinyl acetate copolymer S630 (PVP-VA) in dissolution. Methods: Solid dispersion with carrier of Eudragit E100 or PVP-VA was prepared by hot-melt extrusion and then characterized by differential scanning calorimetry (DSC), X‐ray diffraction, in vitro dissolution test, and in vivo bioavailability study. Results: Fenofibrate exited as noncrystal state in these two kinds of solid dispersions that can be proved by DSC and X-ray diffraction. Eudragit E100 1:2 solid dispersion has the dissolution of 84% and 65% at 60 minutes in 0.1M HCl and water, respectively. Eudragit E100 1:4 solid dispersion has lower dissolution in 0.1M HCl and higher dissolution in water; the values are 73.6% and 87.3%. PVP-VA 1:2 solid dispersion has the dissolution of 60% and 65% at 60 minutes in 0.1M HCl and water, respectively. PVP-VA 1:4 solid dispersion has higher dissolution in 0.1M HCl and lower dissolution in water; the values are 64% and 53%. The different dissolution of fenofibrate from the two polymers is because of their different solubility and gelling tendency. When Eudragit E100 1:4 solid dispersion was administrated to beagle dogs, its relative bioavailability to micronization Lipanthyl capsule was 177.1%. Conclusion: Hot-melt extrusion is an excellent method to improve the dissolution and therefore the bioavailability of fenofibrate.

Role of polymer chemistry in influencing crystal growth rates from amorphous felodipine

The inhibition of crystallization from organic amorphous solids is currently of great interest in the pharmaceutical field, since the amorphous form of the drug can enhance drug delivery. Polymers have been found to be effective crystallization inhibitors for many organic glasses and supercooled liquids. The objective of this study was to investigate potential correlations between drug–polymer hydrogen bonding and crystal growth inhibition. Quench cooled samples of a model hydrophobic drug, felodipine, were prepared with various polymers: poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(vinylpyrrolidone)/vinyl acetate (PVP/VA) and poly(vinyl acetate) (PVAc). Crystal growth rates as a function of temperature (70–110 °C) were measured using optical microscopy, in the presence and absence of 3% w/w polymer. Differential scanning calorimetry (DSC) was used to evaluate glass transition temperatures (Tg) and melting points. Infrared (IR) spectroscopy was used to probe drug–polymer hydrogen bonding interactions. The various polymers were found to inhibit the crystal growth to different degrees. The order of inhibition effectiveness was PVP > PVP/VA > HPMCAS > PVAc with PVP being the best inhibitor among the polymers used. The growth rates in the presence of the polymers were similar to those of the drug alone at high temperatures but showed a significant reduction as the temperature was reduced. The Tg's of the drug–polymer dispersions were not significantly different from that of the pure drug. The order of the strength/extent of drug–polymer hydrogen bonding interactions was PVP > PVP/VA > HPMCAS ≥ PVAc. Hence polymers which can form stronger/more extensive hydrogen bonds with the drug appear to be better crystallization inhibitors.

Stabilization of Low Glass Transition Temperature Indomethacin Formulations: Impact of Polymer-Type and Its Concentration

The objectives of this study were to formulate and stabilize amorphous formulation of low T(g) drug (Indomethacin, INM) with selected polymers and compare these formulations based on solubility and dissolution rate studies. Eudragit EPO (EPO), Polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), and Polyvinylpyrrolidone K30 (PVPK30) were selected as hydrophilic polymers. The melt extrudates were characterized using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), intrinsic dissolution rate and solubility studies. The formation of single-phase amorphous form was confirmed by DSC and PXRD. The melt extrudates showed a higher intrinsic dissolution rate (IDR), and solubility compared to the pure drug. The amorphous drug in solid solutions with EPO, PVP-VA, and PVPK30 showed tendency to revert back to crystalline form. However, the rate of reversion was dependent on the nature and concentration of the polymer. The solid solution with high ratio of EPO provided superior stabilization of the amorphous INM from crystallization. The stability of the amorphous form of INM could not be related to the glass transition temperature of the formulation as the mechanism of stabilization with EPO appears to be molecular interaction rather than immobilization. The presence of specific molecular interactions between INM and EPO was also shown by the antiplasticization effect.