Carvedilol Solid Dispersions Research Articles

Comprehensive Characterization and Comparative Assessment of Carvedilol Solid Dispersions: Insights into Enhanced Bioavailability and Stability Profiles

Carvedilol, a non-selective beta-adrenergic antagonist, poses a challenge in achieving optimal bioavailability due to its poor aqueous solubility. This study aimed to enhance the solubility and dissolution rate of carvedilol through the formulation and evaluation of solid dispersions. Various solid dispersion formulations were prepared using different carriers and methods, including solvent evaporation, fusion, and spray-drying techniques. The prepared formulations were systematically characterized using Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM) to investigate drug-carrier interactions, solid-state changes, and morphological characteristics. Evaluation of the formulated solid dispersions involved in vitro dissolution studies, solubility enhancement assays, and stability assessments. Dissolution profiles revealed significantly improved drug release rates for the solid dispersion formulations compared to the pure drug. The solubility of carvedilol was notably enhanced in the solid dispersion systems, indicating improved drug dissolution behavior. Stability studies demonstrated the robustness of selected formulations against environmental factors over an extended period. Moreover, pharmacokinetic studies conducted in animal models showcased enhanced bioavailability of carvedilol from the optimized solid dispersion formulation compared to the conventional drug formulation. This comprehensive investigation provides valuable insights into the development of carvedilol solid dispersions, elucidating the influence of formulation variables on drug solubility, dissolution, stability, and ultimately, bioavailability enhancement. The findings underscore the potential of solid dispersion technology as a promising strategy to overcome the solubility challenges associated with carvedilol, paving the way for improved therapeutic efficacy and patient compliance.

Preparation and Characterization of Carvedilol Solid Dispersion by Kneading Method

Solid dispersion using hydrophilic carrier is one of the approaches that has a potential to increase solubility, dissolution rate and consequently the oral bioavailability of poorly-water soluble drugs. In this study, class II drug "Carvedilol" (CVD) was used because of its poor solubility, it serves as a model drug that contributes to irregular dissolution and limited bioavailability. CVD: PVP K30 solid dispersion formulations SD1, SD2 and SD3 were prepared by kneading method at different weight ratios ,1:1; 1:2 and 1:4 respectively and evaluated for drug content, solubility and dissolution rate. Kneading method enhances the stability of drugs and suitable for processing thermolabile substances. The optimum solid dispersion ratio was characterized also for drug-carrier interaction by FTIR spectroscopy, and crystallinity by SEM and PXRD and compared with physical mixture and pure drug powder.
 The results showed that the solubility of carvedilol increased by increasing the proportion of PVP K30 used in the dispersion of the drug. On the other hand, dissolution study revealed a significant enhancement in the dissolution rate of the drug using solid dispersion compared to pure drug and physical mixture. X-ray diffraction of the solid dispersion suggest that the drug's transformation from crystalline to amorphous form may be responsible for the observed improvement in dissolving rate. The carvedilol solid dispersion improved the solubility and dissolution, which depend on the carrier concentration ratio. The dissolution of drugs increased with an increase in carrier content. The studies of PXRD, SEM, and FTIR revealed the amorphous nature of the drug in solid dispersion. The solid dispersion by kneading approach using PVP K30 as a carrier is a potential method for improving CVD's solubility and dissolution rate.

The Effect of Surfactant Type and Concentration on Physicochemical Properties of Carvedilol Solid Dispersions Prepared by Wet Milling Method.

The present study mainly aimed to prepare solid dispersions (SDs) of a poorly water-soluble compound, carvedilol (CA), in the presence of pluronic F68 (F68) and myrj 52 by wet milling technique in order to enhance drug dissolution. The process enabled the preparation of SDs without using any toxic organic solvents. SDs with different CA: surfactant ratios were prepared by wet milling followed by freeze-drying method and evaluated for their particle size and dissolution. They were also characterized based on/using X-ray diffraction (XRD), differential scanning calorimetry (DSC), fourier transform infrared (FTIR) spectroscopy, scanning electron microscope (SEM), and saturated solubility. The effect of cryoprotectant type on the dissolution and particle size of SDs was also investigated. Wet milling process resulted in the reduced particle size depending on the type of surfactant. The significant drug dissolution and saturated solubility enhancement were recorded for milled SD formulations. In this regard, Myrj had a greater impact compared to F68. Dissolution efficiencies (DE30) obtained for the myrj-included SDs were up to 8.2-fold higher than that of untreated CA. The type of cryoprotectant was also found to affect the drug dissolution. According to the results, partial amorphization occurred in wet-milled samples, as confirmed by XRD and DSC analysis. It was concluded that using an appropriate surfactant along with wet-milling method may have been an effective approach for improving the dissolution rate of CA, a poorly soluble compound.

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.

Preparation and dissolution characteristic evaluation of carvedilol-Kollicoat IR solid dispersions with HPMC and MC as combined carriers

In this study, the abilities of hydroxypropyl methylcellulose (HPMC) and methylcellulose (MC) as nonionic surfactants to improve the dissolution rate of carvedilol solid dispersions (CAR SDs) with Kollicoat IR as a carrier were clearly demonstrated. CAR SDs were prepared using the solvent evaporation method, and their physicochemical properties were characterized by scanning electron microscopy (SEM) and Powder X-Ray diffraction (PXRD). The results suggested that CAR in SDs existed in an amorphous form. In vitro dissolution experiments and molecular docking (MD) simulations were conducted to confirm the storage stability of CAR SDs. In order to study the mechanism of solubilization ability, molar solubilization ratio (MSR) and micelle-water partition coefficient (Kmic) were calculated. The results showed that the MSR and lg Kmic values of MC/Kollicoat IR 1:3 were around 30 fold higher than the single surfactant. Above all, HPMC and MC have great potentials to improve the dissolution characteristics of CAR-Kollicoat IR SDs.

Soluplus®, Eudragit®, HPMC-AS foams and solid dispersions for enhancement of Carvedilol dissolution rate prepared by a supercritical CO2 process

The present work is aimed towards designing advanced materials by means of sustainable processes. In that sense, the utilization of supercritical CO2 (scCO2) for processing of pharmaceutical polymers (Soluplus®, Eudragit®, and hydroxypropyl methylcellulose acetate succinate), alone and with an addition of cardiovascular drug Carvedilol, was explored. Employed single-step static scCO2 process (pressure of 30 MPa and temperature of 100 °C for 2 h) enabled fabrication of solvent-free polymeric foams and Carvedilol solid dispersions with controlled microstructure and average pore diameter of 101–257 μm suitable for application in the pharmaceutical industry. ScCO2 did not remain in the foams after processing or affected the polymer composition, while Carvedilol formed hydrogen bonds with the polymers. Carvedilol was molecularly dispersed in the fabricated solid dispersions and its transition from the crystalline to amorphous form was complete. Korsmeyer-Peppas model was successfully used for the mathematical description of Carvedilol dissolution from solid dispersions. The dissolution rate of Carvedilol in acidic medium was significantly enhanced by its dispersion in tested polymers using the proposed high-pressure method.

Selection of the suitable polymer for supercritical fluid assisted preparation of carvedilol solid dispersions

Solid dispersions production is one of the substantial approaches for improvement of poor drug solubility. Additionally, supercritical fluid assisted method for preparation of solid dispersions can offer many advantages in comparison to the conventional melting or solvent-evaporation methods. Miscibility analysis provides valuable guidance for selection of the most appropriate polymeric carrier for dispersion of the drug of interest. In addition to the increased drug release rate, solid dispersions should have proper mechanical attributes in order to be successfully formulated in the final solid dosage form such as tablet. Therefore, several pharmaceutical grade polymers have been selected for development of BCS Class II drug carvedilol (CARV) solid dispersions. They were compared based on behavior in supercritical CO2 and affinity towards CARV calculated from the miscibility analysis. By utilization of the supercritical CO2 assisted method, solid dispersions of CARV with the selected (co)polymers (polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), Soluplus® and Eudragit®) were obtained. Properties of the prepared CARV-polymer dispersions were observed by the polarizing and scanning electron microscopy and analyzed by differential scanning calorimetry and Fourier transform infrared spectroscopy. CARV was additionally characterized by X-ray powder diffraction. Furthermore, in vitro dissolution studies and dynamic compaction analysis were performed on the selected samples of solid dispersions. Among the studied polymers, PVP and HPMC have been identified as polymers with the highest affinity towards CARV, based on the calculated δp values. This has been also confirmed with the highest dissolution efficiency of CARV-PVP and CARV-HPMC solid dispersions. Solid state characterization indicated that CARV was dispersed either molecularly, or in the amorphous form, depending on interactions with each polymer. Determination of CARV-PVP and CARV-HPMC mechanical properties revealed that CARV-PVP solid dispersion has superior compactibility and tabletability. Therefore, CARV-PVP solid dispersion has been highlighted as the most appropriate for the further development of tablets as the final dosage form. Presented study provides an example for efficient approach for development of poorly soluble drug solid dispersion with satisfactory tableting properties.

Development and Evaluation of press coated tablets of Carvedilol using solid dispersion prepared by spray drying technique

Carvedilol is a non-selective beta and alpha blocker which is insoluble in water. It is used in the treatment of mild to severe congestive heart failure (CHF) and high blood pressure. As the solubility is very poor the bioavailability is only 25–35%. The problem of poor solubility can be overcome using any of the physical or chemical methods of solubility enhancement. The purpose of this research was to improve the solubility of Carvedilol by spray drying technique using hydrophilic polymers β-Cyclodextrin and Plasdone-K30. Prepared solid dispersions were evaluated for drug content, saturation solubility and in-vitro drug release study. The compatibility and surface morphology was studied by Fourier Transforms Infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and Scanning Electron Microscopy (SEM) respectively. The spray dried solid dispersions of Carvedilol were incorporated into press coated tablets and were subjected to various precompression and postcompression parameters. The effect of the various barrier layer compositions on the lag time was studied. This research emphasizes on the role of chronotherapy for treatment of hypertension.

Process optimization and characterization of carvedilol solid dispersion with hydroxypropyl-β-cyclodextrin and tartaric acid

The present investigation concerns the experimental design in preparing a solid dispersion of ionized carvedilol with hydroxypropyl-β-cyclodextrin (HPβCD), tartaric acid (TA) by adopting ‘kneading technique’. Simplex lattice design has been chosen to develop model equations that correlate the process variables such as HPβCD (mg), TA (mg), and kneading time (min) with the response variables, such as solubility (mg/mL) and drug release (%) from the solid dispersion. Software-generated ANOVA results confirmed the sufficiency of model equations. Results predicted by model equations are in good agreement with that of experimental results. Optimized formulation with variables ‘CV: HPβCD: TA-kneading time’ (200mg: 689.6mg: 227.6mg–45 min) showed complete drug release (∼99%) within 15 min and enhanced solubility of 1.89mg/mL. The instrumental analysis (DSC, XRD& FTIR) of the optimized solid dispersion suggests a transformation of crystallinity of drug to amorphous form, due to its complexation with HPβCD. Hence, this combination of drug and carriers suggests an improvement of carvedilol bioavailability.

English

In vitro dissolution testing should discriminate between the impact of excipients on release profile of Biopharmaceutics Classification System class 2 drugs. Among the four batches of carvedilol solid dispersion tablets, SDT-2-L containing 30% w/w mannitol and 2.5% w/w L-hydroxypropyl cellulose LH-11 exhibited  least mean dissolution time in gastric buffer (pH = 1.2) and phosphate buffer (pH = 6.8). However, inter-batch differences in release parameters from phosphate buffer were usually higher and also statistically significant at p < 0.05. Drug release from an individual formulation exhibited different kinetics in two media. Therefore, improper selection of dissolution medium may fail to discriminate between product performances. Key words: Solid dispersion tablet, dissolution efficiency, mean dissolution time.

A novel surface-attached carvedilol solid dispersion with enhanced solubility and dissolution

A novel surface-attached, spray-dried solid dispersion containing poorly water-soluble carvedilol (CV) without any change in the crystallinity was prepared using water, polyvinylpyrrolidone (PVP K30) and Tween 80. The solid dispersion was optimized by investigating the effects of the weight ratios of Tween 80/PVP K30 and carrier/drug on the aqueous solubility of CV. The optimum solid dispersion consisted of a relatively low carrier to drug weight ratio: the weight ratio of CV/PVP K30/Tween 80 was 12/4/2. Unlike conventional methods of solid dispersion preparation, this method yielded CV-loaded solid dispersion with no change in the crystallinity of the drug as was evident from SEM, DSC and XRD. It was demonstrated that the solid dispersions prepared had hydrophilic carriers attached to the surface of the drug, thus changing it from a hydrophobic to a hydrophilic form without changing the crystalline form. The optimized solid dispersion improved the drug solubility and dissolution rate by about 11,500-fold and twofold, respectively. It was further suggested that this method of solid dispersion preparation is better than conventional methods in terms of environmental and industrial standpoints. Thus, it was concluded that CV-loaded solid dispersion prepared using this method would be of use for delivering poorly water-soluble CV with enhanced solubility and dissolution, but without crystalline changes.

Soluplus®: A novel polymeric solubilizer for optimization of Carvedilol solid dispersions: Formulation design and effect of method of preparation

The aim of this work was to investigate the applicability of different industrially scalable techniques in the preparation of solid dispersions using a novel polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®) for preparing immediate-release formulations of a poorly water-soluble BCS class II drug. Carvedilol (CAR), a non-selective β-blocker, has been selected as poorly water-soluble model drug. The solid dispersions were prepared by three different techniques; solvent evaporation, freeze drying and spray drying in different CAR:Soluplus® ratios using 32 full factorial design. Among the formulations tested, CAR solid dispersion preparation using freeze drying method at ratio of 1:10 (CAR: Soluplus®) showed the highest saturation solubility and was selected for further investigation. Solid state characterization was evaluated by differential scanning calorimetry (DSC) and X-ray diffraction study (XRD), scanning electron microscopy (SEM) and Fourier transformation infrared spectroscopy (FTIR). DSC and XRD analyses indicated the complete transformation of CAR in the solid dispersion from crystalline to amorphous state. Selected CAR solid dispersion was further incorporated into ODTs using three commercially mannitol-based fillers; Pearlitol Flash®, Pharmaburst® and Ludifalsh®. The ODTs were evaluated for hardness, disintegration time and drug dissolution. Pearlitol Flash®, and Pharmaburst® ODTs showed shorter disintegration times (< 1 min) and significantly higher dissolution profile (> 90% within 30 min) compared to Ludifalsh® ODTs. Thus, the development of CAR solid dispersions using Soluplus® as ODTs could be used as a promising approach for improving the solubility and oral bioavailability of poorly water-soluble drugs.

Molecular Effect of PVP on The Release Property of Carvedilol Solid Dispersion

【This study aimed to confirm the effect of molecular weight (MW) in solid dispersion of carvedilol with poly-vinylpyrrolidone (PVP) of various MW. Solid dispersion of carvedilol with PVP was prepared by spray-drying method. Scanning electron microscopy (SEM) was used to analyze the surface of solid dispersion samples. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to analyze the crystalline of solid dispersion. Fourier transform infrared spectroscopy (FT-IR) was used to analyze the change of chemical structure characteristic of solid dispersion. DSC and XRD show that drug crystalline was changed. FT-IR revealed that chemical structure of solid dispersion comparing the chemical structure of drug was changed. The dissolution studies of solid dispersion presented at simulated gastric juice (pH 1.2). The dissolution rate of solid dispersion was dramatically enhanced than pure drug and the MW of PVP has an effect on the release property of carvedilol in solid dispersion. In conclusion, the present study has confirmed the effect of MW of PVP on release property of solid dispersion formulation of carvedilol with PVP.】

Solid Dispersions of Carvedilol with Porous Silica

Solid dispersion particles of carvedilol (CAR) were prepared with porous silica (Sylysia 350) by the solvent evaporation method in a vacuum evaporator to ensure an effective pore-filling procedure. Two sets were prepared, each with various amounts of CAR in solid dispersions, and with the pore-filling process differing each time. Set A was prepared by a one-step filling method and set B by a multiple-step pore-filling method of CAR into porous silica. The solid dispersions were then characterized using thermal analysis, X-ray diffraction, and nitrogen adsorption experiments. The results showed that the drug release can be significantly improved compared with the dissolution of the drug in its pure crystalline or amorphous state. Drug release from solid dispersion was faster when the drug content in the solid dispersion was low, which enabled the drug to be finely dispersed along the hydrophilic carrier's surface. The results also showed that a multiple-step pore-filling procedure is more effective for drug loading as indicated by the absence of a crystalline drug state, greatly reduced porosity, and improved wettability and physical stability of the amorphous CAR.

Solubility enhancement and physicochemical characterization of carvedilol solid dispersion with Gelucire 50/13

The objective of the study was enhancement of dissolution of poorly soluble carvedilol by solid dispersions (SDs) with Gelucire 50/13 using solvent evaporation method. The solubility of carvedilol showed linear increase with increasing concentrations of Gelucire indicating A(L) type solubility diagrams. SDs characterized for physicochemical characteristics using differential scanning calorimetry and X-ray diffractometry revealed transformation of crystalline form of drug to amorphous form which was confirmed by scanning electron micrographs. Further fourier transform infrared spectroscopy results suggested there is no drug carrier interaction. From the dissolution parameters such as mean dissolution time, dissolution efficiency and drug release rate, improved dissolution characteristics for SDs were observed compared with physical mixture and pure drug. Thus SDs of carvedilol in Gelucire 50/13 showed enhanced solubility and dissolution rate compared to pure drug.