Formulation of a Fast-Dissolving Ketoprofen Tablet Using Freeze-Drying in Blisters Technique

ABSTRACT

The aim of this work was to develop a ketoprofen tablet which dissolve-rapidly in the mouth, therefore, needing not be swallowed. The solubility and dissolution rate of poorly water-soluble ketoprofen was improved by preparing a lyophilized tablet (LT) of ketoprofen using freeze-drying technique. The LT was prepared by dispersing the drug in an aqueous solution of highly water-soluble carrier materials consisting of gelatin, glycine, and sorbitol. The mixture was dosed into the pockets of blister packs and then was subjected to freezing and lyophilization. The saturation solubility and dissolution characteristics of ketoprofen from the LT were investigated and compared to the plain drug and the physical mixture (PM). Results obtained showed that the increase in solubility of ketoprofen from LT matrix, nearly three times greater than the solubility of the plain drug, was due to supersaturation generated by amorphous form of the drug. Results obtained from dissolution studies showed that LT of ketoprofen significantly improved the dissolution rate of the drug compared with the PM and the plain drug. More than 95% of ketoprofen in LT dissolved within 5 min compared to only 45% of ketoprofen plain drug dissolved during 60 min. Initial dissolution rate of ketoprofen in LT was almost tenfold higher than that of ketoprofen powder alone. Crystalline state evaluation of ketoprofen in LT was conducted through differential scanning calorimetry (DCS) and x-ray powder diffraction (XRPD) to denote eventual transformation to amorphous state during the process. Scanning electron microscopic (SEM) analysis was performed and results suggest reduction in ketoprofen particle size.     

Formulation of a fast-dissolving ketoprofen tablet using freeze-drying in blisters technique

The aim of this work was to develop a ketoprofen tablet which dissolve-rapidly in the mouth, therefore, needing not be swallowed. The solubility and dissolution rate of poorly water-soluble ketoprofen was improved by preparing a lyophilized tablet (LT) of ketoprofen using freeze-drying technique. The LT was prepared by dispersing the drug in an aqueous solution of highly water-soluble carrier materials consisting of gelatin, glycine, and sorbitol. The mixture was dosed into the pockets of blister packs and then was subjected to freezing and lyophilization. The saturation solubility and dissolution characteristics of ketoprofen from the LT were investigated and compared to the plain drug and the physical mixture (PM). Results obtained showed that the increase in solubility of ketoprofen from LT matrix, nearly three times greater than the solubility of the plain drug, was due to supersaturation generated by amorphous form of the drug. Results obtained from dissolution studies showed that LT of ketoprofen significantly improved the dissolution rate of the drug compared with the PM and the plain drug. More than 95% of ketoprofen in LT dissolved within 5 min compared to only 45% of ketoprofen plain drug dissolved during 60 min. Initial dissolution rate of ketoprofen in LT was almost tenfold higher than that of ketoprofen powder alone. Crystalline state evaluation of ketoprofen in LT was conducted through differential scanning calorimetry (DCS) and x-ray powder diffraction (XRPD) to denote eventual transformation to amorphous state during the process. Scanning electron microscopic (SEM) analysis was performed and results suggest reduction in ketoprofen particle size.     

The effect of spray drying on the compaction properties of hypromellose acetate succinate

Background: The aim of this study was to evaluate the compaction behavior of a model two-component amorphous spray-dried dispersion system compared with the unprocessed excipients, using simulated rotary tablet press production conditions. Method: In this study, the stabilizing polymer, hypromellose acetate succinate (HPMCAS), was solubilized and spray dried with and without sodium lauryl sulfate (SLS). The impact of compression force and speed on the tabletting process was quantified by means of tablet tensile strength, compaction energy, and Heckel analysis. Results: Addition of the surfactant SLS, spray dried or as a physical mix, reduced the tablet strength. However, a lesser impact on the unprocessed excipients was observed in comparison with the spray-dried excipients. In the presence of 1% (w/w) SLS, tablets displayed a tendency to cap when compressed at higher speeds, supported by high elastic energy values indicating high uniaxial stress upon decompression. In the presence of 3% (w/w) SLS, tablets could not be produced at high speeds. Heckel analysis revealed a greater strain rate sensitivity of HPMCAS when spray dried in the presence of surfactant. Exposure of samples to a range of relative humidities before compaction had no effect on tablet strength. Conclusion: This study has shown that spray drying of HPMCAS in the presence of a surfactant affects the compressibility of the material, resulting in decreased tablet strength, increased elastic deformation, and capping.     

Development and evaluation of dexibuprofen formulation with fast onset and prolonged effect

In the present study, in order to improve the solubility and bioavailability of poorly water-soluble dexibuprofen, a novel dexibuprofen-loaded solid dispersion was developed using the spray-drying technique. The controlled-release dexibuprofen formulation was developed by combining the immediate-release dispersion powder and the sustained-release formula. The solid dispersion composed of dexibuprofen/poloxamer 407/hydroxypropyl methylcellulose (HPMC) 2910 (50?cps)/sodium lauryl sulfate (SLS) (10/1/4/0.1?mg) was selected as the immediate-release formulation due to its increased solubility and dissolution rate. This immediate-release formulation showed a significantly higher initial plasma concentration, AUC, and C_max of dexibuprofen than those of dexibuprofen powder. Based on the prolonged effect of high plasma concentration, the formulation consisting of dexibuprofen/ethylcellulose/HPMC 2910 (4000?cps)/magnesium stearate (66/16.5/16.5/1?mg) was selected as the sustained-release formulation. Finally, the controlled-release (CR) formulation was prepared by encapsulating the immediate-release and sustained-release formulations in hard gelatin capsules. The proposed CR formulation showed enhanced AUC (5.5-fold) and C_max (3.5-fold) compared to dexibuprofen powder. The results of the present study suggest that the CR formulation containing dexibuprofen may be a potential oral dosage form for a fast onset and a prolonged effect of poorly water-soluble dexibuprofen.     

Formulation and optimization of spray-dried amlodipine solid dispersion for enhanced oral absorption

Objective: To enhance the oral absorption of photosensitive amlodipine free base, which exhibits a slow dissolution rate and low permeability characteristics, an amorphous solid dispersion system was formulated and characterized.

Material and methods: The solid dispersion was prepared by dispersing the amlodipine free base in excess dextrin (1:10 by weight) using a spray-drying technique in the presence of a minimum amount (0.9% w/w) of SLS as an absorption enhancer. The dextrin-based solid dispersion of amlodipine (Amlo-SD) was evaluated in term of formulation, characterization and in vivo absorption study, as well as the spray-drying process was also optimized.

Results and discussion: The Amlo-SD particles were spherical with a smooth surface and an average particle size of 12.9 μm. Amlodipine was dispersed in an amorphous state and its content remained uniform in the Amlo-SD. The physicochemical stability of the Amlo-SD was maintained at room temperature for 6 months and the photostability was considerably improved. The dissolution of the Amlo-SD was much faster than that of amlodipine at pH 1.2 and 6.8. Amlo-SD produced significantly higher plasma concentrations of amlodipine in rats than amlodipine alone. Amlo-SD with and without SLS provided 2.8- and 2.0-fold increase in AUC, respectively: the difference seems to be attributed to a permeability enhancement effect by SLS.

Conclusion: The Amlo-SD with SLS system is a potential formulation option for amlodipine.     

Development of olmesartan medoxomil optimized nanosuspension using the Box–Behnken design to improve oral bioavailability

The aim of the present investigation was to enhance the oral bioavailability of olmesartan medoxomil by improving its solubility and dissolution rate by preparing nanosuspension (OM-NS), using the Box–Behnken design. In this, four factors were evaluated at three levels. Independent variables include: concentration of drug (X₁), concentration of surfactant (X₂), concentration of polymer (X₃) and number of homogenization cycles (X₄). Based on preliminary studies, the size (Y₁), zeta potential (ZP) (Y₂) and % drug release at 5?min (Y₃) were chosen as dependent responses. OM-NS was prepared by high pressure homogenization method. The size, PDI, ZP, assay, in vitro release and morphology of OM-NS were characterized. Further, the pharmacokinetic (PK) behavior of OM-NS was evaluated in male wistar rats. Statistically optimized OM-NS formulation exhibited mean particle size of 492?nm, ZP of –27.9?mV and 99.29% release in 5?min. OM-NS showed more than four times increase in its solubility than pure OM. DSC and XRD analyses indicated that the drug incorporated into OM-NS was in amorphous form. The morphology of OM-NS was found to be nearly spherical with high dispersity by scanning electron microscopic studies. The PK results showed that OM lyophilized nanosuspension (NS) exhibited improved PK properties compared to coarse powder suspension and marketed tablet powder suspension (TS). Oral bioavailability of lyophilized NS was increased by 2.45 and 2.25 folds when compared to marketed TS and coarse powder suspension, respectively. Results of this study lead to conclusion that NS approach was effective in preparing OM formulations with enhanced dissolution and improved oral bioavailability.     

Improving the Dissolution and Bioavailability of Nifedipine Using Solid Dispersions and Solubilizers

ABSTRACT

Nifedipine (NF) is a poorly water-soluble drug, of low and irregular bioavailability after oral administration. Although some reports have attempted to improve the dissolution of NF using solid dispersions and solubilizers, little literature information is available on the in vivo performance of such preparations. The aim of the present work was to improve the therapeutic efficacy of NF via incorporation into different types of carriers, and to investigate their in vitro dissolution and bioavailability in rabbits. Nifedipine solid dispersions were prepared by fusion, solvent, and freeze-drying methods with polyethylene glycol (PEG) 6000 and PEG monomethylether 5000 (PEG MME 5000). Complexation of NF with β-cyclodextrin (β-CyD) and solubilization by sodium lauryl sulfate (SLS) have also been studied. The dissolution was determined by the flow-through cell in order to maintain perfect sink conditions. The solid dispersions resulted in a significant increase in the dissolution rate as compared to pure drug. The highest NF dissolution rate was obtained from solid dispersions containing 95% PEG 6000 prepared by the solvent method. While, unexpectedly, the highest absorption in rabbits was obtained from 95% PEG 6000 prepared by the fusion method. Compared to SLS, β-CyD gave higher in vitro and in vivo values. Differential scanning calorimetry (DSC) and powder x-ray diffractometry indicated that NF in solid dispersions is homogeneously distributed, and no drug crystallized out of the system. The DSC thermograms of NF-β-CyD complex and NF/SLS solid mixture showed a decrease in the NF endothermic peak. The x-rays showed different diffraction patterns of pure NF and pure carrier, suggesting the formation of a new solid form.     

Development and physico-mechanical characterization of carrageenan and poloxamer-based lyophilized matrix as a potential buccal drug delivery system

Context and objectives: The buccal mucosa presents a unique surface for non-invasive drug delivery and also avoids first-pass metabolism. The objective of this study was the formulation development of polymeric mucoadhesive lyophilized wafers as a matrix for potential buccal drug delivery.

Materials and methods: Differential scanning calorimetry (DSC) was used to develop an optimum freeze-cycle, incorporating an annealing step. The wafers were prepared by lyophilization of gels containing three polymers, κ-carrageenan (CAR 911), poloxamer (P407) and polyethylene glycol 600 (PEG 600). The formulations were characterized using texture analysis (for mechanical and mucoadhesion properties), hydration studies, thermogravimetric analysis (TGA), DSC, X-ray powder diffraction (XRPD) and scanning electron microscopy (SEM).

Results and discussion: DSC showed the eutectic temperature (12.8?°C) of the system where the liquid solution and pure solids both existed at a fixed pressure which helped determine the freeze-annealing cycle at 55?°C for 7?h. Mechanical resistance to compression, hydration and mucoadhesion studies showed that optimized wafers were obtained from aqueous gels containing 2% w/w CAR 911, 4% w/w P407 and 4.4% w/w PEG 600. TGA showed residual water of approximately 1% and SEM showed a porous polymeric network that made ease of hydration possible.

Conclusions: Lyophilized wafers by freeze-drying gels containing 2% w/w CAR 911, 4% w/w P407 and 4.4% w/w PEG 600 with optimum physico-mechanical properties has been achieved.     

Lyophilization monophase solution technique for preparation of amorphous flutamide dispersions

Flutamide (FLT) is a poorly soluble anticancer drug. Therefore, lyophilized dispersions (LDs) of FLT with polyvinylpyrrolidone (PVP) K30, polyethylene glycol (PEG) 6000, and pluronic F127 were prepared via lyophilization monophase solution technique with the aim of increasing its dissolution rate. FLT showed an A_L-type phase solubility diagrams with PVP and PEG, whereas A_N-type diagram was obtained with pluronic. The amount of residual tertiary butyl alcohol, determined by gas chromatography, was 0.015–0.021% w/w. Differential scanning calorimetry and X-ray diffractometry revealed that FLT–polymer 1:1 LDs were partially amorphous, whereas the 1:3 and 1:5 LDs were completely amorphous. After 6 months storage, polymers under study inhibited FLT recrystallization maintaining its amorphous form. The particle size of FLT–polymer LDs was between 0.81 and 2.13 μm, with a high surface area (268.43–510.82 m²/g) and porosity (354.01–676.23 e^?3 mL/g). Also, the poor flow properties of FLT could be improved but to a limited extent. FLT dissolution was significantly enhanced with the fastest dissolution that was achieved using pluronic. After 30?min, about 66.52%, 78.23%, and 81.64% of FLT was dissolved from 1:5 FLT–PVP, PEG, and pluronic LDs, respectively, compared with only 13.45% of FLT. These data suggest that these polymers might be useful adjuncts in preparation and stabilization of amorphous immediate-release FLT LDs.     

Lyophilized flutamide dispersions with polyols and amino acids: preparation and in vitro evaluation

Context: Flutamide (FLT) has poor aqueous solubility and low oral bioavailability. Objective: Lyophilization monophase solution was used for preparing lyophilized dispersions of FLT with polyols and amino acids to increase its poor dissolution. Methods: Physical properties and dissolution behavior of their physical mixtures and lyophilized dispersions were investigated. Results and discussion: The carriers increased the aqueous solubility of FLT but to a limited extent with arginine and glycine showing a linear A_L-phase solubility diagrams. Gas chromatography indicated that residual tertiary butyl alcohol was in range of 0.007?0.023% (w/w) in the dispersions. In all dispersions, the crystal structure of FLT was confirmed using differential scanning calorimetry, X-ray diffractometry, and scanning electron microscopy. However, the percent drug crystallinity was found to decrease with increasing the carrier content. Infrared spectroscopy revealed no interaction between drug and carriers. The particle size of FLT dispersions ranged between 0.61 and 1.81 μm, with a high surface area (293.93?465.37 m²/g) and porosity (447.69?754.33 e^-3 mL/g). In addition, the poor flow properties of FLT were improved but to a limited extent. FLT dissolution from the dispersions was enhanced with 46.35% and 36.43% of FLT dissolved after 30 minutes from 1:5 FLT–mannitol and FLT–trehalose dispersions, respectively, compared with only 13.45% of pure FLT. On the other hand, after 30 minutes 38.57% and 46.78% of FLT was dissolved from 1:3 FLT–arginine and FLT–glycine dispersions, respectively. Conclusion: These data suggest that polyols and amino acids might be useful adjuncts in preparation of immediate-release formulations of FLT.     

Optimization of the lyophilization process for long-term stability of solid–lipid nanoparticles

Objectives: To optimize a lyophilization protocol for solid–lipid nanoparticles (SLNs) loaded with dexamethasone palmitate (Dex-P) and to compare the long-term stability of lyophilized SLNs and aqueous SLN suspensions at two storage conditions.

Materials and Methods: The effect of various parameters of the lyophilization process on SLN redispersibility was evaluated. A three month stability study was conducted to compare changes in the particle size and drug loading of lyophilized SLNs with SLNs stored as aqueous suspensions at either 4°C or 25°C/60% relative humidity (RH).

Results and Discussion: Of nine possible lyoprotectants tested, sucrose was shown to be the most efficient at achieving SLN redispersibility. Higher freezing temperatures, slower freezing rates, and longer secondary drying times were also shown to be beneficial. Loading of the SLNs with Dex-P led to slightly larger particle size and polydispersity index increases, but both parameters remained within an acceptable range. Drug loading and particle shape were maintained following lyophilization, and no large aggregates were detected. During the stability study, significant growth and drug loss were observed for aqueous SLN suspensions stored at 25°C/60% RH. In comparison, lyophilized SLNs stored at 4°C exhibited a consistent particle size and showed <20% drug loss. Other storage conditions led to intermediate results.

Conclusions: A lyophilization protocol was developed that allowed SLNs to be reconstituted with minimal changes in their physicochemical properties. During a three month period, lyophilized SLNs stored at 4°C exhibited the greatest stability, showing no change in the particle size and a minimal reduction in drug retention.     

Enhancement of oral bioavailability of fenofibrate by solid self-microemulsifying drug delivery systems

A solid form of self-microemulsifying drug delivery system (Solid SMEDDS) was developed by spray-drying with dextran as the inert solid carrier, to improve the oral bioavailability of a poorly water-soluble drug, fenofibrate. The optimized liquid SMEDDS, composed of Labrafil M 1944 CS/Labrasol/Capryol PGMC (15/75/10%v/v) with 10% w/v fenofibrate gave a z-average diameter of around 240?nm. There was no significant difference in the mean droplet size and size distribution of the emulsions obtained from the liquid and solid forms of SMEDDS. Solid state characterizations of solid SMEDDS showed that the crystal state of fenofibrate in solid SMEDDS was converted from crystalline to amorphous form. Solid SMEDDS had significantly higher dissolution rates than the drug powder, due to its fast self-emulsification in the dissolution media. Furthermore, the AUC value of solid SMEDDS was twofold greater than that of the powder, indicating this formulation greatly improved the oral bioavailability of drug in rats. Thus, these results suggest that solid SMEDDS could be used as an effective oral solid dosage form to improve dissolution and oral bioavailability of fenofibrate.     

Application of scCO2 technology for preparing CoQ10 solid dispersion and SFC-MS/MS for analyzing in vivo bioavailability

Objective: In this study, solid dispersion (SD) for oral delivery of a poorly water-soluble drug, coenzyme Q10 was developed by supercritical fluid technology and characterized in vitro and in vivo.

Methods: Dissolution was used to optimize the formulations of CoQ10-SD. The physicochemical properties of SD were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The supercritical fluid chromatography–electrospray ionization tandem mass spectrometry (SFC–ESI-MS/MS) was used for the in vivo study.

Results: The results of DSC and PXRD indicated that the drug in SD was in amorphous state. In vitro drug release, the dissolution of coenzyme Q10 in solid dispersion improved to 78.8% compared with commercial tablets of 0.16%. The area under c–t curve (AUC_0–72h) and mean maximum concentrations (C_max) of CoQ10-SD were 2.43-fold and 3.0-fold, respectively higher than that of commercial tablets in rats, confirming improved bioavailability.

Conclusion: Supercritical fluid technology was successfully used for the preparation and analysis of CoQ10-SD for the first time and significantly improved the dissolution and bioavailability of coenzyme Q10.     

A new self-microemulsifying mouth dissolving film to improve the oral bioavailability of poorly water soluble drugs

A new self-microemulsifying mouth dissolving film (SMMDF) for poorly water-soluble drugs such as indomethacin was developed by incorporating self-microemulsifying components with solid carriers mainly containing microcrystalline cellulose, low-substituted hydroxypropyl cellulose and hypromellose. The uniformity of dosage units of the preparation was acceptable according to the criteria of Chinese Pharmacopoeia 2010. The SMMDF was disintegrated within 20 s after immersion into water, released completely at 5?min in the dissolution medium and achieved microemulsion particle size of 28.81?±?3.26?nm, which was similar to that of liquid self- microemulsifying drug delivery system (SMEDDS). Solid state characterization of the SMMDF was performed by SEM, DSC and X-ray powder diffraction. Results demonstrated that indomethacin in the SMMDF was in the amorphous state, which might be due to self-microemulsifying ingredients. Pharmacokinetic parameters in rats including T_max, C_max, AUC were similar between the SMMDF and liquid SMEDDS. AUC and C_max from the SMMDF were significantly higher than those from the common mouth dissolving film or the conventional tablet, and T_max from SMMDF group was also significantly decreased. These findings suggest that the SMMDF is a new promising dosage form, showing notable characteristics of convenience, quick onset of action and enhanced oral bioavailability of poorly water-soluble drugs.     

Dissolution rate enhancement of the poorly water-soluble drug Tibolone using PVP,SiO2, and their nanocomposites as appropriate drug carriers

Background: Creation of immediate release formulations for the poorly water-soluble drug Tibolone through the use of solid dispersions (SDs). Aim: SD systems of Tibolone (Tibo) with poly(vinylpyrrolidone) (PVP), fumed SiO₂ nanoparticles, and their corresponding ternary systems (PVP/SiO₂/Tibo) were prepared and studied in order to produce formulations with enhanced drug dissolution rates. Method: The prepared SDs were characterized by the use of differential scanning calorimetry and wide-angle X-ray diffractometry techniques. Also dissolution experiments were performed. Results: From the results it was concluded that PVP as well as SiO₂ can be used as appropriate carriers for the amorphization of Tibo, even when the drug is used at high concentrations (20–30%, w/w). This is due to the evolved interactions taking place between the drug and the used carriers, as was verified by Fourier transform infrared spectroscopy. At higher concentrations the drug was recrystallized. Similar are the observations on the ternary PVP/SiO₂/Tibo SDs. The dissolution profiles of the drug in PVP/Tibo and SiO₂/Tibo SDs are directly dependent on the physical state of the drug. Immediately release rates are observed in SD with low drug concentrations, in which Tibo was in amorphous state. However, these release profiles are drastically changed in the ternary PVP/SiO₂/Tibo SDs. An immediate release profile is observed for low drug concentrations and an almost sustained release as the concentration of Tibo increases. This is due to the weak interactions that take place between PVP and SiO₂, which result in alterations of the characteristics of the carrier (PVP/SiO₂ nanocomposites). Conclusions: Immediate release formulation was created for Tibolone as well as new nanocomposite matrices of PVP/SiO₂, which drastically change the release profile of the drug to a sustained delivery.     

Application and functional characterization of POVACOAT,a hydrophilic co-polymer poly(vinyl alcohol/acrylic acid/methyl methacrylate) as a hot-melt extrusion carrier

Objective: The aim of this study was to evaluate the applicability of POVACOAT^TM, a hydrophilic PVA copolymer, as a solid dispersion (SD) carrier for hot-melt extrusion (HME).

Methods: Bifendate (DDB), a water-insoluble drug, was chosen as the model drug. DDB was hot-melt extruded by a co-rotating twin screw extruder with POVACOAT^TM. The SD formability of POVACOAT^TM was investigated by varying the composition ratios. Solid state characterization was evaluated by differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy and Fourier transformation infrared spectroscopy. In order to have a better knowledge of the mechanism of dissolution enhancement, dissolution study, phase solubility study and crystallization study of DDB from supersaturated solutions were performed. In addition, the storage stability of the extrudate containing 10% DDB was investigated.

Results: Physical characterizations showed that DDB was amorphous up to 15% drug loading. The phase solubility study revealed an A_L-type curve. Moreover, POVACOAT^TM was found to have an inhibitory effect on crystallization from supersaturated solutions. Compared with the pure DDB and physical mixture, the dissolution rate and solubility of extrudates were significantly enhanced and the drug loading markedly affected the dissolution of SDs. Furthermore, the stability test indicated that 10% DDB-SD was stable during storage (40?°C/75% RH).

Conclusion: The results of this study demonstrate that POVACOAT^TM is a valuable excipient for the formulation of solid dispersions prepared by HME to improve dissolution of poorly water-soluble drugs.     

Evaluation of the impact of sodium lauryl sulfate source variability on solid oral dosage form development

Objective: The objective of this study was to investigate the effects of sodium lauryl sulfate (SLS) from different sources on solubilization/wetting, granulation process, and tablet dissolution of BILR 355 and the potential causes. Methods: The particle size distribution, morphology, and thermal behaviors of two pharmaceutical grades of SLS from Spectrum and Cognis were characterized. The surface tension and drug solubility in SLS solutions were measured. The BILR 355 tablets were prepared by a wet granulation process and the dissolution was evaluated. Results: The critical micelle concentration was lower for Spectrum SLS, which resulted in a higher BILR 355 solubility. During wet granulation, less water was required to reach the same end point using Spectrum than Cognis SLS. In general, BILR 355 tablets prepared with Spectrum SLS showed a higher dissolution than the tablets containing Cognis SLS. Micronization of SLS achieved the same improved tablet dissolution as micronized active pharmaceutical ingredient. Conclusions: The observed differences in wetting and solubilization were likely due to the different impurity levels in SLS from two sources. This study demonstrated that SLS from different sources could have significant impact on wet granulation process and dissolution. Therefore, it is critical to evaluate SLS properties from different suppliers, and then identify optimal formulation and process parameters to ensure robustness of drug product manufacture process and performance.     

Effect of PVP K30 and/or l-Arginine on Stability Constant of Etoricoxib–HPβCD Inclusion Complex: Preparation and Characterization of Etoricoxib–HPβCD Binary System

The effect of polyvinyl pyrrolidone (PVP) K30 and/or l-arginine on etoricoxib–HPβCD complex was investigated. The phase solubility profiles were classified as A_L-type, both in absence or presence of auxiliary substances used. The apparent stability constant (K_c) of binary complex obtained at room temperature, 371.80 ± 2.61 M^?1, was decreased with the addition of PVP and arginine indicating no benefit of addition of auxiliary substances to promote higher complexation efficiency. Therefore, solid etoricoxib–HPβCD binary systems were prepared and characterized by proton nuclear magnetic resonance spectroscopy (¹HNMR), X-ray powder diffractometry, Fourier transformation-infrared spectroscopy, and dissolution studies. Among all binary systems, a lyophilized product showed superior performance in enhancing dissolution of etoricoxib.     

Improving the dissolution and bioavailability of nifedipine using solid dispersions and solubilizers

Nifedipine (NF) is a poorly water-soluble drug, of low and irregular bioavailability after oral administration. Although some reports have attempted to improve the dissolution of NF using solid dispersions and solubilizers, little literature information is available on the in vivo performance of such preparations. The aim of the present work was to improve the therapeutic efficacy of NF via incorporation into different types of carriers, and to investigate their in vitro dissolution and bioavailability in rabbits. Nifedipine solid dispersions were prepared by fusion, solvent, and freeze-drying methods with polyethylene glycol (PEG) 6000 and PEG monomethylether 5000 (PEG MME 5000). Complexation of NF with β-cyclodextrin (β-CyD) and solubilization by sodium lauryl sulfate (SLS) have also been studied. The dissolution was determined by the flow-through cell in order to maintain perfect sink conditions. The solid dispersions resulted in a significant increase in the dissolution rate as compared to pure drug. The highest NF dissolution rate was obtained from solid dispersions containing 95% PEG 6000 prepared by the solvent method. While, unexpectedly, the highest absorption in rabbits was obtained from 95% PEG 6000 prepared by the fusion method. Compared to SLS, β-CyD gave higher in vitro and in vivo values. Differential scanning calorimetry (DSC) and powder x-ray diffractometry indicated that NF in solid dispersions is homogeneously distributed, and no drug crystallized out of the system. The DSC thermograms of NF-β-CyD complex and NF/SLS solid mixture showed a decrease in the NF endothermic peak. The x-rays showed different diffraction patterns of pure NF and pure carrier, suggesting the formation of a new solid form.     

A potent preparation method combining neutralization with microfluidization for rebamipide nanosuspensions and its in vivo evaluation

Backgrounds: Rebamipide (REB) is classified as a Biopharmaceutics Classification System (BCS) Class-IV compound with poor aqueous solubility and poor permeability. The local concentration in the mucosa makes REB exhibiting the therapeutic activities, and the strategy of increasing the dissolution rate has the possibility to improve the oral gastrointestinal (GI) distribution when using REB nanosuspensions.

Objective: The purpose of this work was to prepare REB nanosuspensions (REB-NSs) by combining neutralization with microfluidization to improve its dissolution rate and orally pharmacokinetic properties.

Methods: The feasibility of using acid-base neutralization and microfluidization to prepare REB-NSs was studied, and the preparation was optimized by central composite design (CCD). Physical states were characterized by using some technical methods, while the plasma drug concentration and GI distribution in rodents were determined.

Results: The experimental results identified a formulation with 10 mg/mL REB, 0.9% (w/v) Lutrol F127, and 0.6% (w/v) Kollidon 90F. The dissolution rate of the dried REB-NSs was faster than that of Mucosta^® tablets in different media, and the pharmacokinetic study showed a slight increase (1.3-fold and 1.1-fold) in the AUC_{0–12 h} compared with unprocessed conventional suspensions (CSs) and solutions. Also, the GI distribution of REB-NSs improved compared with REB-CSs, and this would be preferable to assist in protecting GI mucosa.

Conclusion: The REB-NSs prepared by the combining method exhibited a higher plasma drug concentration and superior GI distribution, thereby demonstrating positive results for preparing nanosuspensions of local effective BCS IV drugs with pH dependence such as REB by this method.