Parijat Kanaujia

Formulation design, preparation and physicochemical characterizations of solid lipid nanoparticles containing a hydrophobic drug: Effects of process variables

This study aimed to prepare solid lipid nanoparticles (SLNs) of a hydrophobic drug, tretinoin, by emulsification-ultrasonication method. Solubility of tretinoin in the solid lipids was examined. Effects of process variables were investigated on particle size, polydispersity index (PI), zeta potential (ZP), drug encapsulation efficiency (EE), and drug loading (L) of the SLNs. Shape and surface morphology of the SLNs were investigated by cryogenic field emission scanning electron microscopy (cryo-FESEM). Complete encapsulation of drug in the nanoparticles was checked by cross-polarized light microscopy and differential scanning calorimetry (DSC). Crystallinity of the formulation was analyzed by DSC and powder X-ray diffraction (PXRD). In addition, drug release and stability studies were also performed. The results indicated that 10mg tretinoin was soluble in 0.45±0.07 g Precirol® ATO5 and 0.36±0.06 g Compritol® 888ATO, respectively. Process variables exhibited significant influence in producing SLNs. SLNs with <120 nm size, <0.2 PI, >I30I mV ZP, >75% EE, and ∼0.8% L can be produced following the appropriate formulation conditions. Cryo-FESEM study showed spherical particles with smooth surface. Cross-polarized light microscopy study revealed that drug crystals in the external aqueous phase were absent when the SLNs were prepared at ≤0.05% drug concentration. DSC and PXRD studies indicated complete drug encapsulation within the nanoparticle matrix as amorphous form. The drug release study demonstrated sustained/prolonged drug release from the SLNs. Furthermore, tretinoin-loaded SLNs were stable for 3 months at 4°C. Hence, the developed SLNs can be used as drug carrier for sustained/prolonged drug release and/or to improve oral absorption/bioavailability.

Detection of trace crystallinity in an amorphous system using Raman microscopy and chemometric analysis

A novel analytical method to detect and characterize active pharmaceutical ingredient (API) trace crystallinity in an amorphous system using Raman microscopy and chemometric methods, namely band-target entropy minimization (BTEM) and target transformation factor analysis (TTFA) is developed. The method starts with Raman mapping measurements performed on some random areas of the amorphous system. This is followed by chemometric data analysis. In the case of a system without any a priori information, the BTEM algorithm is used to recover a set of pure component Raman spectral estimates followed by component and/or crystal structure identification. In the case of a system with some a priori information, TTFA is used to predict the presence or existence of a suspected component and/or crystal structure in the observed system. Four different amorphous systems were used as models. It is demonstrated that combined Raman microscopy and chemometric methods (BTEM or TTFA) outperformed powder X-ray diffraction (PXRD) in detecting trace crystallinity in amorphous systems. The spatial distributions of drug and polymer can also be directly obtained in order to study the homogeneity of the APIs in the solid dispersions. The present methodology appears very general and applicable to many other types of systems.

Nanoparticle Formation and Growth During In Vitro Dissolution of Ketoconazole Solid Dispersion

The aim of this study is to examine the physical mechanisms during the dissolution of a solid dispersion, so as to provide further understanding behind the enhanced dissolution properties. X-ray amorphous solid dispersions of ketoconazole (KC), a poorly aqueous soluble drug, were prepared by melt extrusion with polyvinlypyrrolidone 17 (PVP 17) and PVP-vinyl acetate (PVP-VA64) copolymer. Prior to dissolution, Raman mapping showed a fully homogeneous spatial distribution of KC in polymer and possible drug dispersion at molecular level, whereas Fourier transform infrared spectroscopy revealed no drug-polymer chemical interaction. During in vitro dissolution test, a burst release followed by a gradual decline in dissolution could be explained by the release of KC in molecular form followed by formation of drug nanoparticles and their subsequent growth to micron size range as shown by dynamic light scattering analysis. Observations using transmission electron microscopy and cryogenic scanning electron microscopy provided support to the suggested mechanisms. The results suggested that the release of KC from the solid dispersions was carrier controlled initially, and PVP 17 PF is more efficient in inhibiting particle growth as compared with PVP-VA64. The particle growth inhibition during dissolution may be an important consideration to achieve the full benefits of dissolution enhancement of solid dispersions.

Investigating the effect of moisture protection on solid-state stability and dissolution of fenofibrate and ketoconazole solid dispersions using PXRD, HSDSC and Raman microscopy

Enhanced dissolution of poorly soluble active pharmaceutical ingredients (APIs) in amorphous solid dispersions often diminishes during storage due to moisture-induced re-crystallization. This study aims to investigate the influence of moisture protection on solid-state stability and dissolution profiles of melt-extruded fenofibrate (FF) and ketoconazole (KC) solid dispersions. Samples were kept in open, closed and Activ-vials® to control the moisture uptake under accelerated conditions. During 13-week storage, changes in API crystallinity were quantified using powder X-ray diffraction (PXRD) (Rietveld analysis) and high sensitivity differential scanning calorimetry (HSDSC) and compared with any change in dissolution profiles. Trace crystallinity was observed by Raman microscopy, which otherwise was undetected by PXRD and HSDSC. Results showed that while moisture protection was ineffective in preventing the re-crystallization of amorphous FF, KC remained X-ray amorphous despite 5% moisture uptake. Regardless of the degree of crystallinity increase in FF, the enhanced dissolution properties were similarly diminished. Moisture uptake above 10% in KC samples also led to re-crystallization and significant decrease in dissolution rates. In conclusion, eliminating moisture sorption may not be sufficient in ensuring the stability of solid dispersions. Analytical quantification of API crystallinity is crucial in detecting subtle increase in crystallinity that can diminish the enhanced dissolution properties of solid dispersions.

Solid self-emulsifying drug delivery system (S-SEDDS) for improved dissolution rate of fenofibrate.

Abstract Purpose: The aim of this work was to develop and characterise S-SEDDS containing fenofibrate (FF) for dissolution enhancement. Methods: The self-emulsifying pre-concentrate was prepared by using different proportion of Labrafac WL1349 as oily phase, Cremophor EL as surfactants and Gelucire 44/14 as co-surfactant. The prepared pre-concentrate was solidified with PEG 6000. For comparison, formulations containing TPGS as surfactant and solidifier were prepared and studied. Results: The cremophor/PEG and TPGS based S-SEDDS formulations containing 10 and 15% w/w FF when dispersed in water, formed nanoemulsion with a size range of 150–200 nm. FF was present in the crystalline state in the formulations. The formulations containing 10% w/w FF showed 90–100% dissolution in 60 min whereas the untreated FF showed only 2–4% dissolution. Conclusion: A novel S-SEDDS was developed for FF using cremophor/PEG and TPGS. The dissolution of FF was enhanced by approximately 20-fold in SGF pH 1.2.

Hot-melt extrusion microencapsulation of quercetin for taste-masking

Abstract Besides its poor dissolution rate, the bitterness of quercetin also poses a challenge for further development. Using carnauba wax, shellac or zein as the shell-forming excipient, this work aimed to microencapsulate quercetin by hot-melt extrusion for taste-masking. In comparison with non-encapsulated quercetin, the microencapsulated powders exhibited significantly reduced dissolution in the simulated salivary pH 6.8 medium indicative of their potentially good taste-masking efficiency in the order of zein > carnauba wax > shellac. In vitro bitterness analysis by electronic tongue confirmed the good taste-masking efficiency of the microencapsulated powders. In vitro digestion results showed that carnauba wax and shellac-microencapsulated powders presented comparable dissolution rate with the pure quercetin in pH 1.0 (gastric) and 6.8 (intestine) medium; while zein-microencapsulated powders exhibited a remarkably slower dissolution rate. Crystallinity of quercetin was slightly reduced after microencapsulation while its chemical structure remained unchanged. Hot-melt extrusion microencapsulation could thus be an attractive technique to produce taste-masked bioactive powders.

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.

Evaluating Suspension Formulations of Theophylline Cocrystals With Artificial Sweeteners

Pharmaceutical cocrystals have garnered significant interest as potential solids to address issues associated with formulation development of drug substances. However, studies concerning the understanding of formulation behavior of cocrystals are still at the nascent stage. We present results of our attempts to evaluate suspension formulations of cocrystals of an antiasthmatic drug, theophylline, with 2 artificial sweeteners. Stability, solubility, drug release, and taste of the suspension formulations were evaluated. Suspension that contained cocrystal with acesulfame showed higher drug release rate, while a cocrystal with saccharin showed a significant reduction in drug release rate. The cocrystal with saccharin was found stable in suspension for over 9 weeks at accelerated test condition; in contrast, the cocrystal with acesulfame was found unstable. Taste analysis using an electronic taste-sensing system revealed improved sweetness of the suspension formulations with cocrystals. Theophylline has a narrow therapeutic index with a short half-life which necessitates frequent dosing. This adversely impacts patient compliance and enhances risk of gastrointestinal and cardiovascular adverse effects. The greater thermodynamic stability, sweetness, and sustained drug release of the suspension formulation of theophylline-saccharin could offer an alternative solution to the short half-life of theophylline and make it a promising formulation for treating asthmatic pediatric and geriatric patients.

Synergistic enhancement of tabletability and physicochemical properties through co-crystallization

Pharmaceutical cocrystals are defined as molecular complexes comprising an API and one or more pharmaceutically acceptable coformers (FDA-approved GRAS compounds), which are solids at room temperature [1]. Over the past two decades, interest in pharmaceutical cocrystals has increased tremendously in both industry and academia. This is primarily because physicochemical properties such as solubility, dissolution rate, tabletability, stability, etc. could be fine-tuned by choosing an appropriate coformer. However, barring a few bioavailability studies, the majority of the cocrystal research has been mainly focused on crystal engineering based design, preparation, characterization, and scale-up of cocrystals, but studies concerning formulation issues of cocrystals are seldom reported [2].