Vivek S. Dave

Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches

Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn’s disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.

Assessment of the critical factors affecting the porosity of roller compacted ribbons and the feasibility of using NIR chemical imaging to evaluate the porosity distribution

The purpose of this study was to assess the porosity variation of roller compacted ribbons made using different process parameters; in addition, the feasibility of using near-infrared chemical imaging (NIR-CI) to evaluate porosity variations was examined. Ribbons of neat microcrystalline cellulose were compacted using a range of roll pressures (RP), roll speeds (RS) and feed screw speeds (FSS). The ribbon porosity decreased as RP increased with the exception of ribbons produced by the combination of high RS and low FSS where increasing RP increases the porosity of the ribbons. Lower RS was found to produce ribbons with lower porosity and the porosity increases as the RS increased. Increased FSS will decrease ribbon porosity at higher RS while it slightly increase the ribbon porosity at lower RS. A simple linear regression model showed NIR-CI was able to predict the ribbon porosity with a correlation of 0.9258. NIR-CI is able to characterize differences in porosity as a function of position on the ribbon where regions with lower porosity show higher absorbance. Nevertheless, NIR-CI is able to show sinusoidal variation in intensities along the roller compacted ribbon among all settings studied.

Qualitative and quantitative methods to determine miscibility in amorphous drug–polymer systems

Amorphous drug-polymer systems or amorphous solid dispersions are commonly used in pharmaceutical industry to enhance the solubility of compounds with poor aqueous solubility. The degree of miscibility between drug and polymer is important both for solubility enhancement as well as for the formation of a physically stable amorphous system. Calculation of solubility parameters, Computational data mining, Tg measurements by DSC and Raman mapping are established traditional methods used to qualitatively detect the drug-polymer miscibility. Calculation of Flory-Huggins interaction parameter, computational analysis of X-Ray Diffraction (XRD) data, solid state Nuclear Magnetic Resonance (NMR) spectroscopy and Atomic Forced Microscopy (AFM) have been recently developed to quantitatively determine the miscibility in amorphous drug-polymer systems. This brief review introduces and compiles these qualitative and quantitative methods employed in the evaluation of drug-polymer miscibility. Combination of these techniques can provide deeper insights into the true miscibility of the drug-polymer systems.

Excipient Variability and Its Impact on Dosage Form Functionality

Pharmaceutical excipients are essential components of most modern dosage forms. Although defined as pharmacologically inert, excipients can be thought of as the true enablers of drug product performance. Unintentional variability in the properties of the excipients may be unavoidable, albeit minimizable. The variability may originate from the source, the excipient-manufacturing process, or during the manufacturing of dosage forms. Excipient variability may have a range of influences on their functionality and performance in the dosage form. A better understanding of these influences on the critical quality attributes of the final product is of prime importance. Modern analytical tools provide a significant assistance in characterizing excipient variability to achieve this understanding. The principles and concepts of Quality-by-Design, process analytical technology, and design space, provide a holistic risk-based approach toward manufacture and application of excipients in pharmaceutical formulations. The International Pharmaceutical Excipients Council (IPEC) has developed guidelines for proper selection, use, and evaluation of excipients in pharmaceutical products.

Formulation and characterization of an apigenin-phospholipid phytosome (APLC) for improved solubility, in vivo bioavailability, and antioxidant potential

&NA; The apigenin‐phospholipid phytosome (APLC) was developed to improve the aqueous solubility, dissolution, in vivo bioavailability, and antioxidant activity of apigenin. The APLC synthesis was guided by a full factorial design strategy, incorporating specific formulation and process variables to deliver an optimized product. The design‐optimized formulation was assayed for aqueous solubility, in vitro dissolution, pharmacokinetics, and antioxidant activity. The pharmacological evaluation was carried out by assessing its effects on carbon tetrachloride‐induced elevation of liver function marker enzymes in a rat model. The antioxidant activity was assessed by studying its effects on the liver antioxidant marker enzymes. The developed model was validated using the design‐optimized levels of formulation and process variables. The physical‐chemical characterization confirmed the formation of phytosomes. The optimized formulation demonstrated over 36‐fold higher aqueous solubility of apigenin, compared to that of pure apigenin. The formulation also exhibited a significantly higher rate and extent of apigenin release in dissolution studies. The pharmacokinetic analysis revealed a significant enhancement in the oral bioavailability of apigenin from the prepared formulation, compared to pure apigenin. The liver function tests indicated that the prepared phytosome showed a significantly improved restoration of all carbon tetrachloride‐elevated rat liver function marker enzymes. The prepared formulation also exhibited antioxidant potential by significantly increasing the levels of glutathione, superoxide dismutase, catalase, and decreasing the levels of lipid peroxidase. The study shows that phospholipid‐based phytosome is a promising and viable strategy for improving the delivery of apigenin and similar phytoconstituents with low aqueous solubility. Graphical abstract Figure. No caption available.

Eudragit® RS PO/RL PO as rate-controlling matrix-formers via roller compaction: Influence of formulation and process variables on functional attributes of granules and tablets

The influence of plasticizer level, roll pressure and sintering temperature was investigated on the granule properties, tablet breaking force and theophylline release from tablets. Nine formulations using theophylline as a model drug, Eudragit® RL PO, Eudragit® RS PO, or both as a matrix former and triethyl citrate (TEC) as a plasticizer were prepared. The formulations were roller compacted and the granules obtained were evaluated for particle size distribution and flowability. These granules were compacted into tablets at a compression force of 7 kN. The tablets were thermally treated at different temperatures (50 and 75°C) for 5 h and were evaluated for breaking force and dissolution. Increase in roll pressure and TEC levels resulted in a progressive increase in the mean particle size of the granules. The flowability of the granules also improved with increasing roll pressures and TEC levels. Tablet breaking force increased with an increase in TEC levels and sintering temperatures. But these effects were significant only at the highest level of plasticizer and sintering temperature respectively. For the tablets containing Eudragit® RS PO, theophylline release decreased proportionately with increase in TEC levels and sintering temperatures. Tablets containing either Eudragit® RL PO or a mixture of RS PO and RL PO failed to impart an extended-release property to the tablets at the studied variables i.e. roll pressure, TEC levels and sintering temperature. It was clearly demonstrated that with suitable optimization of these parameters, the release-rate of a water soluble drug from the matrix tablets prepared via roller compaction can be finely controlled.

Vegetable-derived magnesium stearate functionality evaluation by DM3 approach

This study quantifies the lubricating efficiency of two grades of crystalline vegetable-derived magnesium stearate (MgSt-V) using the DM(3) approach, which utilizes design of experiments (D) and multivariate analysis techniques (M3) to evaluate the effect of a materials (M1) molecular and macroscopic properties and manufacturing factors (M2) on critical product attributes. A 2(3) factorial design (2 continuous variables plus 1 categorical factor) with three center points for each categorical factor was used to evaluate the effect of MgSt-V fraction and blend time on running powder basic flow energy (BFE), tablet mechanical strength (TMS), disintegration time (DT), and running powder lubricant sensitivity ratio (LSR). Molecular characterization of MgSt-V employed moisture sorption-desorption analysis, (13)C nuclear magnetic resonance spectroscopy, thermal analysis, and powder X-ray diffraction. MgSt-V macroscopic analysis included mean particle size, specific surface area, particle morphology, and BFE. Principal component analysis and partial least squares multivariate analysis techniques were used to develop predictive qualitative and quantitative relationships between the molecular and macroscopic properties of MgSt-V grades, design variables, and resulting tablet formulation properties. MgSt-V fraction and blending time and their square effects showed statistical significant effects. Significant variation in the molecular and macroscopic properties of MgSt-V did not have a statistically significant impact on the studied product quality attributes (BFE, TMS, DT, and LSR). In setting excipient release specifications, functional testing may be appropriate in certain cases to assess the effect of statistically significant different molecular and macroscopic properties on product quality attributes.

Near-infrared spectroscopic analysis of the breaking force of extended-release matrix tablets prepared by roller-compaction: influence of plasticizer levels and sintering temperature

Abstract The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for the determination of the influence of sintering temperature and plasticizer levels on the breaking force of extended-release matrix tablets prepared via roller-compaction. Six formulations using theophylline as a model drug, Eudragit® RL PO or Eudragit® RS PO as a matrix former and three levels of TEC (triethyl citrate) as a plasticizer were prepared. The powder blend was roller compacted using a fixed roll-gap of 1.5 mm, feed screw speed to roller speed ratio of 5:1 and roll pressure of 4 MPa. The granules, after removing fines, were compacted into tablets on a Stokes B2 rotary tablet press at a compression force of 7 kN. The tablets were thermally treated at different temperatures (Room Temperature, 50, 75 and 100 °C) for 5 h. These tablets were scanned in reflectance mode in the wavelength range of 400–2500 nm and were evaluated for breaking force. Tablet breaking force significantly increased with increasing plasticizer levels and with increases in the sintering temperature. An increase in tablet hardness produced an upward shift (increase in absorbance) in the NIR spectra. The principle component analysis (PCA) of the spectra was able to distinguish samples with different plasticizer levels and sintering temperatures. In addition, a 9-factor partial least squares (PLS) regression model for tablets containing Eudragit® RL PO had an r2 of 0.9797, a standard error of calibration of 0.6255 and a standard error of cross validation (SECV) of 0.7594. Similar analysis of tablets containing Eudragit® RS PO showed an r2 of 0.9831, a standard error of calibration of 0.9711 and an SECV of 1.192.

Emerging technologies for the non-invasive characterization of physical-mechanical properties of tablets

The density, porosity, breaking force, viscoelastic properties, and the presence or absence of any structural defects or irregularities are important physical-mechanical quality attributes of popular solid dosage forms like tablets. The irregularities associated with these attributes may influence the drug product functionality. Thus, an accurate and efficient characterization of these properties is critical for successful development and manufacturing of a robust tablets. These properties are mainly analyzed and monitored with traditional pharmacopeial and non-pharmacopeial methods. Such methods are associated with several challenges such as lack of spatial resolution, efficiency, or sample-sparing attributes. Recent advances in technology, design, instrumentation, and software have led to the emergence of newer techniques for non-invasive characterization of physical-mechanical properties of tablets. These techniques include near infrared spectroscopy, Raman spectroscopy, X-ray microtomography, nuclear magnetic resonance (NMR) imaging, terahertz pulsed imaging, laser-induced breakdown spectroscopy, and various acoustic- and thermal-based techniques. Such state-of-the-art techniques are currently applied at various stages of development and manufacturing of tablets at industrial scale. Each technique has specific advantages or challenges with respect to operational efficiency and cost, compared to traditional analytical methods. Currently, most of these techniques are used as secondary analytical tools to support the traditional methods in characterizing or monitoring tablet quality attributes. Therefore, further development in the instrumentation and software, and studies on the applications are necessary for their adoption in routine analysis and monitoring of tablet physical-mechanical properties.

Influence of the Component Excipients on the Quality and Functionality of a Transdermal Film Formulation

The influence of formulation variables, i.e., a hydrophilic polymer (Methocel® E15) and a film-forming polymer (Eudragit® RL 100 and Eudragit® RS 100), on the physicochemical and functional properties of a transdermal film formulation was assessed. Several terpenes were initially evaluated for their drug permeation enhancement effects on the transdermal film formulations. d-Limonene was found to be the most efficient permeation enhancer among the tested terpenes. Transdermal film formulations containing granisetron (GRN) as a model drug, d-limonene as a permeation enhancer, and different ratios of a hydrophilic polymer (Methocel® E15) and a film-forming polymer (Eudragit® RL 100 or Eudragit® RS 100) were prepared. The prepared films were evaluated for their physicochemical properties such as weight variation, thickness, tensile strength, folding endurance, elongation (%), flatness, moisture content, moisture uptake, and the drug content uniformity. The films were also evaluated for the in vitro drug release and ex vivo drug permeation. The increasing ratios of Methocel®:Eudragit® polymers in the formulation linearly and significantly increased the moisture content, moisture uptake, water vapor transmission rate (WVTR), and the transdermal flux of GRN from the film formulations. Increasing levels of Methocel® in the formulations also increased the rate and extent of the GRN release and the GRN permeation from the prepared films.